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Original Article
The Relation of Platelet–Lymphocyte Ratio
and Coronary Collateral Circulation in
Patients With Stable Angina Pectoris
and Chronic Total Occlusion
Göksel Açar, MD1, Mehmet Emin Kalkan, MD1, Anıl Avci, MD1,
Elnur Alizade, MD1, Mehmet Mustafa Tabakci, MD1,
Cüneyt Toprak, MD1, Birol Özkan, MD1, Gökhan Alici, MD1,
and Ali Metin Esen, MD1
Abstract
Objectives: We aimed to investigate the relationship between the platelet-lymphocyte ratio (PLR) and coronary collateral
circulation (CCC) in patients with stable angina pectoris (SAP) and chronic total occlusion (CTO). Methods: A total of 294
patients with both SAP and CTO were classified according to their Rentrop collateral grades as either poor (Rentrop grades/0-1)
or good (Rentrop grades/2-3). Results: The PLR values were significantly higher in patients with poor CCC than in those with
good CCC (156.8 + 30.7 vs 132.1 + 24.4, P < 0.001). In regression analysis, PLR (unit ¼ 10) [odds ratio 1.48, 95% confidence
interval (CI) 1.33 -1.65; P < 0.001] and high-sensitivity C-reactive protein were found to be the independent predictors of poor
CCC. In receiver operator characteristic curve analysis, optimal cut-off value of PLR to predict poor CCC was found as 138.1,
with 76% sensitivity and 65% specificity. Conclusion: PLR may be an important, simple, and cost effective tool predicting the
degree of collateralization in patients with SAP and CTO.
Keywords
cardiology, atherosclerosis, vascular disease
Introduction
The coronary collateral circulation (CCC) has been shown to deter-
mine the survival of the myocardium upon total occlusion of the
coronary arteries.1-3 Recently, a meta-analysis by Meier et al4
demonstrated that patients with high degree of collateralization
have a 36% lower risk of mortality than those with low degree of
collateralization. However, the heterogeneity in the degree of col-
lateralization among patients with coronary artery disease is poorly
understood.5 Inflammation which is a central factor for the initia-
tion and progression of atherosclerosis may be implicated in the
variability of the collateralization, because a complex interaction
exists between inflammation and new blood vessel formation.6 Pre-
vious studies have proven the association between elevated blood
platelet count and major adverse cardiovascular outcomes.7-9 In
contrast, a low blood lymphocyte count was associated with major
adverse cardiovascular outcomes.10-12 Interestingly, the platelet–
lymphocyte ratio (PLR) was found to be a significant inflammatory
marker to predict mortality in cancer population.13-15 Moreover,
higher PLR value emerged as a significant independent predictor
of long-term survival in patients who presented with non-ST-
segment elevation myocardial infarction (NSTEMI).16 Therefore
in this study, we aimed to investigate the effect of this recently
defined cardiovascular risk marker, PLR, on the collateral develop-
ment in patients with stable angina pectoris (SAP) and chronic total
occlusion (CTO) of a major coronary artery.
Methods
Study Population
The study population consisted of 385 consecutive patients
with CTO who underwent coronary angiography at our
1 Department of Cardiology, Kartal Kosuyolu High Specialty Education and
Research Hospital, Istanbul, Turkey
Corresponding Author:
Göksel Açar, Department of Cardiology, Kartal Kosuyolu High Specialty
Education and Research Hospital, Denizer Street, Cevizli Kavsagi, No: 2, Postal
code: 34846, Kartal/Istanbul/Turkey.
Email: gokselacar81@hotmail.com
Clinical and Applied
Thrombosis/Hemostasis
2015, Vol. 21(5) 462-468
ª The Author(s) 2013
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DOI: 10.1177/1076029613508599
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hospital. All patients had stable anginal symptoms and/or pos-
itive stress test results indicating ischemia. Clinical information
including age, sex, body mass index (BMI), history of hyper-
tension and diabetes mellitus, smoking, current medications,
complete blood count, serum cholesterol, fasting glucose
levels, and left ventricular ejection fraction (LVEF) values
(that was calculated using a modified Simpson method) was
obtained from a review of the patients’ chart. The patients
were defined as hypertensive if their blood pressure was
�140/90 mm Hg or if the individual was taking any antihy-
pertensive medications. Diabetes mellitus was defined as the
presence of a history of antidiabetic medication usage or
fasting glucose level above 126 mg/dL. Patients with total
cholesterol �200 mg/dL or triglyceride �150 mg/dL were
considered to have hyperlipidemia. Current smokers were
defined as those who had smoked for some period during the
past year. Patients were excluded from the study if they had
recent (within 3 months) history of acute coronary syndrome
(n ¼ 14), decompensated heart failure (n ¼ 9), a recent his-
tory of blood transfusion (n ¼ 4), active and ongoing infec-
tion (n ¼ 8), chronic inflammatory or autoimmune disease
(n ¼ 4), active cancer or hematological proliferative diseases
(n ¼ 2), severe hepatic diseases (n ¼ 2), renal failure (n ¼ 5),
and history of percutaneous coronary intervention (n ¼ 26)
or coronary artery bypass grafting (n ¼ 17). Finally, 294
patients with both SAP and CTO were enrolled into the
study. The study protocol was approved by the local ethics
committee.
Blood Samples and Analyses
Results of the blood samples and analyses were obtained from
the review of the patients’ chart. All blood samples were drawn
at admission before coronary angiography. Hematologic
indices such as hemoglobin, white blood cell, platelet counts,
and mean platelet volume were measured as part of the auto-
mated complete blood count using simultaneous optical and
impedance measurements (Cell Dyn 3700 Abbott Diagnostics,
IL, USA). All routine biochemical tests were carried out on an
automatic biochemical analyzer (Beckman Coulter AU640,
Germany). High-sensitivity C-reactive protein (hs-CRP) was
determined by nephelometry on an IMMAGE 800 analyzer
(Beckman Coulter, CA, USA).
Coronary Angiography and Assessment of CCC
Two specialists, who were blinded to the clinic and laboratory
results of the patients, read the coronary arteriographic data of
each patient to assess the coronary artery lesion and CCC.
Chronic total occlusion was defined as a lesion with a thrombo-
lysis in myocardial infarction grade 0 flow within the occluded
segment and angiographic or clinical evidence or high likeli-
hood of occlusion duration �3 months.17 The CCC was graded
according to the Rentrop classification.18 Grades of collateral
filling from the contralateral vessel were as follows: 0 ¼ none;
1 ¼ filling of side branches of the artery to be dilated through
collateral channels without visualization of the epicardial seg-
ment; 2 ¼ partial filling of the epicardial segment through col-
lateral channels; and 3 ¼ complete filling of the epicardial
segment of the artery being dilated through collateral channels.
In patients with more than one collateral vessel supplying the
distal region of the diseased artery, the highest collateral grade
was recorded. Patients were then classified according to their
collateral grades as either poor (Rentrop grades 0-1) or good
(Rentrop grades 2-3). Definition of the number of coronary
vessels diseased included stenosis of �50% of the major epi-
cardial arteries or their main branches or both. Intra- and inter-
observer agreements of Rentrop collateral grades were
determined from a random sample of 50 coronary angiograms
(k values were 0.925 [intraobserver] and 0.815 [interobserver]
agreement; P < .001 for both].
Statistical Analysis
Statistical analysis was performed using the SPSS for Windows
(version 19.0; SPSS Inc, Chicago, Illinois). Continuous vari-ables are expressed as mean + standard deviation; categorical
variables were defined as percentages. The comparisons
between the 2 CCC groups were performed using the chi-
square test for categorical variables. The differences between
the continuous variables were compared using the Student t test
or Mann-Whitney U test where appropriate. Comparison
between Rentrop grades was made using the analysis of var-
iance. Multiple logistic regression analysis was performed to
identify the independent predictors of poor CCC. Variables
showing marginal associations with poor CCC on univariate
testing were included in the regression analysis (P < .10). A
receiver–operating characteristic (ROC) curve was constructed
to determine the predictive value of PLR on poor CCC devel-
opment. A P value of <.05 was considered statistically signif-
icant. Moreover, power analysis and calculations of sample
size were performed before the study to detect a 20% difference
in PLR values between poor and well-developed CCC, 245
patients were required to achieve power of 80% with a P value
of <.05.
Results
A total of 294 patients (mean age 59.9 + 9.7 years, 244 men)
with both SAP and CTO were included in the study. In the
study group, 163 of the 294 patients were found to have poorly
developed CCC. Comparisons of the clinical, laboratory, and
angiographic characteristics of the patients according to the
collateral development are shown in Tables 1 and 2. Both the
groups were similar in terms of age, gender, BMI, or LVEF.
Furthermore, there was no significant difference in the cardio-
vascular risk profiles of the 2 subgroups, such as the presence
of diabetes mellitus, hypertensive disease, smoking, or
hypercholesterolemia. Compared to the patients with well-
developed CCC (Rentrop grades 2 and 3), patients with poorly
developed CCC (Rentrop grades 0 and 1) exhibited higher hs-
CRP, platelet count, and mean platelet volume whereas lower
Açar et al 463
value of absolute lymphocyte count (Table 1). Compared to the
patients with well-developed CCC, patients with poorly devel-
oped CCC had significantly higher PLR values (156.8 + 30.7
vs 132.1 + 24.4, P < .001). Beyond this, an inverse stepwise
association was present between collateral score and mean PLR
values (Figure 1). The PLR values decreased with increasing
Rentrop grade, with a mean PLR value of 165.6 + 32.1,
153.7 + 29.2, 136.5 + 23.9, and 125.7 + 22.6 in patients with
Rentrop grades of 0, 1, 2, and 3, respectively (P for trend
<.001). Also, correlation analysis showed an inverse associa-
tion between hs-CRP and Rentrop score (r¼ �.376, P <
.001) and a significant positive correlation between hs-CRP
and PLR (r ¼ .412, P < .001). Moreover, PLR (unit ¼ 10; odds
ratio [OR] 1.48, 95% confidence interval [CI] 1.33-1.65; P <
.001) and hs-CRP (OR 1.58, 95% CI 1.07-2.32; P¼ .001) were
found as independent predictors of poor CCC in multivariate
logistic regression analysis (Table 3). The ROC analysis
yielded a cutoff value of 138.1 for PLR to predict insufficient
CCC with 76% sensitivity and 65% specificity, with the
area under the ROC curve being 0.771 (95% CI 0.718-0.814,
Figure 2).
Stratified Subgroup Analyses
Since low lymphocyte and high platelet counts were signifi-
cantly associated with a poorly developed CCC in the univari-
ate analysis, we decided to perform a stratified analysis to
investigate the superiority of PLR to individual platelet or
Table 1. Comparison of the Clinical and Laboratory Properties of Patients With Poorly Developed and Well-Developed Coronary Collateral
Circulation.a
Poorly Developed CCC (n ¼ 163) Well-Developed CCC (n ¼ 131) P Value
Baseline characteristics
Age, years 59.0 + 9.4 60.9 + 9.9 .092
Men 137 (84%) 107 (82%) .591
Body mass index, kg/m2 28.1 + 3.6 27.5 + 3.7 .187
Hypertension 105 (64%) 78 (59%) .391
Diabetes 55 (34%) 32 (24%) .082
Current smoking 92 (56%) 71 (54%) .701
LVEF, % 55.2 + 8.6 54.8 + 7.4 .680
Laboratory findings
Creatinine, mg/dL 0.91 + 0.20 0.94 + 0.23 .338
Fasting glucose, mg/dL 134.2 + 59.9 125.5 + 58.1 .065
LDL-cholesterol, mg/dL 120.3 + 45.9 113.1 + 37.8 .143
HDL-cholesterol, mg/dL 41.6 + 10.6 39.8 + 8.2 .177
Triglyceride, mg/dL 166.6 + 82.1 157.9 + 87.7 .174
hs-CRP, mg/L 2.5 + 0.8 2.1 + 0.6 <.001
WBC (�103 mL) 7.5 + 1.9 7.1 + 1.8 .058
Platelet (�103 mL) 282.1 + 32.1 261.7 + 31.6 <.001
Lymphocyte (�103 mL) 1.8 + 0.4 2.0 + 0.5 <.001
Platelet–lymphocyte ratio 156.8 + 30.7 132.1 + 24.4 <.001
Mean platelet volume, fL 8.3 + 0.8 8.0 + 0.8 <.001
Hemoglobin, g/dL 13.7 + 1.5 13.5 + 1.6 .270
Medication
Antiplatelets agents 111 (68%) 83 (63%) .394
ACE inhibitors/ARBs 91 (56%) 68 (52%) .503
b-Blockers 79 (49%) 63 (48%) .949
Calcium antagonists 26 (16%) 24 (18%) .591
Statins 82 (50%) 74 (57%) .291
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CCC, coronary collateral circulation; hs-CRP, high sensitivity C-reactive
protein; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LVEF, left ventricular ejection fraction; WBC, white blood cell; SD, standard deviation.
aData are presented as the number (%) of patients or mean value + SD.
Table 2. Coronary Angiographic Features of the Study Population.a
Poorly Developed
CCC (n ¼ 163)
Well-Developed
CCC (n ¼ 131)
P
Value
Position of chronic total occlusion lesion
LAD 67 (41%) 56 (43%) .776
LCX 28 (17%) 31 (24%) .168
RCA 68 (42%) 44 (33%) .154
Rentrop collateral grades
0 41 (14%) - -
1 122 (41%) - -
2 - 82 (28%) -
3 - 49 (17%) -
Number of diseased
coronary vessels
1.6 + 0.7 1.8 + 0.8 .058
Abbreviations: CCC, coronary collateral circulation; LAD, left anterior des-
cending coronary artery; LCX, left circumflex coronary artery; RCA, right cor-
onary artery; SD, standard deviation.
aData are presented as the number (%) of patients or mean value + SD.
464 Clinical and Applied Thrombosis/Hemostasis 21(5)
lymphocyte count in predicting poor CCC. We compared the
highest tertile of PLR (PLR > 153) with the 2 lower tertiles
(PLR � 153). In the subgroup with lymphocyte count �1.5
� 103/mL, there was a significant higher rate of poor CCC
among the patients with PLR >153 (31/45 ¼ 69%) compared
to those with PLR�153 (77/179¼ 43%), P¼ .002. In the sub-
group of lymphocyte count <1.5 � 103/mL, the patients with
PLR >153 still had a higher rate of poor CCC than patients with
PLR�153 (85% vs 59%, P¼ .023). In the subgroup with a pla-
telet count of <300 � 103/mL (n ¼ 227), patients with PLR
>153 had significantly higher rate of poor CCC compared to
patients with PLR �153 (76% vs 42%, P < .001). This effect
persisted in the subgroup of platelet count �300 � 103/mL (n
¼ 67), with poor CCC 81% in highest PLR tertile versus
57% in the lower 2 tertiles (P ¼ .029). Moreover, we evaluated
the association between the highest tertile of PLR (PLR > 153
vs PLR �153) and received antiplatelet therapy in predicting
poor CCC. The rate of poor CCC was not statistically signifi-
cant between patients who received antiplatelet therapy and
those without antiplatelets in the subgroups with PLR >153 and
Figure 1. Platelet, lymphocyte, and platelet–lymphocyte ratio according to Rentrop collateral grades.
Figure 2. Receiver–operating characteristic curves for platelet–lym-
phocyte ratio in prediction of poorly developed coronary collateral
circulation with high sensitivity and specificity. CI indicates confidence
interval.
Table 3. Univariate and Multivariate Analyses of Poorly Developed Coronary Collateral Circulation.a
Variable
Univariate Multivariate
b P OR (95% CI) P OR (95% CI)
Age, years �0.021 .093 0.98 0.96-1.00
Diabetes 0.455 .083 1.58 0.94-2.63
Fasting glucose, mg/dL 0.003 .099 1.00 0.99-1.01
Multivessel disease �0.302 .058 0.74 0.54-1.01
hs-CRP, mg/L 0.617 <.001 1.85 1.33-2.57 .001 1.58 1.07-2.32
PLR (unit ¼ 10) 0.379 <.001 1.46 1.32-1.62 <.001 1.48 1.33-1.65
WBC (�103 mL) 0.143 .065 1.15 1.00-1.33
MPV, fL 0.373 <.001 1.45 1.14-1.84
Abbreviations: CI, confidence interval; OR, odds ratio; hs-CRP,high sensitivity C-reactive protein; MPV, mean platelet volume; PLR, platelet/lymphocyte ratio;
WBC, white blood cell.
aAll the variables from Tables 1 and 2 were examined and only those significant at P < .1 level are shown in univariate analysis. Admission platelet count and lym-
phocyte count were excluded from the selection process as they are used in the calculation of admission PLR. Multivariate logistic regression model including all
the variables is shown in univariate analysis.
Açar et al 465
PLR �153 (75% vs 86%, P¼ .261 and 46% vs 42%, P ¼ .634,
respectively).
Discussion
Our findings indicated that a poorly developed CCC might only
be predicted by high levels of PLR and hs-CRP. We also
showed that the effect of PLR on coronary collateral develop-
ment was independent of platelet or lymphocyte counts alone.
The functional relevance of collateral vessels in humans has
been a matter of debate for many years.19 There have been
numerous investigations demonstrating a protective role of
well-grown versus poorly grown collateral arteries showing
smaller infarcts,20 less ventricular aneurysm formation,
improved ventricular function,20 fewer future cardiovascular
events,21 and improved survival.22 However, there have been
conflicting reports regarding this postulated link and observed
clinical outcomes.23-25 Similarly, we observed no differences
in the LVEF according to the collateral development.
The degree of coronary artery stenoses is consistently
described as positively determining the extent of coronary col-
lateral formation.26 We chose patients with CTO for this study
so that all would have the same degree of stenoses (100%).
Consequently, the effect of severity of coronary artery stenosis
on collateral formation did not interfere with the results of our
study. However, the development of CCC varies much among
patients even with the same degree of stenosis, suggesting the
contribution of other determinants in the formation of CCC. In
the present study, univariate analysis showed that higher plate-
let count and mean platelet volume and lower value of absolute
lymphocyte count were significantly associated with poorly
developed CCC (Table 1).
Platelets regulate new blood vessel growth during wound
healing, tumor growth, and in response to ischemia, because
they contain a number of angiogenesis promoters and inhibi-
tors.27 Among the angiogenesis promoters found in platelets
are vascular endothelial growth factor, platelet-derived growth
factor, basic fibroblastic growth factor, and epidermal growth
factor.27 Furthermore, platelets contain matrix metalloprotei-
nases that are also known to promote angiogenesis. A number
of angiogenesis inhibitors are also found in platelets. Among
these, angiostatin is especially important in the coronary collat-
eral development. It has been recently reported that angiostatin
plays a role in mediating the reduced coronary angiogenesis in
the context of inhibition of nitric oxide synthesis,28 and also
angiostatin levels in pericardial fluid are negatively associated
with collateral formation in patients undergoing coronary
bypass surgery.29 Nevertheless, thrombocytosis is commonly
associated with a coronary arterial disease and has been widely
reported as an adverse prognostic marker.7-9 It is reported that
patients with pathologically increased platelet counts have an
enhanced risk of thrombotic complications.30 Furthermore pla-
telets both initiate atherogenesis and trigger its complications.7
Therefore, higher platelet count may play a role in both the
development and the consequences of cardiovascular disease.
In addition to the role in the pathogenesis of atherosclerosis,
inflammation was also shown to inhibit the collateral formation
mainly by affecting the endothelial function.31 Moreover, low-
grade inflammation may increase circulating platelet count32
and mean platelet volume levels,33 which reflect underlying
inflammation, as several inflammatory mediators stimulate
megakaryocytic proliferation and produce relative thrombocy-
tosis. Therefore in this study, we have hypothesized that,
although not directly but may be as a result of the inflammatory
process in the atherosclerosis, higher platelet count, and larger
platelets, thrombopoiesis may be related to the insufficient
CCC. Also, previous reports have stated that lymphopenia is
associated with the progression of atherosclerosis. Lymphocyte
apoptosis in atherosclerotic lesions may result in lymphopenia,
which gradually increases with atherosclerotic burden. Like-
wise, a low peripheral blood lymphocyte count has also been
associated with poorer prognosis.10-12 Eventually, both throm-
bocytosis and lymphocytopenia correlate with the degree of
systemic inflammation, and the PLR represents a novel marker
incorporating both the hematologic indices.
However, to date no study has been performed on the rela-
tionship between PLR and development of CCC. In the present
study, we demonstrated that an inverse stepwise association
between collateral grade and mean PLR values. Also, there was
a significant positive correlation between hs-CRP and PLR.
And importantly, they were independent predictors of poor
CCC in multivariate logistic regression analysis. These find-
ings are in line with previous reports emphasizing the relation
between inflammation and development of coronary collat-
erals.34-36 Since there was no significant difference in the car-
diovascular risk profiles (eg, diabetes and blood cholesterol
levels) between the 2 subgroups, the present study may suggest
that the subclinical inflammation rather than other metabolic
factors may be the dominant characteristic leading to poor col-
lateral development. In the subgroup analysis, we showed that
the effect of PLR on coronary collateral development was inde-
pendent of platelet or lymphocyte counts alone. The superiority
of PLR to either individual lymphocyte or platelet counts can
be explained by the PLR which represents a novel marker
incorporating 2 inversely related predictors and immune path-
ways and may also have higher stability compared to the indi-
vidual platelet or lymphocyte counts, which could be altered by
many physiological and pathological conditions.
Our study has some limitations. First, the cross-sectional
design of our study makes it difficult to comment on the causal
relationship of PLR and poorly developed CCC. Also, the qua-
litative evaluation of collaterals with Rentrop may underesti-
mate the collateral formations; however, a recent study3
reported a good correlation between angiographic and func-
tional methods for the assessment of collaterals in patients with
SAP. Being a retrospective study, spot laboratory parameters
rather than follow-up values are also among limitations of our
study.
In conclusion, for the first time in the literature, we showed
the relationship between the PLR and coronary collateral
development. We have demonstrated that PLR with an optimal
cutoff value of 138.1 predicts insufficient CCC with a
466 Clinical and Applied Thrombosis/Hemostasis 21(5)
sensitivity of 76% and a specificity of 65%. The PLR may be an
important, simple, and cost-effective tool predicting the degree
of coronary collateralization in patients with SAP and CTO.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
References
1. Sand NP, Rehling M, Bagger JP, Thuesen L, Flø C, Nielsen TT.
Functional significance of recruitable collaterals during tempo-
rary coronary occlusion evaluated by 99mTc-sestamibi single-
photon emission computerized tomography. J Am Coll Cardiol.
2000;35(3):624-632.
2. Pohl T, Hochstrasser P, Billinger M, Fleisch M, Meier B, Seiler
C.Influence on collateral flow of recanalising chronic total cor-
onary occlusions: a case–control study. Heart. 2001;86(4):
438-443.
3. Werner GS, Ferrari M, Heinke S, et al. Angiographic assessment
of collateral connections in comparison with invasively
determined collateral function in chronic coronary occlusions.
Circulation. 2003;107(15):1972-1977.
4. Meier P, Hemingway H, Lansky AJ, Knapp G, Pitt B, Seiler C.
The impact of the coronary collateral circulation on mortality: a
meta-analysis. Eur Heart J. 2012;33(5):614-621.
5. Simons M. Angiogenesis: where do we stand now? Circulation.
2005;111(12):1556-1566.
6. Imhof BA, Aurrand-Lions M. Angiogenesis and inflammation
face off. Nat Med. 2006;12(2):171-172.
7. Thaulow E, Erikssen J, Sandvik L, Stormorken H, Cohn PF.
Blood platelet count and function are related to total and cardio-
vascular death in apparently healthy men. Circulation. 1991;
84(2):613-617.
8. Iijima R, Ndrepepa G, Mehilli J, et al. Relationship between pla-
telet count and 30 day clinical outcomes after percutaneous coron-
ary interventions. pooled analysis of four ISAR trials. Thromb
Haemost. 2007;98(4):852-857.
9. Nikolsky E, Grines CL, Cox DA, et al. Impact of baseline platelet
count in patients undergoing primary percutaneous coronary
intervention in acute myocardial infarction (from the CADILLAC
trial). Am J Cardiol. 2007;99(8):1055-1061.
10. Ommen SR, Gibbons RJ, Hodge DO, Thomson SP. Usefulness of
the lymphocyte concentration as a prognostic marker in coronary
artery disease. Am J Cardiol. 1997;79(6):812-814.
11. Zouridakis EG, Garcia-Moll X, Kaski JC. Usefulness of the blood
lymphocyte count in predicting recurrent instability and death in
patients with unstable angina pectoris. Am J Cardiol. 2000;86(4):
449-451.
12. Acanfora D, Gheorghiade M, Trojano L, et al. Relative lympho-
cyte count: a prognostic indicator of mortality in elderly patients
with congestive heart failure. Am Heart J. 2001;142(1):167-173.
13. Smith RA, Ghaneh P, Sutton R, Raraty M, Campbell F, Neopto-
lemos JP. Prognosis of resected ampullary adenocarcinoma by
preoperative serum CA19-9 levels and platelet–lymphocyte ratio.
J Gastrointest Surg. 2008;12(8):1422-1428.
14. Smith RA, Bosonnet L, Raraty M, et al. Preoperative platelet–
lymphocyte ratio is an independent significant prognostic marker
in resected pancreatic ductal adenocarcinoma. Am J Surg. 2009;
197(4):466-472.
15. Proctor MJ, Morrison DS, Talwar D, et al. A comparison of
inflammation-based prognostic scores in patients with cancer. a
glasgow inflammation outcome study. Eur J Cancer. 2011;
47(17):2633-2641.
16. Azab B, Shah N, Akerman M, McGinn JT Jr. Value of platelet/
lymphocyte ratio as a predictor of all-cause mortality after non-
ST-elevation myocardial infarction. J Thromb Thrombolysis.
2012;34(3):326-334.
17. Di Mario C, Werner GS, Sianos G, et al. European perspective in
the recanalisation of chronic total occlusions (CTO): consensus
document from the EuroCTO Club. Eurointervention. 2007;
3(1):30-43.
18. Rentrop KP, Cohen M, Blanke H, Phillips RA. Changes in
collateral filling after controlled coronary artery occlusion by an
angioplasty balloon in human subjects. J Am Coll Cardiol.
1985;5(3):587-592.
19. Helfant RH, Vokonas PS, Gorlin R. Functional importance of the
human coronary collateral circulation. N Engl J Med. 1971;
284(23):1277-1281.
20. Habib GB, Heibig J, Forman SA, et al. Influence of coronary col-
lateral vessels on myocardial infarct size in humans. results of
phase I thrombolysis in myocardial infarction (TIMI) trial.
Circulation. 1991;83(3):739-746.
21. Billinger M, Kloos P, Eberli F, Windecker S, Meier B, Seiler C.
Physiologically assessed coronary collateral flow and adverse
cardiac ischemic events: a follow-up study in 403 patients with
coronary artery disease. J Am Coll Cardiol. 2002;40(9):
1545-1550.
22. Meier P, Gloekler S, Zbinden R, et al. Beneficial effect of recrui-
table collaterals: a 10-year follow-up study in patients with stable
coronary artery disease undergoing quantitative collateral mea-
surements. Circulation. 2007;116(9):975-983.
23. Boehrer JD, Lange RA, Willard JE, Hillis LD. Influence of collat-
eral filling of the occluded infarct-related coronary artery on prog-
nosis after acute myocardial infarction. Am J Cardiol. 1992;69(1):
10-12.
24. Gohlke H, Heim E, Roskamm H. Prognostic importance of collat-
eral flow and residual coronary stenosis of the myocardial infarct
artery after anterior wall Q-wave acute myocardial infarction. Am
J Cardiol. 1991;67(15):1165-1169.
25. Antoniucci D, Valenti R, Moschi G, et al. Relation between pre-
intervention angiographic evidence of coronary collateral circula-
tion and clinical and angiographic outcomes after primary
angioplasty or stenting for acute myocardial infarction. Am J Car-
diol. 2002;89(2):121-125.
26. Pohl T, Seiler C, Billinger M, et al. Frequency distribution of col-
lateral flow and factors influencing collateral channel develop-
ment. functional collateral channel measurement in 450 patients
Açar et al 467
with coronary artery disease. J Am Coll Cardiol. 2001;38(7):
1872-1878.
27. Radziwon-Balicka A, Moncada de la Rosa C, Jurasz P. Platelet-
associated angiogenesis regulating factors: a pharmacological
perspective. Can J Physiol Pharmacol. 2012;90(6):679-688.
28. Matsunaga T, Weihrauch DW, Moniz MC, Tessmer J, Warltier
DC, Chilian WM. Angiostatin inhibits coronary angiogenesis dur-
ing impaired production of nitric oxide. Circulation. 2002;
105(18):2185-2191.
29. Matsunaga T, Chilian WM, March K. Angiostatin is negatively
associated with coronary collateral growth in patients with coron-
ary artery disease. Am J Physiol Heart Circ Physiol. 2005;288(5):
2042-2046.
30. Stissing T, Dridi NP, Ostrowski SR, Bochsen L, Johansson PI. The
influence of low platelet count on whole blood aggregometry assessed
by Multiplate. Clin Appl Thromb Hemost. 2011;17(6):211-217.
31. Schneeweis C, Gräfe M, Bungenstock A, Spencer-Hänsch C, Fleck E,
Goetze S. Chronic CRP-exposure inhibits VEGF induced endothelial
cell migration. J Atheroscler Thromb. 2010;17(2):203-212.
32. Alexandrakis MG, Passam FH, Moschandrea IA, et al. Levels of
serum cytokines and acute phase proteins in patients with essen-
tial and cancer-related thrombocytosis. Am J Clin Oncol. 2003;
26(2):135-140.
33. Gasparyan AY, Ayvazyan L, Mikhailidis DP, Kitas GD. Mean
platelet volume: a link between thrombosis and inflammation?
Curr Pharm Des. 2011;17(1):47-58.
34. Seiler C, Pohl T, Billinger M, Meier B. Tumour necrosis factor
alpha concentration and collateral flow in patients with coronary
artery disease and normal systolic left ventricular function. Heart.
2003;89(1):96-97.
35. Guray U, Erbay AR, Guray Y, et al. Poor coronary collateral cir-
culation is associated with higher concentrations of soluble adhe-
sion molecules in patients with single-vessel disease. Coron
Artery Dis. 2004;15(7):413-417.
36. Gulec S, Ozdemir AO, Maradit-Kremers H, Dincer I, Atmaca Y,
Erol C. Elevated levels of C-reactive protein are associated with
impaired coronary collateral development. Eur J Clin Invest.
2006;36(6):369-375.
468 Clinical and Applied Thrombosis/Hemostasis 21(5)
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