One of the major complications of myocardial infarction (MI) is left ventricular apical thrombus (AT) formation, which may favor blood stasis, increased coagulability and endothelial injury.¹ Its incidence has reported to range between 30-40% in postmortem studies.^{2 , 3} Left ventricular AT usually occurs in the presence of left ventricular aneurysm or apical akinesia after large anterior MI. Additionally, hypercoagulable or inflammatory states might accelerate thrombus formation.^{4 , 5}

Platelet-to-lymphocyte ratio (PLR) has been suggested as an important and cheap prognostic factor in coronary heart disease.⁶ It is an inflammatory marker derived from complete blood count and has been studied in various cancers,⁷ chronic renal failures,⁸ and coronary artery disease.⁹

Platelet size has been reported to reflect platelet activity. Larger size platelets are metabolically and enzymatically more active.¹⁰ Mean platelet volume (MPV) is an indirect marker of platelet activity and that is readily available in clinical settings and has been linked to poor prognosis following ST-elevation myocardial infarction (STEMI).¹¹

In view of the fact that platelet size reflects platelet activity more accurately than platelet count itself, the notion of replacing platelet count with MPV in the PLR to form mean platelet volume-to-lymphocyte ratio (MPVLR) seems plausible. In our study we aimed to evaluate whether MPVLR has a predictive value for the development of AT after myocardial infarction.

A total of 107 patients with anterior myocardial infarction were included. Fifty-six patients with AT, 51 control subjects without AT, matched by age, sex and ejection fraction were enrolled in this study retrospectively. Data regarding individual patients were retrospectively collected from patient files. Exclusion criteria were presence of infection, cancer, nonischemic cardiomyopathy, hematological disorders, and current therapy with corticosteroid, non-steroidal anti-inflammatory drugs or oral anticoagulants. Blood samples were drawn from a large antecubital vein into Vacuntainer tubes (Becton Dickinson, Rutherford, New Jersey) for determination of biochemical and hemostatic parameters (Symex K-1000, Kobe, Japan) at admission. All routine biochemical tests were performed using an auto-analyzer (Roche Diagnostic Modular Systems, Tokyo, Japan). PLR was defined as the absolute platelet count in the peripheral blood divided by the total lymphocyte count, and MPVLR was calculated as the ratio of MPV to lymphocyte count.

All patients underwent 2D echocardiography four weeks after anterior myocardial infarction. Two-dimensional echocardiography was performed with a 3.5 MHz transducer (IE33, Philips Medical Systems, Andover, Massachusets). Simpson's method was used to assess the left ventricular ejection fraction in two-dimensional echocardiographic apical four-chamber view, as recommended by the American Society of Echocardiography guidelines.¹² All images were stored and evaluated by independent cardiologist who were blinded to patients’ data.

A total of 107 patients with anterior myocardial infarction were included in the study. The mean age of the study population was 60.7±7 years. Baseline demographic, clinical and echocardiographic features are summarized in Table 1 . Presence of diabetes mellitus, hypertension, atrial fibrillation did not differ between patients with AT and without AT. Body mass index and rate of smoking were lower in patients with AT than without AT. Echocardiographic parameters (left ventricular ejection fraction, left atrium diameter) were not significantly different between the two groups as shown in Table 1 . Medications were similar in both groups. MPV was higher in patients with AT than patients without AT (9.71±1.09 vs 8.84±0.61fL, p<0.001). Lymphocyte count was lower in patients with AT than patients without AT (1.37±0.48 vs 2.0±0.77 10^3/mm³, p<0.001). While PLR did not differ between the two groups (p=0.068), MPVLR was higher in patients with AT than patients without AT (7.91±2.5 vs 5.1±2.1, p<0.001). The ROC analysis yielded a cut-off value of 4.75 for the MPVLR to predict AT, with a sensitivity of 82.1% and specificity of 70.2% (Area under the curve=0.811, 95% confidence interval [CI]:0.731-0.891, p<0.001) ( Figure 1 ).

Table 1

Variables	Thrombus (+) patients (n:56)	Thrombus (-) patients (n:51)	p value
Gender (female) (n, %)	17(30%)	8(15%)	0.048
Age (years±SD)	65.3 ± 7.1	56 ± 7.9	0.001
Diabetes mellitus (n,%)	31(55%)	18(35%)	0.38
Hypertension (n,%)	33(58%)	29(56%)	0.831
Body mass index, kg/m2	25.7 ± 2.2	27.4 ± 2.7	0.001
Coronary heart disease (n,%)	51(91%)	49(96%)	0.298
Percutaneous coronary intervention (n,%)	53(94%)	49(96%)	0.727
Coronary artery bypass grafting (n,%)	4(7%)	2(3%)	0.472
Stroke (n,%)	6(10%)	2(3%)	0.184
Atrial fibrillation (n,%)	3(5%)	1(2%)	0.360
Heart failure (n,%)	56(100%)	51(100%)	1
Current smokers (n,%)	28(50%)	38(74%)	0.009
ACE blockers (n,%)	53(94%)	49(96%)	0.727
Aldosterone antagonists (n,%)	52(92%)	47(92%)	0.891
Betablockers (n,%)	56	51	1
Aspirin (n,%)	50(89%)	45(88%)	0.864
Clopidogrel (n,%)	48(85%)	44(86%)	0.934
Anticoagulants (n,%)	6(10%)	2(3%)	0.184
Statins (n,%)	56	51	1

Figure 1

According to the cut-off > 4.75 for MPVLR, patients were divided into two groups; patients with a MPVLR > 4.75 were older, had a higher prevalence of female gender, and a lower frequency of smoking compared with the MPVLR ≤ 4.75 group ( Table 2 ).

Table 2

Variables	MPVLR ≤ 4.75 (n:45)	MPVLR > 4.75 (n:62)	p-value
Gender (female) (n, %)	6 (15%)	20 (32%)	0.023
Age (years ± SD)	57.3 ± 8.9	60.1 ± 7.6	< 0.001
Diabetes mellitus (n,%)	26(55%)	23(35%)	0.378
Hypertension (n,%)	23(58%)	39(56%)	0.415
Body mass index, kg/m2	27.4±2.6	26.4±2.4	0.04
Percutaneous coronary intervention (n,%)	43(94%)	59(96%)	0.727
Coronary artery bypass grafting (n,%)	2(7%)	4(3%)	0.472
Stroke (n,%)	5(11%)	3(5%)	0.047
Atrial fibrillation (n,%)	0(0%)	4(6%)	0.084
Heart failure (n,%)	56(100%)	51(100%)	1
Current smokers (n,%)	34(75%)	32(51%)	0.012
ACE blockers (n,%)	42(94%)	60(96%)	0.407
Aldosterone antagonists (n,%)	41(92%)	58(92%)	0.638
Betablockers (n,%)	45(100%)	62(100%)	1
Aspirin (n,%)	41(89%)	54(88%)	0.518
Clopidogrel (n,%)	41(85%)	51(86%)	0.199
Anticoagulants (n,%)	1(10%)	7(03%)	0.080
Statin (n,%)	45(100%)	62(100%)	1
Diuretics (loop diuretic) (n,%)	42(92%)	58(94%)	0.969
Glucose (mg/dl±SD)	134 ± 61	156 ± 71	0.037
Creatinine (mg/dl±SD)	1.08 ± 0.21	1.09 ± 0.19	0.788
Total cholesterol (mg/dl±SD)	270 ± 58	290 ± 71	0.241
LDL cholesterol (mg/dl±SD)	139 ± 21	141 ± 26	0,535
HDL cholesterol (mg/dl±SD)	32 ± 8	34 ± 6	0.685
Triglyceride (mg/dl±SD)	208 ± 63	225 ± 67	0.102
Hemoglobin (g/l±SD)	11.7 ± 1.3	11.8 ± 1.7	0.681
White blood cell (103/µL±SD)	11.4 ± 3.9	10.19 ± 3.6	0.79
Platelet (103/mm3±SD)	208 ± 77	194 ± 71	0.356
Lymphocyte count, (/mm3)	2.2 ± 0.5	1.2 ± 0.4	< 0.001
Left ventricular ejection fraction, (%±SD)	31 ± 5	29 ± 5	0.082

ACE: angiotensin converting enzyme; LDL: low-density lipoprotein, HDL: high-density lipoprotein

In multivariate logistic regression analysis, MPVLR (odds ratio [OR]: 1.406, 95% CI: 1.156-1.711, P ¼.0.001), MPV (OR: 2.293, 95% CI: 1.306-4.028, P ¼ .004), and smoking ((OR: 2.388, 95% CI: 0.886-6.434, P ¼ .020) were independent predictors of AT ( Table 3 ).

Table 3

Variables	Univariate		Multivariate
	r	p	B	p
Age	0.166	0.087	-0,028	0.782
Sex	0.192	0.048	-0.056	0.584
Current smoker	-0.252	0.009	-0.195	0.020
Body mass index	-0.322	0.001	-0.136	0.102
Diabetes mellitus	0.201	0.038	0.121	0.553
Ejection fraction	-0.176	0.070	-0.050	0.585
Glucose	0.241	0.012	0.010	0.960
Platelet count	-0.198	0.041	-0.290	0.213
Lymphocyte count	-0.431	< 0.001	-0.301	0.179
Platelet-to-lymphocyte ratio	0.177	0.068	0.230	0.452
Neutrophil-to-lymphocyte ratio	0.408	< 0.001	0.210	0.068
Mean platelet volume	0.440	< 0.001	0.350	0.004
Mean platelet volume-to- lymphocyte ratio	0.501	< 0.001	0.441	0.001

In this study, we showed that MPVLR was significantly higher in patients with AT after anterior myocardial infarction than without AT. To the best of our knowledge, this is the first study to determine the clinical utility of MPVLR in predicting AT after a myocardial infarction.

Left ventricular AT formation is known to occur in patients with acute anterior MI and dilated cardiomyopathy as a result of low flow and inflammatory states.³ . AT can also be found in patients with severe congestive heart failure.^{14 , 15} Reportedly, the incidence of LV apical thrombi was approximately 60% in patients with acute anterior MI particularly in the pre-thrombolytic era.^{16 , 17} The formation of an LV apical thrombus was associated with reduced LVEF (≤35%) and presence of apical aneurysms.¹⁸ Recently, percutaneous coronary intervention has replaced thrombolytic therapy and caused a decrease in the incidence of LV apical thrombi. A study by Choi et al.,¹⁹ showed an incidence of LV apical thrombi of 3.3% (34 of 1,045) in patients with acute anterior MI.¹⁹

Besides the low LVEF, inflammatory states play an important role in thrombotic process. Erythrocyte sedimentation rate (ESR), c-reactive protein (CRP), PLR and neutrophil-to-lymphocyte ratio (NLR) have been studied in a large number of epidemiological studies as indicators of systemic inflammation.^{20 , 21} Lymphocytes are known to play a crucial role for a complete inflammatory response, and reduced lymphocyte counts induced by apoptosis may increase inflammatory damage.^{22 , 23} PLR has been reported to reflect hyperactive inflammatory pathways.⁶ High platelet counts reflect underlying inflammation, because many inflammatory mediators stimulate megakaryocyte proliferation and lead to relative thrombocytosis.⁶ Higher cytokine levels may lead to the production of large size platelets in the bone marrow.²⁴ The platelet size shows platelet activity more accurately than the platelet count.²⁵ MPVLR, which was calculated using MPV instead of platelet count in PLR, was claimed to be a more plausible index of platelet activity.²⁵ Several studies have shown that a high MPV is associated with cardiovascular events.^{26 , 27} The mechanism mediating the relationship between high MPV and cardiovascular disease is not obvious. One of the reasons for increased number of larger platelets is cytokines released from ischemic tissues.²⁸ On the other hand, lymphocytes are involved the mechanisms of cell death caused by inflammation.²⁹ Some studies have claimed that lymphocyte-mediated apoptosis is the most important type of cell death in ischemic myocardial tissue.³⁰ Increased physiologic stress can cause the release of cortisol and catecholamines during acute coronary syndrome.³¹ In this situation, redistribution of lymphocytes to lymphatic organs results in apoptosis, which leads to lymphopenia,³² and lower lymphocyte count.

In previous studies, researchers showed that higher PLR levels were associated with adverse events in various cardiovascular diseases.^{29 , 30 , 33} Ertem et al.,¹³ reported that PLR-like inflammatory marker, NLR, was associated with AT. Studies evaluating MPVLR in cardiac conditions are limited. Hudzik et al.,³⁴ reported that MPVLR was associated with high coronary thrombus burden and late mortality in STEMI patients. MPVLR was also found to be higher in patients with poor coronary collaterals.³⁵ In the present study, we found that MPVLR was strongly associated with AT. In response to increased inflammatory and thrombotic status, both higher MPV levels and lower lymphocyte counts may be associated with newly developed AT after a myocardial infarction. Taken together, the MPVLR is a simple and readily available biomarker that combines the predictive risk of MPV and lymphocyte counts into a single risk factor. According to our data, we suggest that the MPVLR is a better predictor than NLR, MPV, and PLR for AT.

MPVLR is an easily calculated and efficient index that can be considered a powerful and independent predictor of AT in anterior MI patients. The authors suggest that it can be a useful adjunct to standard tests in the diagnosis of AT.