Value of platelet indices in prediction of pulmonary embolism

Yasser M Kamal; Ali M Kassem; Hasnaa A Abo Elwafa; Asmaa Abdel-Baset

doi:10.4103/mmj.mmj_247_22

ORIGINAL ARTICLE

Year : 2022 | Volume : 35 | Issue : 4 | Page : 1779-1786

Value of platelet indices in prediction of pulmonary embolism

Yasser M Kamal¹, Ali M Kassem¹, Hasnaa A Abo Elwafa², Asmaa Abdel-Baset¹
¹ Department of Internal Medicine, Faculty of Medicine, Sohag University, Sohag, Egypt
² Department of Clinical Pathology, Faculty of Medicine, Sohag University, Sohag, Egypt

Date of Submission	24-Jul-2022
Date of Decision	03-Sep-2022
Date of Acceptance	05-Sep-2022
Date of Web Publication	04-Mar-2023

Correspondence Address:
Yasser M Kamal
Department of Internal Medicine, Faculty of Medicine, Sohag University, Sohag 82545
Egypt

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/mmj.mmj_247_22

Abstract

Objectives
To assess the platelet (PLT) indices, such as mean platelet volume (MPV), plateletcrit (PCT), and platelet distribution width (PDW), in pulmonary embolism (PE) prediction.
Background
PE is the third most frequent cardiovascular disease worldwide. The changes in PLT indices (MPV, PDW, and PCT) are gold standard markers for the pathogenesis in different cardiovascular diseases.
Patients and methods
A total of 100 patients with venous thromboembolism and 50 controls were recruited. Overall, 46 patients presented with first episode of deep venous thrombosis (DVT) without PE (group I) and 54 patients with PE (group II).
Results
MPV was significantly higher in patients with PE (10.72 ± 2.05 fl) than patients with DVT (9.25 ± 1.31 fl) (P = 0.02). Similarly, PDW was significantly higher in patients with PE (24.78 ± 6.76 fl) than patients with DVT (22.39 ± 4.33 fl), with P value of 0.04. The cutoff values of MPV and PDW for prediction of PE at presentation were 10 and 17.5 fl, respectively, with sensitivities of 77 and 83%, respectively, and specificities of 87 and 80%, respectively. PCT was significantly higher in the PE (0.25 ± 0.09 ng/ml) group and DVT (0.26 ± 0.07 ng/ml) group compared with the control (0.22 ± 0.04 ng/ml) group. PLT count was significantly lower in the PE group (229.39 ± 67.98 × 10³/μl) than DVT (249.85 ± 54.7 × 10³/μl) and control (279.13 ± 61.83 × 10³/μl) groups. White blood cell were significantly higher in patients with PE (9.36 ± 3.67 × 10⁹/l) than DVT (8.01 ± 2.53 × 10⁹/l) and control (8 ± 2.37 × 10⁹/l) groups. The highest values of MPV, PDW, right ventricular dimensions, pulmonary pressure, and cardiac troponin I level were significantly correlated to the severity of PE. MPV and PDW were directly related to thrombus size in Doppler ultrasonography finding in patients with DVT and to the level of obstruction of pulmonary vessels in computed tomography pulmonary angiogram for patients with PE.
Conclusion
The current study suggested that serial measurements of MPV, PDW, and PLT count are reliable markers for predicting the occurrence of acute PE in patients with first episode of acute proximal DVT.

Keywords: cardiac troponin I, cardiovascular diseases, Doppler ultrasonography, platelets, pulmonary embolism, venous thromboembolism

How to cite this article:
Kamal YM, Kassem AM, Abo Elwafa HA, Abdel-Baset A. Value of platelet indices in prediction of pulmonary embolism. Menoufia Med J 2022;35:1779-86

How to cite this URL:
Kamal YM, Kassem AM, Abo Elwafa HA, Abdel-Baset A. Value of platelet indices in prediction of pulmonary embolism. Menoufia Med J [serial online] 2022 [cited 2023 Oct 2];35:1779-86. Available from: http://www.mmj.eg.net/text.asp?2022/35/4/1779/370994

Introduction

Venous thromboembolism (VTE) encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE). It is the third most frequent cardiovascular disease (CVD) with an overall annual incidence of 100–200 per 100 000 inhabitants, worldwide ^[1]. Diagnostic testing is complicated, as biomarkers, like the D-dimer, are frequently false positive, and imaging, like computed tomography pulmonary angiography (CTPA), carries risks of radiation and contrast dye exposure. In recent years, several advances in treatment have also emerged ^[2]. Platelets (PLT) play a major role in the pathogenesis, morbidity, and mortality in VTE and atherosclerosis. Mean platelet volume (MPV) is a simple and accurate marker of PLT activation and PLT function ^[3]. Platelet distribution width (PDW) measures the variability in PLT size and is another marker of PLT activation ^[4]. Previous studies have shown that increased MPV was associated with both arterial and venous diseases such as myocardial infarction, poor coronary collaterals, stroke, and VTE ^[5]. Additionally, an elevated level of MPV was shown to be related to different kinds of diseases such as infective endocarditis, rheumatoid arthritis, and gestational diabetes. Increased PDW levels have been reported in myeloproliferative disorders, diabetes mellitus, cerebral venous sinus thrombosis, and various CVDs such as coronary artery disease ^[6],[7]. The present study aimed to investigate the value of PLT indices including MPV, PDW, and plateletcrit (PCT) as predictors of acute PE in patients with the first episode of acute DVT.

Patients and methods

The study was approved by the ethics board of the Faculty of Medicine, Sohag University, Sohag, Egypt. The written consent forms were obtained from each participant. The current study was conducted on cases with first occasion DVT and/or PE at Sohag University Hospital between October 2016 and March 2019. Cases that were enrolled in this study were classified into three groups.

Group I included 50 cases (24 women and 22 men, with age range from 18 to 81 years and mean age of 46.9 ± 16.5 years) with acute DVT and without PE. The follow-up period was 1 year. Four cases in that group developed acute PE during follow-up, so they were added to group II.

Group II included 54 cases (29 women and 25 men, with age range from 21 to 80 years and mean age of 48.1 ± 16.4 years) with an acute PE.

Control group included 50 supposedly healthy participants (29 women and 21 men, with age range from 21 to 80 years and mean age of 43.2 ± 14.9 years) matched for age, sex, and BMI.

The cases with a medical history of chronic DVT, chronic PE, current pregnancy, diabetes mellitus, atrial fibrillation, obesity, acute coronary syndromes, ventricular systolic dysfunction, stroke, chronic renal, hepatic diseases, infection, malignancy, hematological disorders, trauma, previous surgical operation, and/or peripheral vascular disease were excluded.

The methodological plan was applied to all participants as follows:

Medical history: a detailed clinical history including age, sex, and associated comorbidity, particularly diabetes mellitus, and hypertension.
Clinical examination: it included general, cardiac, chest, and abdominal examinations.
Laboratory assessments, which included complete blood count, hemoglobin, and PLT indicators (MPV, PDW, and PCT) by CELL-DYN Ruby Hematology System (Abbot, Illinois, USA).

Fasting and postprandial blood glucose by glucose Colorimetric Assay Kit (Elabscience, Texas, USA).
Lipid profile: total cholesterol, triglyceride, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) using a kit from Vitro Scient, Egypt (Belbes, Bilbeis, Ash Sharqia Governorate).
Serum creatinine and urea using kits from Spinreact, Carr. de Sta. Coloma, 7, 17176 la, Girona, Spain.
Serum troponin (cTnI) and D-dimer by Certest Biotec Inc., Polígono Industrial Río Gallego II Calle J, 1, 50840 Zaragoza, Spain.
Arterial blood gases in room air.
Prothrombin time (PT) and coagulation time by HumaClot Junior instrument (Human Co., Max-Planck-Ring 21, 65205 Wiesbaden, Germany).

Radiology assessment:

Abdominal ultrasonography.
Transthoracic echocardiogram.
CTPA.

The statistical analysis of data was performed by STATA v. 14.2 (College Station, Texas, USA). Quantitative data were represented as mean, SD, median, and range. The Student t test was used to compare the means of two groups, whereas one-way analysis of variance was used for comparison of the means of three groups or further. Qualitative data were presented as frequencies (numbers and percentages) using either the χ² test or Fisher exact test. Besides, receiver operating characteristic curve analysis was used to analyze the cutoff points of MPV and PDW as predictors of PE. Graphs were produced by Excel or STATA program. P value less than 0.05 was considered significant.

Results

The mean BMI of the DVT group was 27.61 ± 1.55 versus 27.34 ± 1.72 in the PE group. The mean respiratory rate in the DVT group was 14 cycles/min, whereas in the PE group was about 21 cycles/min. The mean heart rate in the DVT group was 105.52 ± 12.52 beats/min, whereas in the PE group was about 72.26 ± 8.5 beats/min.

The mean D-dimer of patients with PE was not significantly higher than those of DVT patients. PaO₂ and PaCO₂ levels were significantly higher in patients with DVT [Table 1]. MPV was significantly higher in patients with PE (10.72 ± 2.05 fl) than patients with DVT (9.25 ± 1.31 fl) (P = 0.02). Similarly, PDW was significantly higher in patients with PE (24.78 ± 6.76 fl) than patients with DVT (22.39 ± 4.33 fl) (P = 0.04). The cutoff values of MPV and PDW for prediction of PE at presentation were 10 and 17.5 fl, respectively, with sensitivities of 77 and 83%, respectively, and specificities of 87 and 80%, respectively. PCT was significantly higher in the PE (0.25 ± 0.09 ng/ml) group and DVT (0.26 ± 0.07 ng/ml) group compared with the control (0.22 ± 0.04 ng/ml) group. PLT count was significantly lower in the PE group (229.39 ± 67.98 × 10³/μl) than DVT (249.85 ± 54.7 × 10³/μl) and control (279.13 ± 61.83 × 10³/μl) groups. White blood cell (WBCs) were significantly higher in patients with PE (9.36 ± 3.67 × 10⁹/l) than in DVT (8.01 ± 2.53 × 10⁹/l) and control (8 ± 2.37 × 10⁹/l) groups. The highest values of MPV, PDW, right ventricular (RV) dimensions, pulmonary pressure, and cTnI level were significantly correlated to the severity of PE. MPV and PDW were directly related to thrombus size in Doppler ultrasonography finding in patients with DVT and to the level of obstruction of pulmonary vessels in CTPA for patients with PE. T test analysis a group-related significance compared with each other in all variables [Table 1]. Further laboratory investigations were listed in [Table 2] and [Table 3] and [Figure 1].

Table 1: Clinical Characteristics of study population (patients) and complete blood count results are at the seventh day of the study

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Table 2: Comparison between deep vein thrombosis cases progressed and not progressed to pulmonary embolism, as regard blood picture at 1 year (after rolling out missed cases)

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Table 3: Optimum diagnostic cut off value, area under the curve (parentheses 95% confidence interval), sensitivity, specificity, and positive and negative predictive values (percentages) of mean platelet volume and platelet distribution width for pulmonary embolism

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Figure 1: Graphical distribution of results among the studied groups. (a) Box plot showing the MPV distribution of studied population. (b) Box Plot showing MPV in DVT cases progressed to PE and DVT cases not progressed to PE at 1 year of follow-up. (c) Scatter diagram showing the correlation between MPV and D-dimer in cases. DVT, deep venous thrombosis; MPV, mean platelet volume; PE, pulmonary embolism.

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Discussion

PE had a substantial morbidity and mortality rate in both the short and long terms ^[8]. The absence of a specific clinical characteristic or a reliable parameter of PE compels physicians to make a synthesis of clinical, biochemical, and imaging findings to confirm the diagnosis of PE ^[9]. The best solution would be to discover the ideal predictive marker for PE ^[10]. Larger PLTs produce more prothrombotic substances such as thromboxane A2, serotonin, b-thrombomodulin, p-selectin, and glycoprotein IIIa, which cumulatively can hyperactivate PLTs and subsequently accelerate their turnover ^[10]. Prior studies proved the association between increased MPV levels and coronary artery disease risk factors ^[11]. Undoubtedly, MPV is not specific for diagnosing PE; however, it may be useful in the initial estimation of PE risk ^[10]. The PLT indices (PLTs count, MPV, PDW, and PDW) were investigated for their diagnostic and prognostic values in PE ^[9].

The current study suggested that a higher MPV may be an independent predictor of PE in patients with DVT. Similar results regarding the role of MPV as a predictor have been reported in various CVDs and VTE ^[12],[13]. Moreover, Tromsø Study suggested that increased MPV may be a predictor for VTE of unprovoked origin with cutoff value of 9.5% ^[14]. Icli et al.^[15] reported that MPV is elevated in patients with DVT, and the higher MPV may be associated with PE with the cutoff point of 9.15%, which predicted the presence of PE with a sensitivity of 86% and specificity of 82%. In another retrospective study, MPV was significantly higher in patients with PE than in the control; the cutoff value was set at 8.45%, had a sensitivity of 88.7% and specificity of 50.0% ^[16]. In a retrospective study, it was reported that a 6.6% increase in admission MPV during follow-up provided 74% sensitivity and 83% specificity for the prediction of PE ^[7].

In the current study, we found that the cutoff level of MPV is higher than the previously mentioned studies. MPV is affected by several factors such as ethnicity, age, sex, and preanalytical influences ^[17]. This may explain the different cutoff values of MPV in these studies. The MPV reference intervals of an Egyptian study were 9.3–12.2 fl in females and 9.5–11.8 fl in males ^[18]. A single-center prospective recent study concluded that MPV may be considered useful as an adjunctive or independent predictive marker for PE ^[10]. Another recent study suggests that MPV and inflammatory markers like PLT-lymphocyte ratio are significantly higher in patients with newly diagnosed acute DVT compared with the control ^[19].

In contrast to our findings, some studies reported that MPV is not significantly elevated in PE, whereas others found the opposite ^[9]. Some case–control studies concluded that MPV did not differ between patients with PE and the controls ^[20],[21]. On the contrary, the MPV values were significantly lower in the PE group than in the healthy control group ^[9]. A case–control study suggested that PLT indices do not increase in patients with PE ^[22]. Another prospective study carried out at Minia University Hospital, Minia, Egypt, concluded that MPV is significantly higher in the PE group. The best cutoff value for MPV for the prediction of the RV dysfunction was more than 9.4 fl (sensitivity 46.7% and specificity 94.7%) ^[23].

In the current study, PDW was significantly higher in patients with PE than in patients with DVT at initial presentation (23.61 ± 9.15 vs. 20.10 ± 6.39 fl). Both groups have higher PDW than the control. PDW was significantly higher on day 7 in the PE group versus the DVT group. PDW was significantly higher in patients with DVT who developed PE than in DVT who did not develop PE (21 ± 4 vs. 19 ± 5 fl). The cutoff value of PDW for the prediction of PE is 17.5% with a sensitivity of 83% and specificity of 80%. The current results agreed with Çevik and colleagues who reported that PDW was significantly higher in patients with PE than in healthy controls ^{[9],[16],[24]}. Lin et al.^[7] reported that a 5.2% increase in admission PDW during follow-up provided 70% sensitivity and 82% specificity. Wang et al.^[25] reported that the combination of PLT microparticles, D-dimer, PDW, and P-selectin presents a novel noninvasive strategy for the diagnosis of PE with high sensitivity and specificity. Abd El-Ghany et al.^[23] reported that PDW was significantly higher in acute PE than in other patients, and the best cutoff value for PDW was more than 15.85% (sensitivity 75%; specificity 65.9%). Moharamzadeh et al.^[22] reported that PLT indices did not increase in patients with PE in contrast to the aforementioned studies.

In the current study, PCT was not significantly different in PE and DVT groups, whereas PCT was significantly higher in both the PE group and DVT group versus the control group at the initial presentation. Moreover, PCT was significantly different between patients with DVT who developed PE and who did not. We disagreed with Varol et al.^[26] who reported that patients of PE had normal PCT. A prospective case–control study, the RETROVE study, indicated that the independent risk of VTE attributed to PCT seems to be sex specific to females only ^[27]. Another suggested mechanism for the increased PLT activity in PE is hypoxemia ^[28]. PLTs activated by abnormal venous blood flow may interact with erythrocytes endothelial cells, neutrophils, and monocytes and release fibrinogen, and other tissue factors resulting in venous thrombosis. Increased levels of P-selectin, expressed by large, activated PLTs, have been measured in patients with VTE, with high levels of circulating P-selectin being associated with increased risk of recurrent VTE ^[3],[15]. Chung et al.^[29] proposed that chronic elevation of soluble P-selectin for six or more months may predispose PLT activation in the initiation of PE. Although our study did not measure P-selectin, our findings are generally accordant with other previous studies and add strong support for the role of increased MPV being linked to the initiation of PE in patients with DVT. Thus, increased MPV may reflect more aggressive PLT behavior, with larger, hyperactive PLTs accelerating the formation and propagation of thrombus, leading to the occurrence of PE ^[15].

PLT count was significantly lower in the PE group than in the DVT group (225 vs. 248 × 10³/μl). Both groups had lower PLTs count than the control group. PLT count was also significantly lower in patients with DVT who developed PE than in DVT who did not develop PE (220 vs. 249 × 10³/μl). This lower PLT count in patients with PE might be due to the consumption of the PLTs ^[15]. PLT count was independent risk of VTE in females only ^[27]. Our study agreed with Cil et al. ^[30], who reported lower PLT count in DVT than the control group. Moreover, lower PLT count was documented in patients with PE ^[26]. PLT count was significantly lower among patients with DVT with and without PE when compared with the control group ^[15]. Another study reported that PLT count was not significantly different between patients with PE and the control group ^[23]. Some studies reported similar findings ^{[9],[20],[24],[28]}. On the contrary, PLT count was significantly higher among patients with DVT when compared with the control group (221.5 vs. 195.0 × 10³/μl, respectively) ^[31].

In the current study, WBCs were significantly higher in patients with PE than in patients with DVT than in the control group at initial presentation (12.69 ± 5.73 vs. 9.48 ± 2.78 × 10⁹/l). WBCs became lower on the seventh day in the PE group but were not statistically significant. WBC subtypes, especially neutrophils, play a key role in modulating the inflammatory response in the atherosclerotic process ^[32]. Higher WBCs at presentation may be linked to the acute stage of PE, so the count improved later ^[26].

In the current study, we detected that both MPV and PDW were significantly related to thrombus size in Doppler ultrasonography in patients with DVT. Moreover, the current study found both MPV and PDW strongly related to the level of obstruction of pulmonary vessels in CTPA for patients with PE. The current study found a significant correlation between increased values of both MPV, PDW, and RV dimensions, pulmonary pressure, cTnI level, and clinical severity in PE. Hypoxemia, renovascular disease (RVD), and RV failure, in association with impaired left ventricular filling and reduced cardiac output, are potent stimuli of PLT activation ^{[21],[23],[24]}. Vasoconstrictor mediators such as thromboxane release from PLTs may also augment pulmonary vascular resistance and promote RV ischemia and dysfunction ^[33]. Increased cTnI levels and their prognostic significance in acute PE were reported previously in many studies ^[34],[35]. Increased cTnI and MPV levels, in our study, were found in patients with PE with RVD. Increased MPV levels may be a contributing factor to myocardial injury, especially in PE patients with RVD. It is suggested that in addition to hemodynamics factors such as increased RV overload, hypotension, and hypoxemia, PLT activation can contribute to myocardial injury. Multiple studies reported a significant correlation between MPV and RV dysfunction ^[33],[36].

In the current study, D-dimer was higher in both DVT and PE groups than the control. It was significantly correlated to MPV and PDW. D-dimer has the most important role in the diagnosis of VTE. It has been demonstrated that tandem measurement of MPV and D-dimer was more beneficial in VTE exclusion for the diagnosis of PE ^[37].

In the current study, MPV was positively correlated to age but not correlated to sex. Factors like age, sex, race and ethnicity, lifestyle, and genetic factors may strongly influence MPV and PLT count. A high heritability of 84 and 75% for PLT count and MPV, respectively, was shown due to genetic variations ^[38],[39]. Data concerning the MPV value depending on sex are conflicting. Some authors identified higher MPV values in women ^[14],[40], whereas others in men ^[41]. Some studies failed to report any significant differences in MPV value between women and men ^[38],[42].

The present study showed a strong positive correlation between MPV and LDL level, and MPV negatively correlated to HDL. Moreover, PDW was significantly positively correlated to LDL and negatively correlated to HDL. This is indicative of increased PLT turnover in hyperlipidemia and assuming that larger immature PLTs predominate in this condition ^[43]. Few previous studies reported the association between MPV and dyslipidemia, that is, MPV was significantly larger in patients with hypercholesterolemia ^[44],[45] and low HDL ^[26]. PLT indices increased with increased total cholesterol; however, it was statistically insignificant. Triglyceride showed statistically significant correlation with MPV and PDW. PDW was significantly increased with LDL levels. However, MPV had no statistically significant correlation with LDL and HDL levels ^[46]. In contrast to a concurrent study, Sansanayudh et al.^[47] did not observe a significant association between MPV and serum cholesterol, LDL, or HDL.

Our study excluded obese patients whose BMI was more than or equal to 30, as we thought that MPV and PDW were not related to BMI less than 30. Coban et al.^[48] observed a mean MPV significantly higher in the group of obese women, in comparison with the nonobese group (P = 0.004). In the group of obese women, there was a positive correlation between the MPV and BMI (r = 0.43, P = 0.017) and the reduction of MPV and weight loss (r = 0.41, P = 0.024). On the contrary, Montilla et al.^[49] did not observe any significant difference in MPV values between the groups with and without abdominal obesity. MPV was significantly correlated to creatinine level in the PE group (P = 0.04), whereas MPV was not strongly correlated to creatinine in the DVT group and all cases (P = 0.39 and P = 0.1, respectively). This might be due to higher serum creatinine in the PE group, whereas in the DVT group, creatinine was in the normal range.

Conclusion

Our findings suggest that serial measurements of MPV, PDW, and PLT count appear to be a useful marker for predicting occurrence of acute PE in patients with the first episode of acute proximal DVT. Moreover, a single measurement of MPV and PDW at the presentation of patients with PE strongly related to clinical severity, CTPA finding, and RV dysfunction. Further prospective studies are needed to clarify the value of MPV and PDW in identifying the presence of PE in patients with the first episode of acute proximal DVT. The current study recommends continuous follow-up for all patients with DVT for the risk of development of PE. Further studies are needed to assess the value of PLT indices as predictors of the outcome, recurrence rates, and mortality in patients with PE.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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