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 Table of Contents  
ORIGINAL ARTICLE
Year : 2013  |  Volume : 38  |  Issue : 2  |  Page : 56-62

Correlation between platelet–monocyte aggregates and prevalence of vascular complications in type II diabetes


1 Department of Clinical and Chemical Pathology, Faculty of Medicine, Benha University, Benha, Egypt
2 Department of Clinical and Chemical Pathology, Faculty of Medicine, Zagazig University, Zagazig, Egypt

Date of Submission22-Nov-2012
Date of Acceptance11-Feb-2013
Date of Web Publication20-Jun-2014

Correspondence Address:
Howyda M. Kamal
Department of Clinical and Chemical Pathology, Faculty of Medicine, Benha University, 13511 Benha
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.7123/01.EJH.0000427963.62047.0a

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  Abstract 

Background

Platelet–monocyte aggregates (PMA) play an important role in the development of microvascular disease and atheromatous lesions. Increased numbers of circulating proinflammatory monocytes, activated platelets, and/or leukocyte–platelet aggregates have been observed in patients with chronic inflammatory conditions such as diabetes mellitus (DM).

Objective

The aim of the study was to investigate whether the circulating PMA levels were increased in patients with DM, whether they may be correlated to the vascular damage presently observed in DM, and whether PMA can be used as a simple marker for the early prediction of diabetic microvascular complications.

Patients and methods

We examined PMA in 15 apparently healthy normal individuals who were included as the control group A, in 19 patients with DM without microvascular injuries who constituted control group B, and in 59 patients with DM with microvascular injuries who constituted group C, admitted to Benha University hospitals. All groups were subjected to a full medical history taking, thorough clinical examination and laboratory investigations (complete blood counts and measurement of the levels of cholesterol, triglycerides, serum creatinine, HbA1c), and detection of CD14 (monocyte marker) and CD41 (platelet marker) using flow cytometry.

Results

There was a significant increase in the PMA% in patients with DM compared with the control group A, and it was increased in patients of group C compared with group B. Moreover, the study revealed that there was a significant positive correlation between the PMA% and glycemic state in patients with DM, represented by the HbA1c levels and a significant positive correlation between the PMA% and lipid state of patients (cholesterol and triglycerides).

Conclusion

Determination of levels of circulating PMA using flow cytometry can be used as a simple marker of microvascular injury in patients with DM.

Keywords: microvascular, macrovascular injury, monocytes, platelets, platelet– monocyte aggregates, type II diabetes


How to cite this article:
Zeidan MA, Rageh IM, Kamal HM, Esh AM. Correlation between platelet–monocyte aggregates and prevalence of vascular complications in type II diabetes. Egypt J Haematol 2013;38:56-62

How to cite this URL:
Zeidan MA, Rageh IM, Kamal HM, Esh AM. Correlation between platelet–monocyte aggregates and prevalence of vascular complications in type II diabetes. Egypt J Haematol [serial online] 2013 [cited 2019 Dec 9];38:56-62. Available from: http://www.ehj.eg.net/text.asp?2013/38/2/56/134789


  Introduction Top


Patients with diabetes mellitus (DM) presenting with acute coronary syndrome (ACS) have a higher risk of cardiovascular complications and recurrent ischemic events when compared with their nondiabetic counterparts. Different mechanisms including endothelial dysfunction, platelet hyperactivity, and abnormalities in coagulation and fibrinolysis have been implicated for this increased atherothrombotic risk. Platelets play an important role in atherogenesis and its thrombotic complications in diabetic patients with ACS 1.

DM is commonly associated with both microvascular and macrovascular complications and is associated with multiple disorders including metabolic, cellular, and blood coagulation disturbances, leading to many complications affecting various organs, such as kidney, retina, peripheral nerves, and microvascular and macrovascular compartments 2. DM is associated with a significant increase in the levels of numerous markers involved in coagulation and plasma factors leading to a hypercoagulable state 3. Platelets in patients with DM show important membrane expression of adhesive molecules, such as P-selectin, thrombospondin, GPIIb–IIIa (CD41), and CD62 4.

Glycoprotein IIb/IIIa (CD41) is an integrin complex found on the platelets. It is a receptor for fibrinogen and aids platelet activation. The complex is formed by a calcium-dependent association of GPIIb and GPIIIa, a required step during normal platelet aggregation and endothelial adherence 5.

When the endothelium is damaged, the normally isolated underlying collagen is exposed to the circulating platelets, which bind directly to collagen through collagen-specific glycoprotein Ia/IIa surface receptors. This adhesion is further strengthened by the von Willebrand factor , which is released from the endothelium and platelets; these adhesions also activate the platelets 6. Activated platelets undergo degranulation, after which they adhere to the circulating monocytes forming platelet–monocyte aggregates (PMA) 7. Consequently, the activated monocytes secrete several proinflammatory proteins and express a prothrombotic membrane phenotype 8.

Evidence proves that the platelet–monocyte interaction has a key role in the thrombotic pathogenesis. Thus, elevated levels of circulating PMA have been reported in various prothrombotic states such as DM 9. The aim of our study was to investigate whether the circulating PMA levels were increased in patients with DM, whether they may be correlated to the vascular damage presently observed in DM, and whether PMA can be used as a simple marker for the early prediction of diabetic microvascular complications.


  Patients and methods Top


Patients

This study was carried out on 15 apparently healthy normal individuals included as the control group A (age range 44–62 years, with the mean age of 54.7±5.9 years), 19 patients with type II diabetes without microvascular injuries who constituted control group B (age range 33–65 years, with a mean age of 55.7±9.8 years), and 59 type II diabetic patients with microvascular injuries constituting group C (age range 40–75 years, with a mean age of 56.8±8.3 years), who were regrouped according to the type of complications, admitted to Benha University Hospital between January and August 2011. A written informed consent was obtained from all the studied groups.

Patients were subjected to a full clinical examination including ophthalmological, cardiac, and neurological tests. The microvascular complications such as diabetic neuropathy, nephropathy, and retinopathy and macrovascular complications such as peripheral vascular diseases, myocardial infarction, and stroke were observed and recorded. Laboratory investigations included: a CBC (complete blood count), which was carried out using an automated blood counter (Sysmex KX 21N, Sysmex, New Jersey, USA); serum chemical analysis using a Biosystem A15 (Barcelona, Spain) which included a lipid profile [cholesterol, triglycerides levels (TG)] and determination of serum creatinine levels; determination of glycosylated hemoglobin (GHb or HbA1C) using the ion exchange resin method 10; and detection of CD14 (monocyte marker) and CD41 (platelet marker) using flow cytometry (FCM).

Microvascular and macrovascular complications were detected as follows: Diabetic retinopathy was diagnosed by a fundus examination performed by an ophthalmologist. Nephropathy was preceded by a lower degree of microalbuminuria (30–299 mg/24 h) but was followed by proteinuria of more than 500 mg in 24 h. Serum creatinine levels were determined for all the studied groups, especially for those patients who were diagnosed earlier at the nephrology unit with diabetic nephropathy. Diabetic neuropathy was defined by the presence of burning distal pain and loss of or reduction in sensation. Cardiac complications were diagnosed by the cardiologist.

Methods

Sample collection


For each patient, 5 ml venous blood was drawn as follows: 2 ml using EDTA (1.2 mg/ml) as an anticoagulant, to be used for performing CBC and for detection of CD14 and CD41 using FCM, and 3 ml blood was taken in a plain tube and then centrifuged for 10 min. The resultant serum was used for clinical chemical analysis.

Reagents

Phycoerythrin (PE)-labeled monoclonal antibody (MoAb) against platelet glycoprotein IIb (anti-CD41 PE) and fluorescein isothiocyanate (FITC)-labeled MoAb against monocytes (anti-CD14 FITC) were purchased from Becton Dickinson (Becton Dickinson, Franklin Lakes, New Jersey, USA). The whole blood PMA were monitored according to the procedure described by Li et al. 11. Circulating PMA were quantified using a flow cytometer (Becton Dickinson). The flow cytometric analysis was performed using the CellQuest software (Becton Dickinson).

Immunophenotyping of platelet–monocyte aggregates

The staining procedure for the surface markers was as follows: For each sample, two tubes were prepared (test and control). A volume of 50 μl of venous blood was dispensed into each tube; 10 μl of each MoAb was added, specific PE-labeled MoAb against platelet glycoprotein IIb (ant-CD41-PE) and FITC-labeled MoAb against monocyte CD14 (anti-CD14 FITC), to the test tube only. The tubes were vortexed and then incubated for 20–30 min in the dark at room temperature. A volume of 1 ml of the lysing solution (NH4Cl 1.5 mmol/l, KHCO3 100 mmol/l, and tetrasodium EDTA 10 mmol/l, made up to 1 l with distilled water, and pH adjusted to 7.2) diluted to 1×10 was added to each tube and mixed well by vortexing; the tubes were then incubated for 10 min in the dark at room temperature. The tubes were centrifuged at 1200 rpm for 5 min, and then the supernatant was discarded. A volume of 2 ml of PBS [NaCl 8.5 mmol/l, NaHPO4 (anhydrous) 1.07 mmol/l, and NaH2PO4·2H2O 0.39 mmol/l, made up to 1 l with distilled water, and pH adjusted to 7.4] was added, as a wash buffer, to each tube and mixed well. The tubes were centrifuged at 1200 rpm for 5 min, and then the supernatant was discarded. The tubes were washed twice. The cells were suspended in 500 μl of PBS and analyzed using FCM. If the tubes were not analyzed within 2 h, 0.5 ml of a fixative (4 g paraformaldehyde in 100 ml PBS with 0.1% sodium azide, pH 7.4) was added, and the tubes were kept at 4°C in a dark room until analysis within 24 h.

Sample analysis on a flow cytometry

A minimum of 10 000 events were studied. Cells stained with anti-CD41/anti-CD14 MoAb were identified as PMA. PMA were evaluated as the percentage of total monocytes carrying the platelet marker (anti-CD41 PE).

Typical flow cytometric plots for CD 14 and CD 41 double staining are shown in [Figure 1]. A majority of the cells in the monocyte gate were CD 14-positive. Thus, CD14 staining was omitted for analyzing the samples in this study. The positive analysis region was determined using the isotypic controls. The percentage of monocyte–platelet aggregates was determined as the coexpression of CD14 and CD41 in the upper right region of the dot plot histograms.
Figure 1: Flow cytometric analysis of platelet–monocyte aggregates (PMA). Blood samples were double-stained with CD14 FITC (monocyte marker) and CD41 PE (platelet marker). Monocytes were identified by their characteristic light scattering properties (a), and PMA were analyzed for the coexpression of positive CD14 and CD41 (b).

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Statistical analysis

The collected data were tabulated and analyzed using the SPSS software, version 16 (Chicago, Illinois, USA). Categorical data were presented as number and percentages, whereas quantitative data were expressed as mean and SD. The χ2-test, Student’s t-test, analysis of variance (F) test, and ‘r’ (Pearson’s product correlation coefficient) were used as tests of significance. The accepted level of significance in this study was 0.05 (P<0.05 was considered significant).


  Results Top


In this study, we found that there was no statistically significant difference between the control group and diabetic groups as regards age, sex, red blood cell count, platelet count, absolute monocyte count, and gated monocyte percentage (P>0.05). The mean values of the white blood cell count, levels of creatinine level triglycerides, cholesterol, and HbA1c, and PMA% (P<0.05, P<0.05, P<0.001, P<0.001 and P<0.001, and P<0.05, respectively) were significantly higher in the diabetic groups compared with the control group. The mean values of the Hb levels were lower in the diabetic groups when compared with the control group, and these differences were statistically significant (P<0.05) [Table 1].
Table 1: Comparison between the control group and the patients with diabetes as regards the clinical and laboratory data

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Moreover, there was no statistically significant difference between group B and C as regards age, sex, CBC results, absolute monocyte count, and gated monocyte percentage (P>0.05). The mean value of the duration of disease, levels of HbA1c, triglycerides, cholesterol, and creatinine, and PMA% was higher in group C compared with group B, and this difference was statistically highly significant (P<0.001, P<0.001, P<0.01, P<0.05, P<0.05, and P<0.05, respectively) [Table 2].
Table 2: Comparison between the studied diabetic groups (group B and group C) as regards the clinical and laboratory data

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As shown in [Table 3], there was no statistically significant difference between the patients of group C as regards age, duration of DM, CBC results, levels of triglycerides, cholesterol, and HbA1c, absolute monocyte count, and gated monocyte percentage (P>0.05). However, there was a significant difference between the groups as regards the creatinine levels, wherein the highest level was observed in patients with nephropathy and the lowest level was observed in those with ischemic heart disease (P<0.001). There was a significant difference between the groups as regards the PMA%, wherein the highest level was observed in patients with retinopathy and the lowest level was observed in those with neuropathy (P<0.001). The correlation between the PMA% and different parameters is shown in [Table 4]. A statistically significant positive correlation between the PMA% and levels of HbA1c, cholesterol, and triglycerides, duration of disease, and absolute monocyte count was found among the diabetic groups (P<0.05, P=0.01, P=0.01, P<0.05, and P<0.01, respectively). The correlation between the PMA% and duration of disease, absolute monocyte count, and HbA1c levels is shown in [Figure 2], [Figure 3] and [Figure 4].
Figure 2: Correlation between the PMA% and duration of disease in the diabetic groups. PMA, platelet–monocyte aggregates.

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Figure 3: Correlation between the PMA% and absolute monocyte count in the diabetic groups. PMA, platelet–monocyte aggregates.

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Figure 4: Correlation between the PMA% and HbA1c in the diabetic groups. PMA, platelet–monocyte aggregates.

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Table 3: Comparison between clinical and laboratory data among the patients of group C

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Table 4: Correlation between the PMA% and different parameters among the diabetic groups

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  Discussion Top


Platelets play a major role in the hemostatic process, and increased platelet activation and aggregation are the center of the pathophysiology of arterial thrombosis 12. Patients with DM have increased atherothrombotic risk and recurrent ischemic events after ACS, despite being on currently recommended dual antiplatelet therapy, when compared with the nondiabetic population. This may partly be due to abnormal endothelial function, abnormal platelet hemostasis resulting in platelet hyperactivity, and dysregulation in the coagulation processes 1. In this study, we have investigated whether the circulating PMA levels were increased in patients with DM, whether they may be correlated to the vascular damage presently observed in DM, and whether PMA can be used as a simple marker for early prediction of diabetic microvascular complications.

The present study showed that there was a significant decrease in the Hb levels in patients with DM compared with the control group. Anemia is a common complication of DM, particularly in patients with diabetic kidney disease. Many factors have been suggested as the reason for the earlier onset of anemia in patients with DM, including severe symptomatic autonomic neuropathy that causes efferent sympathetic denervation of the kidney and loss of appropriate erythropoietin (Epo) production, damage to the renal interstitium, systemic inflammation, and inhibition of Epo release 13,14. Other probable causes might be nutritional deficiencies that may or may not be directly caused by DM but often can result in anemia and the use of some medications in the treatment of DM such as metformin (Glucophage) that can increase the risk of developing anemia by interfering with vitamin B12 absorption and may lead to a mild B12 deficiency 15.

In the present study, a significant increase was observed in the creatinine levels in the diabetic groups compared with the control group and in group C compared with group B. This occurs as a result of pathological changes in the kidney, as the progression of diabetic nephropathy starts during the early course of DM, leading to increased glomerular basement membrane thickness and microaneurysm formation 16.

Laboratory data of the diabetic groups showed a statistically significant higher level of HbA1c in the diabetic groups compared with the control group and in group C (with vascular complications) compared with group B (without vascular complications), suggesting that most of the studied patients had a poor glycemic control. This is in agreement with reports of the International Expert Committee 17. Koeing et al. 18 reported that the formation of HbA1c is nonenzymatic, formed by the condensation between glucose and the N-terminal valine amino acid of each β-globin chain, and occurs over the life span of red blood cells (about 120 days). Therefore, the formation of HbA1c depends on the time-averaged glucose concentration over the 2–3 months before the measurement. Selvein et al. 19 reported that glycated hemoglobin was superior to fasting glucose for assessment of the long-term risk of subsequent cardiovascular disease, especially at values above 6.0%. The results of Cipolletta et al. 20 showed that monocytes from patients with high levels of HbA1c demonstrated a significantly increased ability to attach to endothelial cells, which is one of the early steps leading to atheroma formation.

This study revealed a significant increase in the levels of cholesterol and triglycerides in patients with DM compared with the control group and in group C compared with group B. These factors collectively in a chronic manner (prolonged duration) affect normal endothelial production of nitric oxide by chronic impairment of the nitric oxide synthase enzyme activity in patients with DM, leading to the loss of its important role in preventing vascular disease 21. Moreover, hypercholesterolemia enhances the tendency of platelets to aggregate and reduces the production of nitric oxide, leading to interactions between blood platelets and the vascular endothelium and between platelets and monocytes, forming PMA 22. Wolf et al. 23 reported a significant positive correlation between the PMA% and duration of DM, levels of HbA1c, cholesterol, and triglycerides, and the absolute monocyte count. Elalamy et al. 24 established a relationship between the increased circulating PMA and incidence of microvascular injury observed in patients with DM.

The present study demonstrated a significant increase in the levels of circulating PMA in the diabetic population compared with controls and in group C (diabetics with microvascular complications) compared with group B (diabetics without microvascular complications), suggesting the involvement of inflammatory monocytes in vessel damage. Cipolletta et al. 20 demonstrated that peripheral blood CD14 monocytes in patients with poorly controlled DM are functionally activated and show some of the differentiation markers associated with macrophages (CD36 and CD68). Of major importance is the fact that the monocytes demonstrate an increased ability for endothelial cell attachment, one of the early stages in atheroma formation. This result is in accordance with the findings of Hu et al. 25.

Platelet activation occurs mainly because of increased levels of platelet-derived thromboxane and prostaglandin metabolites detected in patients with DM. Platelets have been recognized as having a major role in inflammation, hemostasis, and thrombosis, being the source of inflammatory mediators and being able to both produce and respond to chemoattractant cytokines 26. The binding of platelets or platelet-derived microparticles to monocytes in ACS is one of the clues to the interaction of inflammation and thrombosis: when inflammation begets local thrombosis, this in turn exacerbates inflammation, resulting in a vicious circle 27.

The interactions between platelets and monocytes are increased in DM. These aggregates are formed when platelets are activated and degranulated, after which they adhere to circulating monocytes forming PMA 7. PMA formation has proinflammatory effects, linking coagulation and development of atherosclerosis. Proatherogenic activity of monocytes and circulating levels of soluble cell adhesion molecules are more pronounced in DM. Devaraj and Jialal 28 previously reported that monocytes from type II diabetic patients exhibit increased proatherogenic activity compared with matched controls. Ueno et al. 29 suggested that a lower responsiveness to insulin occurs in patients with type II DM, leading to increased platelet adhesion, aggregation, and procoagulant activity.

In the study by Michelson et al. 30, it was demonstrated by three independent methods that circulating monocyte–platelet aggregates are more sensitive markers of in-vivo platelet activation compared with platelet surface P-selectin, which was (generally) considered to be the gold standard marker of platelet activation 31.


  Conclusion Top


According to the results obtained from the present study, which are supported by previous studies, it is clear that PMA levels were increased in patients with DM and even more increased in patients suffering from the complications of DM; therefore, we can use PMA as a simple marker for early prediction of diabetic microvascular complications. Further studies are needed to investigate whether PMA can also be used as a marker for the early prediction of thrombotic lesions in diseases other than DM, such as acute myocardial infarction, sickle cell disease, and acute and subacute ischemic stroke.[31]

 
  References Top

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8.Hidari KI, Wevrich AS, Zimmerman GA, McEver RP. Engagement of P-selectin glycoprotein ligand-1 enhances tyrosine phosphorylation and activates mitogen-activated protein kinases in human neutrophils. J Biol Chem. 1997;272:28750–28756  Back to cited text no. 8
    
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13.Bosman DR, Winkler AS, Marsden JT, Macdougall IC, Watkins PJ. Anemia with erythropoietin deficiency occurs early in diabetic nephropathy. Diabetes Care. 2001;24:495–499  Back to cited text no. 13
    
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17.. International Expert Committee Report on the Role of the A1C assay in diagnosis of diabetes. Diabetes Care. 2009;32:1–18  Back to cited text no. 17
    
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23.Wolf A, Zalpour C, Theilmeier G, Wang BY, Ma A, Anderson B, et al. Dietary L-arginine supplementation normalizes platelet aggregation in hypercholesterolemic humans. J Am Coll Cardiol. 1997;29:479–485  Back to cited text no. 23
    
24.Elalamy I, Chakroun T, Gerotaziafas GT, Petropoulo A, Robert F, Karroum A, et al. Circulating platelet-leukocyte aggregates: a marker of microvascular injury in diabetic patients. Thromb Res. 2008;121:843–848  Back to cited text no. 24
    
25.Hu H, Li N, Yngen M, Ostenson CG, Wallén NH, Hjemdahl P. Enhanced leukocyte–platelet cross talk in type 1 diabetes mellitus: relationship to microangiopathy. J Thromb Haemost. 2004;2:58–64  Back to cited text no. 25
    
26.Weber C. Platelets and chemokines in atherosclerosis: partners in crime. Circ Res. 2005;96:612–616  Back to cited text no. 26
    
27.Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation. 2005;111:3481–3488  Back to cited text no. 27
    
28.Devaraj S, Jialal I. Low-density lipoprotein postsecretory modification, monocyte function, and circulating adhesion molecules in type 2 diabetic patients with and without macrovascular complications: the effect of alpha-tocopherol supplementation. Circulation. 2000;102:191–196  Back to cited text no. 28
    
29.Ueno M, Ferreiro JL, Tomasello SD, Capodanno D, Tello-Montoliu A, Kodali M, et al. Functional profile of the platelet P2Y12 receptor signaling pathway in patients with type 2 diabetes mellitus and coronary artery disease. Thromb Haemost. 2011;105:730–732  Back to cited text no. 29
    
30.Michelson AD, Barnard MR, Krueger LA, Valeri CR, Furman MI. Circulating monocyte-platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin. Circulation. 2001;104:1533–1537  Back to cited text no. 30
    
31.Michelson AD, Furman MI. Laboratory markers of platelet activation and their clinical significance. Curr Opin Hematol. 1999;6:342–348  Back to cited text no. 31
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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