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 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 40  |  Issue : 4  |  Page : 177-184

Tissue factor-positive monocytes in children with sickle cell disease: relation to vaso-occlusive crisis


1 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Pediatrics, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission05-Aug-2015
Date of Acceptance08-Aug-2015
Date of Web Publication23-Nov-2015

Correspondence Address:
Seham M Ragab
Menouf 7th, El-Hadetha Street, 32511 Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-1067.170203

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  Abstract 

Background Hemostatic abnormalities are well documented in sickle cell disease (SCD). Nevertheless, whether these perturbations could contribute toward sickle vasculopathy is still not clear.
Aim To evaluate tissue factor (TF) expression (CD142) on monocytes in children with SCD and correlate the results with the clinical state and some inflammatory and coagulation activation markers.
Patients and methods This study included 24 children with SCD in steady state, 24 in painful crisis, and 20 healthy age-matched and sex-matched children as controls. The relevant data including the pain rate were retrieved from patients' files. For each participant, complete blood count, prothrombin time (PT%), activated partial thromboplastin time (aPTT), fibrinogen, d-dimer, thrombin-antithrombin complex, and quantitative C-reactive protein were assayed. TF expression on monocytes was analyzed by flow cytometry.
Results TF-positive monocytes were significantly higher in both patient groups compared with the controls, being higher in patients in painful crisis (2.06 ± 0.64, 8.01 ± 1.53, and 13.5 ± 4.3 for the controls, steady-state group, and the painful crisis group, respectively, P < 0.0001 in all comparisons). The same pattern was found for all tested inflammatory and coagulation markers, except PT and aPTT. In the painful crisis group, TF monocytes expression was correlated positively with the pain rate and all markers of inflammation and coagulation, except PT, aPTT, and thrombin-antithrombin complex, with an inverse correlation with hemoglobin and red blood cells.
Conclusion Collectively, these results confirm the prognostic significance of evaluation of TF-positive monocytes in SCD children.

Keywords: coagulation markers, inflammatory biomarkers, sickle cell disease, tissue factor-positive monocytes


How to cite this article:
Soliman MA, Ragab SM. Tissue factor-positive monocytes in children with sickle cell disease: relation to vaso-occlusive crisis. Egypt J Haematol 2015;40:177-84

How to cite this URL:
Soliman MA, Ragab SM. Tissue factor-positive monocytes in children with sickle cell disease: relation to vaso-occlusive crisis. Egypt J Haematol [serial online] 2015 [cited 2019 Dec 14];40:177-84. Available from: http://www.ehj.eg.net/text.asp?2015/40/4/177/170203


  Introduction Top


Sickle cell disease (SCD) is an inherited hemolytic anemia characterized by a hypercoagulable state [1] .

Tissue factor (TF) is a transmembrane protein that binds plasma factor VII/VIIa. The TF-FVIIa complex acts as the physiological initiator of blood coagulation by activating both factor X and factor IX, leading to the generation of thrombin and fibrin deposition [2] . Abnormal TF expression on circulating endothelial cells has been found in patients with SCD and is increased during pain episodes [3] . TF antigen and TF procoagulant activity are elevated in the circulation of SCD patients compared with that in healthy controls [4] .

Hemostatic abnormalities including thrombin generation, as indicated by elevated levels of the prothrombin fragment F1+2 (a measure of conversion of prothrombin into thrombin); thrombin-antithrombin (TAT) complexes (a measure of thrombin formation); and d-dimer (a measure of formation and degradation of cross-linked fibrin) have been documented in SCD [5] .

Although laboratory and clinical evidence shows hemostatic abnormalities in SCD, the mechanisms accounting for the initiation or the modulation of this process need to be clarified further.

We evaluated TF (CD142) expression on SCD children monocytes by correlating the results with some inflammatory and coagulation activation markers.


  Patients and methods Top


The present study was carried out in the period between November 2013 and December 2014. The patients were recruited from the Hematology and Oncology Unit, Pediatric Department. The laboratory work-up was performed at the Clinical Pathology Department, Faculty of Medicine, Menoufia University.

Informed consent was obtained from the legal guardians of the children included and ethical clearance from the Faculty of Medicine Menoufia University ethical committee was obtained before the study was initiated.

Patients

The study was carried out on three groups:

  1. Patient group (A) included 24 children with SCD in steady state. These patients were enrolled during outpatient visits and were confirmed to have baseline pain scores (which were maintained for at least 6 months before the evaluation). There were 15 males and nine females; their ages ranged from 3 to 12 years, mean age 7.42 ± 3.29 years.
  2. Patient group (B) included 24 children with sickle disease in acute painful crisis at the time of evaluation. There were 12 males and 12 females; their ages ranged from 3.5 to 12 years, mean age 7.22 ± 2.78 years.


For all the SCD children included, patients' records were reviewed to determine hydroxyurea use and number of admissions within the past year. All the SCD children included were receiving hydroxyurea therapy.

Exclusion criteria of the patient group included the following: red blood cell (RBC) transfusions within the last 4 weeks; use of anticoagulation; chronic use of steroids or NSAIDs medication; and diagnosis of end-stage renal disease or creatinine more than 2.0 mg/dl.

  1. The control group included 20 normal children and adolescents matched for age and sex. There were 10 males and 10 females. Their ages ranged from 5 to 12 years, mean age 7.6 ± 2.06 years. Any individual with pallor, abnormal complete blood count (CBC) findings, a history of blood transfusion, or a family history of any type of chronic hemolytic anemia including SCD were excluded.


For all individuals, the following were performed:

  1. Full assessment of history including the pain rate (in the patient group) defined according to Bonds [6] as the average number of days of hospital stay because of painful episodes or days of extreme relevant illness at home from the patient's own calendar during the last year. History of blood transfusion frequency and amount was considered by calculation of the RBC transfusion index (TI) in ml/kg/year.
  2. Thorough clinical examination.
  3. Routine laboratory investigations: complete blood cell count and reticulocytes, coagulation profile including prothrombin time (PT) and %, activated partial thromboplastin time (aPTT) and fibrinogen, d-dimer, TAT complex, quantitative C-reactive protein (CRP), and serum ferritin were performed. For the patient group, the mean yearly serum ferritin at an average of four determinations/year was calculated.
  4. Detection and quantification of TF (CD142) expression on monocytes by flow cytometry.


Sampling collection and preparation

Blood sample

A venous blood sample was withdrawn from each individual under aseptic conditions and dispensed into three tubes: 2 ml of blood was stored in a tube containing K-EDTA for CBC and flow cytometry.

Another 2 ml of blood was stored in a plain tube in which serum was separated by centrifugation on 3000 rpm for 10 min and used for the assessment of CRP and serum ferritin. Finally, 1.8 ml of blood was stored in a tube containing 0.2 ml 3.2% trisodium citrate. Platelet-poor plasma was prepared by a first centrifugation at 3500 g for 15 min, followed by a second centrifugation of the plasma at 9500 g for 10 min. The resulting platelet-poor plasma samples were then divided into two parts: 0.5 ml for coagulation studies and 0.5 ml (for TAT measurement) aliquots, and stored at −80°C. All samples were thawed in water (room temperature) before running the TAT test.

Analytic methods

  1. CBC including reticulocytic count using a Pentra-80 automated blood counter (ABX, Francoville, France). Reticulocytes were counted using the manual method.
  2. Coagulation profile: samples obtained in sodium citrate anticoagulant were used for coagulation studies. Coagulation tests were performed using a stago full automated instrument (STA compact; Diagnostica Stago S.A.S., France), using commercial reagents, and following the standard procedures for each test.


D-dimer was assessed using kits supplied by the PATHFAST d-dimer assay (Mitsubishi Chemical Europe, Dόsseldorf, Germany). The principle is based on a chemiluminescence immune assay and the magtration methodology.

  1. Levels of the TAT complex in collected stored citrated plasma were measured using a commercial enzyme-linked immunosorbent assay (Enzyme Research Laboratory, South Bend, Indiana, USA).
  2. CRP was determined in the serum using a Beckman Coulter AU480 full automated auto analyzer (kits provided by Beckman Coulter, Inc., Brea, California, USA).
  3. Serum ferritin was measured by ST AIA PACK FER (AIA 360), which is a two-site immunoenzymometric assay, by Tosoh Corporation (Tokyo, Japan).
  4. Flow cytometry analysis of TF (CD142) expression on peripheral monocytes by BD FACS Calibur; BD Immune-Cytometry Systems, San Jose, California, USA.


Monoclonal antibodies

Fluorescein isothiocyanate-conjugated (FITC) antihuman antibodies against CD14 were used [FITC mouse monoclonal MEM-15, phycoerythrin (PE)-conjugated mouse monoclonal antihuman CD142 PE clone: HTF-1 (immunoglobulin G); Immunogen BD PharMingen, San Diego, California, USA].

Principle of the test

Isolation of peripheral blood mononuclear cells: 2 ml of Ficoll was placed in a centrifuge tube and layered by 1 ml of blood sample on top and subjected to centrifugation at 1800 rpm for 20 min; then, white blood cells (WBCs) were isolated by Ficoll gradient. The cell suspension was washed three times in PBS with the centrifuge for 5 min at 3200 rpm. For labeling of monocytes, 100 μl cells suspension in PBS was incubated with 10 μl-FITC conjugated anti-CD14 antibodies and costained with 10 μl of PE anti-CD142. The samples were incubated with the antibodies for 30 min at +4°C and subsequently washed with 3 ml PBS twice. Expressions of CD14 and CD142 were analyzed using a fluorescence-activated cell sorter (FACS Calibur; BD Immune-Cytometry Systems).

FITC, PE-conjugated mouse immunoglobulin G antibodies were used as isotype controls for the quantification of background fluorescence. All time points of WBCs preparations for one patient were stained and quantified on the same day. Cells of 100 μl were run in a separate tube as autocontrols without any stain as a control for analysis.

Flow cytometric analysis

Data were acquired on a FACS caliber flow cytometer (BD Immune-Cytometry Systems). The instrument setup was checked weekly using QC windows beads (Flow Cytometry Standard, San Juan, Puerto Rico, USA). Forward scatter and side scatter measurements were performed using linear amplifiers and fluorescence measurements were performed with logarithmic amplifiers and flow cytometric; two parameters, dot plots and quadrant statistics, were generated by cell quest software (Becton Dickinson Immune-Cytometry Systems).

Analysis was carried out after manual gating around a monocyte (CD14 positive) population on a (PE) scatter versus the side scatter dot plot. Results were expressed as percentages of cells positive for CD14 and CD142 ([Figure 1]).
Figure 1 Flow cytometry gating strategy for analysis of the tissue factor (TF) expression on monocytes in the groups studied. (a) Forward against side scatters histogram for peripheral blood (mononuclear cells) with gating on monocytes. (b) Analysis of monocytes in terms of TF (dual histogram CD14 FITC/CD142 PE) in healthy controls (2.41% positive TF monocytes). (c) Analysis of monocytes in terms of TF (dual histogram CD14 FITC/CD142 PE) in patients in steady state (7.92% positive TF monocytes). (d) Analysis of monocytes in terms of TF (dual histogram CD14 FITC/CD142 PE) in patients during vaso-occlusive crises (12.7% positive TF monocytes). FITC, fluorescein isothiocyanate-conjugated; PE, phycoerythrin.

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Statistical analysis

The data were processed on an IBM-PC compatible computer using SPSS, version 18 (SPSS Inc., Chicago, Illinois, USA). Continuous parametric variables were presented as means ± SD, whereas for categorical variables, numbers (%) were used. The χ2 -test was used for qualitative variables. The difference between two independent groups was determined using student's t-test and the Mann-Whitney (U) test for parametric continuous variables and nonparametric variables, respectively. For more than two groups, the one-way analysis of variance test was used for parametric data and the Kruskal-Wallis test was used for nonparametric variables. Pearson correlation (r) was the test used to measure the association between two quantitative parametric variables and the Spearman correlation coefficient was used for nonparametric data. P-value less than 0.05 was considered statistically significant.


  Results Top


Comparisons of the clinical and laboratory parameters between the groups are presented in [Table 1]. The three groups were matched in age and sex. SCD children in painful crisis had a significantly higher pain rate and significant RBCs TI compared with those in steady state. Both patient groups had significantly lower hemoglobin (Hb) and RBCs count with significantly higher mean yearly serum ferritin, reticulocytes (%) WBCs, and CRP compared with the controls. Although a nonsignificant difference was found between the patient groups in Hb level, other CBC parameters, serum ferritin, and CRP were significantly higher in those in painful crisis. PT did not differ between the patient groups or between each in comparison with the controls. aPTT was significantly higher in patients in crisis compared with the controls, without a significant difference between the patient groups or between those in steady state and the controls. Both patient groups had significantly higher fibrinogen (mg/dl), TAT, d-dimer, and TF on monocytes compared with the controls, with these parameters being higher in those in painful crisis.
Table 1 Comparison of clinical and laboratory parameters between the groups studied


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The correlation analysis among SCD children is presented in [Table 2]. In the steady-state group, TF-positive monocytes showed a significant positive correlation with WBCs, whereas among patients in crisis, TF expression on monocytes showed a significant correlation with all of the tested parameters, except age, PT, partial thromboplastin time, and TAT ([Figure 2]).
Figure 2 Correlation analysis between TF monocytes expression and the tested parameters among sickle cell patients in painful crisis. (a) TF expression on monocytes (%) shows a significant positive correlation with the pain rate in the past year (days/year) (r = 0.43, P = 0.04). (b) TF expression on monocytes (%) shows a significant negative correlation with the Hb level (g/dl) (r = −0.6, P = 0.002). (c) TF expression on monocytes (%) shows a significant positive correlation with the mean yearly serum ferritin (ng/ml) (r = 0.54, P = 0.008). (d) TF expression on monocytes (%) shows a significant positive correlation with CRP (mg/l) (r = 0.74, P < 0.0001). (e) TF expression on monocytes (%) shows significant positive correlation with the D-dimer (ng/ml) (r = 0.69, P < 0.0001). (f) TF expression on monocytes (%) shows a significant positive correlation with the fibrinogen level (mg/dl) (r = 0.62, P = 0.001). CRP, C-reactive protein; TF, tissue factor

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Table 2 Correlations between TF monocytes expression and the tested parameters among sickle cell patients


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  Discussion Top


SCD is a chronic disorder with a complex pathophysiology. It is considered an inflammatory disease characterized by chronic hemolysis [7] . In this respect, the hemolytic process was evident because of the lower Hb and higher reticulocytic count (%) in the SCD children studied.

An increased level of reticulocytes was considered a normal bone marrow response to underlying hemolytic disease or tissue hypoxia, which is markedly increased in SCD [8] . However, reticulocytes are associated with a risk of vaso-occlusive accidents as it enhances RBCs adhesion to vascular endothelium [9] . This was apparent in the SCD children in painful crisis studied, who had higher reticulocytes percentage compared with those in the steady state.

Platelets are an important pathophysiological player in SCD. Its activation is an important factor in the pathogenesis of vaso-occlusive events [10] . Consistent with this, we detected a significantly higher platelet count in SCD children during painful crisis compared with those in steady state.

SCD is characterized by a chronic inflammatory state [11] . Elevated leukocyte counts, CRP, and abnormal activation of granulocytes, monocytes, and endothelial cells were documented in SCD [12] . Leukocytosis among SCD patients has been reported previously, but without a known explanation [13] . There was a strong association of elevated leukocyte count with pain and acute chest syndrome [14] . Furthermore, leukocytosis with WBC count more than or equal to 15 100/μl correlates with clinical severity and early death [15] . We detected leukocytosis in both SCD groups, being higher in those in painful crisis.

The role of CRP as a plasma biomarker for low-grade systemic inflammation has been investigated intensively for its predictive associations with adverse outcomes in vascular diseases [16],[17],[18],[19] . CRP is produced in the liver as part of the acute-phase reaction in response to proinflammatory cytokines [20] . Circulating CRP levels are determined solely by the rate of synthesis, and thus reflect the presence and strength of pathological stimuli at the time of evaluation [21] .

In this respect, both the SCD groups studied had significantly higher CRP, being higher in the children in crisis, results that could confirm what was documented previously that from a broad panel of inflammatory markers, CRP was the most significant correlate of hospitalizations for painful episodes in SCD [22] .

We found a significantly high fibrinogen level in SCD children compared with controls, a difference that was more obvious in patients with vaso-occlusive crisis. These findings reflect the wide spectrum of hemostatic abnormalities observed in these patients. Similar findings have also been reported by other researchers [23] .

Although the basic physiological function of fibrinogen in hemostasis is the formation of a fibrin network, it is also a major determinant of whole-blood viscosity [24] . The increased fibrinogen level observed in these patients may be because of increased production as a reactive process probably in response to the chronic hemolytic process [25] . Fibrinogen may or may not be a contributory factor toward the pathogenesis of vaso-occlusive crisis, but as its increases significantly with increasing disease severity, fibrinogen level estimation can be performed to monitor the progression of sickle cell pain crisis [26] .

TAT and d-dimer are known thrombin generation markers and were measured as final markers of coagulation activation [27] . Our results indicated an increase in TAT and d-dimer in SCD children compared with the control group. Again, these two parameters were higher in the crisis group. This is in agreement with what was reported by other authors [27],[28] .

In this study, we found a significant difference in aPTT in SCD during painful crisis compared with normal controls, but we did not find such significance for PT. Buseri et al. [26] . reported either elevated PT or both PT and aPTT levels in SCD patients. The authors speculated that subclinical hepatic injury resulting in decreased synthesis of clotting factors or synthesis of dysfunctional clotting factors may be a possible reason for the prolonged aPTT values observed. Increased consumption of coagulation factors is another alternative plausible explanation.

There is a growing body of evidence suggesting a potential role of a TF-mediated mechanism in a pronounced hypercoagulable prothrombotic state among SCD patients [29],[30] .

In this study, we found the presence of increased numbers of circulating TF-positive monocytes in patients with SCD compared with the normal children that was significantly increased in those during vaso-occlusive crisis. The same results were found in previous studies [31],[32] . In addition, Solovey et al. [33] found that endothelial expression of TF in the SCD murine model may also be a source of circulating cell-associated TF activity. However, other researchers [29],[34] did not identify TF-positive microparticles in patient samples. The authors speculated that differences in sample centrifugation for microparticles assessment may have potentially contributed toward the divergent results.

In the same way, previous studies have reported elevated plasma TF antigen levels in SCD [4],[30] .

Belcher et al. [35] had documented that coincubation of sickle monocytes with endothelial cells can induce TF expression. They suggested that cytokines released during the coincubation may be the actual cause of TF expression on monocytes.

It was suggested that hem, a product of intravascular hemolysis, induces the expression of functionally active TF on both microvascular and macrovascular endothelial cells in vitro, which clarified the critical role of hemolysis in SCD-related pathology [36] .

Hypoxia and reoxygenation cycles of ischemia-reperfusion injury could cause enhanced endothelial TF expression I in an animal study [33] .

Increased expression of TF among patients in crisis compared with those in steady state - found in this work - lends good support to the suggested role of the hypercoagulability state in the pathophysiological process of vaso-occlusion in SCD [28],[37] .

For more clarification of the suggested role of hypercoagulability markers, especially TF-positive monocytes in SCD pathophysiology, a correlation analysis was carried out.

In the steady-state group, TF-positive monocytes correlated directly only with WBCs. In agreement with our data, Setty et al. [32] found a positive correlation between TF-positive monocytes and WBCs count in the steady-state patients, whereas in disagreement with our results, they found a significant correlation with reticulocytes (%).

During the vaso-occlusive crisis, the relationship between TF-positive monocytes and other parameters became very clear as we found strong correlations between TF-positive monocytes and most of clinical and laboratory data, expect age, PT, partial thromboplastin time, and TAT.

Clinically TF-positive monocytes showed a good significant positive correlation with the pain rate, a finding that confirms its significant clinical implication. The pain rate was considered to be a measure of clinical severity and correlated with premature death in patients over older than 20 years of age [10] .

Hb level has a dual effect in SCD; whereas increased Hb concentration is a risk factor for painful crisis, decreased Hb level is a risk for stroke [38] .

In this respect, our results showed that TF-positive monocytes were correlated inversely with the Hb level among patients in painful crisis.

It is noteworthy that TF-positive monocytes showed a significant relation to almost all the parameters of hemolysis studied [reticulocyte (%), inflammation (WBCs and CRP), coagulant markers (fibrinogen and d-dimer) as well as with platelet counts]. These relations could augment the suggested prognostic significance of TF-positive monocytes in SCD children.

Similar correlations between TF-positive monocytes and some hemolytic and inflammatory biomarkers, but during the steady state, were reported in a previous study [32] . However, to our knowledge, this is the first study to confirm this during the painful crisis.

Patients with SCD often receive multiple RBC transfusions and experience iron overload [39] . It was estimated recently that 15% of all pediatric patients with SCD will begin chronic transfusions [40] .

In terms of this factor, both SCD groups had significantly higher mean yearly serum ferritin as an estimate of iron overload compared with the controls.

Proinflammatory effects of iron overload are well described and considered to be secondary to hydroxyl radicals' and oxidative damage [39] . The influence of iron on coagulation has been less understood in SCD. However, Nielsen and Pretorius [23] suggested that iron decreases the onset time of coagulation, increases the velocity of thrombus formation, and markedly alters the ultrastructural characteristics of thrombi. The salient result of this work was that, among patients in painful crisis, TF-positive monocytes showed a significant direct correlation with RBCs TI and the mean yearly serum ferritin.


  Conclusion Top


TF-positive monocytes were expressed more in SCD both in steady state and during painful crisis, being significantly higher in the crisis state. This enhanced expression was significantly related to the pain rate as well as markers of hemolysis, inflammation, and coagulation among patients in painful crisis. Collectively, these results confirm the prognostic significance of TF-positive monocytes evaluation in SCD children.

Acknowledgements

Author contributions: Seham M. Ragab is responsible for the study concept and design, overseeing data collection, data interpretation, literature search, drafting the manuscript, figures, and tables, and writing/revising the manuscript; Mohamed A. Soliman is responsible for carrying out the biochemical analysis of the studied parameters and contributed in data interpretation, literature search, and drafting the manuscript/revising the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]


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[Pubmed] | [DOI]



 

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