The Glenn procedure is a cardiac intervention that can be safely used in the initial phase of palliation in various types of single ventricle defects.
Although primary pulmonary artery hypertension pathogenesis is multifactorial, the most important factor in the pathogenesis is endothelial dysfunction. However, it may also occur due to vasoconstriction, thrombosis, and pulmonary artery remodelling.Reference Badesch, Champion and Sanchez1–Reference Sakao and Tatsumi3 The development of pulmonary artery hypertension is not only associated with inflammatory cells and their activation, but also other cell types, including fibroblasts, endothelial cells, smooth muscle cells, platelets, and other shaped blood elements.Reference De Luca, Venegoni and Iorio4 Previous studies have shown that there is a correlation between pulmonary arteriole characteristics and platelets, which has been, in turn, associated with the development of primary pulmonary artery hypertension.Reference Zanjani5
Mean platelet volume, platelet distribution width, platelet size and variability, and plateletcrit, total mass of platelets in the blood are defined as markers of platelet activation. Physiologically, increases in mean platelet volume and platelet distribution width value are followed by elevated platelet activation which leads to easier aggregation of large platelets and adherence to the endothelium. Elevated mean platelet volume values are considered an independent risk factor for coronary and peripheral artery disease. With the same mechanism, increased platelet distribution width and mean platelet volume values in the aetiology of pulmonary artery hypertension mean platelet volume are thought to cause pulmonary arterial hypertension through triggering of platelet aggregation.Reference Soydinc, Turkbeyler and Pehlivan6,Reference Sansanayudh, Anothaisintawee, Muntham, McEvoy, Attia and Thakkinstian7 Furthermore, previous studies have shown that patients with idiopathic pulmonary hypertension have higher mean platelet volume than the normal population, and it has been suggested that thrombocyte activation directly plays a role in the pathogenesis of pulmonary artery hypertension.Reference Varol, Uysal and Ozaydin8,Reference Can, Tanboga and Demircan9
In our study, we investigated the relationship between platelet activation and postoperative characteristics of patients who underwent Glenn surgery, by comparing platelet activation markers and pulmonary pressure values in single ventricle patients.
Material and methods
Eighty-five patients who underwent the Glenn procedure in our clinic between January 2011 and March 2020 were included in the study. Patients’ characteristics, such as gender, age, weight, operation date, cross clamp duration, total cardiopulmonary by-pass time, and central venous catheter pressure values were obtained retrospectively from patient files. The platelet distribution width, platelet count, plateletcrit, and mean platelet volume values were recorded from routine complete blood count measurements. The pulmonary pressures of the patients were determined from the angiography reports of preoperative catheter measurements performed in the preoperative period and at postoperative days 1, 2, and 3. Invasive measurements were made from the central line of each patient.
The patients’ Mean platelet volume (fL), plateletcrit (%), platelet distribution width (fL), total mass of platelets in the blood (10^3 uL) values measured from the preoperative haemogram were compared with the pulmonary artery pressure values during preoperative catheterization. Pulmonary artery pressure values obtained from central venous catheter on the postoperative 1st, 2nd and 3rd days were compared with Mean platelet volume, plateletcrit, platelet distribution width, total mass of platelets in the blood values obtained from haemogram on the same day.
The blood samples were obtained from central venous catheter inserted during the operation and stored in ethylenediaminetetraacetic acid-containing haemogram tubes and evaluated in the biochemistry laboratory of our center.
The operations of the patients were performed under cardiopulmonary bypass with a routine conventional median sternotomy and selective bicaval-aortic cannulation.
The NCSS (Number Cruncher Statistical System) 2007 (Kaysville, Utah, USA) programme was used for statistical analysis. The study data were described with Mean, Standard Deviation, Median, Frequency, Ratio, Minimum and Maximum values. The Shapiro–Wilk test was also used to evaluate the distribution of continuous variables. The Kruskal–Wallis test was used to compare continuous variables that did not show normal distribution in three or more groups, and the Mann–Whitney U test was used for comparison of two groups. The Friedman test was used for time-bound comparison of variables between three or more groups in the presence of non-normal distribution, and the differences were determined via the Wilcoxon test. Spearman’s correlation test was used assess relationships between quantitative data. Significance was evaluated at p < 0.05 level.
Measurement averages
CPB = Cardiopulmonary bypass; fL = femtoliters; ICU = Intensive care unit; mL = milliliter; mmHg = millimeter of mercury; MPV = Mean platelet volume; PAP = Pulmonary arterial pressure; PCT = plateletcrit; PDW = Platelet distribution width; PLT = Total mass of platelets in the blood; PO1 = Postoperative 1st day.
Comparison of platelet activation values by periods
Friedman Test **p < 0,01.
Comparison of Shunt Group Values by Periods (decreased pulmonary flow)
Friedman Test **p < 0,01.
Comparison of Band Group Values by Periods (increased pulmonary flow)
Friedman Test **p < 0,01.
Results
Of the 85 patients included in the study, 51 were males and 34 were females. The age varied between 4 and 416 months, with an average of 28.64 ± 51 months. The weights of the patients ranged from 4.8 to 80 kg, with an average of 10.57 ± 9.08 kg. The cardiopulmonary bypass duration ranged from 9 to 172 minutes, with an average of 70.42 ± 29.49 minutes (Table 1). Patients who underwent valve repair and pulmonary reconstruction with additional cardiac pathology together with the Glenn surgery were included in the study.
It was found that 12.8% (n = 11) of the patients died and 87.2% (n = 74) were discharged. The duration of intubation in deceased patients was significantly higher than the discharged group (p < 0.01). The duration of stay in the intensive care unit in deceased patients was significantly higher than the discharged group (p = 0.001; p < 0.01). There was no statistically significant difference between the postoperative first day drainage values of the patients who died and were discharged (p > 0.05).
The preoperative platelet distribution width values of the discharged group was found to be significantly higher compared to the deceased patient group (p = 0.04; p < 0.05). The average preoperative platelet distribution width value of the discharged group was 17.43 ± 4.57, while this value was 16.44 ± 1.01 in the deceased group (Table 2).
The mean preoperative pulmonary artery pressure value of patients who died was significantly higher compared to the discharged group (p = 0.021; p < 0.05).
The mean postoperative first day pulmonary artery pressure value of the deceased group was significantly higher than the discharged group (p = 0.001; p < 0.01).
The mean postoperative second day pulmonary artery pressure value of the deceased group was significantly higher compared to the discharged group (p = 0.001; p < 0.01).
Similarly, postoperative third day pulmonary artery pressure values were significantly higher in the deceased group compared to the discharged group (p = 0.001; p < 0.01).
There was a statistically significant difference between platelet distribution width measurements by periods (p = 0.001; p < 0.01). The preoperative platelet distribution width measurements were significantly lower compared to the postop-1 and postop-2 measurements (p = 0.001; p < 0.01).
There was a statistically significant difference between Mean platelet volume measurements by periods (p = 0.019; p < 0.05). The postop-2 Mean platelet volume measurements were significantly higher compared to preop and postop-1 measurements (p = 0.001; p < 0.01).
There was a statistically significant difference between total mass of platelets in the blood measurements by periods (p = 0.001; p < 0.01). Preoperative total mass of platelets in the blood values were found to be significantly higher compared to postop-1 and postop-2 measurements (p = 0.001; p < 0.01).
There was a statistically significant difference between plateletcrit measurements by periods (p = 0.001; p < 0.01). Preoperative plateletcrit measurement results were significantly higher compared to the postop-1 and postop-2 measurements (p < 0.01).
There was a negative and very weak significant correlation between preop platelet distribution width and postoperative first day drainage (r = −0.235, p < 0.05).
There was a positive and weak significant relationship between the amount of drainage on the first day and the duration of intensive care stay (r = 0.280, p < 0.05).
When the patients were separated according to the presence of decreased and increased blood flow, and with respect to previous operation, we found that 26 patients underwent pre-Glenn band and 59 patients underwent shunt operation. Five of the patients who underwent shunting (8.4% mortality) and band (19% mortality) died. In both of these patient groups, no statistically significant relationship was found between plateletcrit, Mean platelet volume, total mass of platelets in the blood, platelet distribution width and pulmonary pressures (p > 0.05) (Tables 3 and 4).
Complications were, Glenn takedown in two patients, chylothorax in three, prolonged need for ventilation (>10 days) in nine, and bleeding revision in one patient.
Discussion
Knowledge regarding the presence/absence of pulmonary hypertension, which is one of the most important determinants of mortality and morbidity in single ventricle patients, plays an important role in postoperative patient follow-up. High pulmonary artery pressure is of great importance in the decision of the Glenn operation and the prognosis after the operation.Reference Kijima, Sasaki and Shinmei10 It is difficult to predict whether pulmonary arterial hypertension is reversible. Its reversibility depends on the underlying pathology. Although there is no definite opinion in the literature regarding the reversibility of postoperative pulmonary artery hypertension, postoperative pulmonary artery hypertension after Glenn shunt surgery is usually reversible.Reference Badesch, Champion and Sanchez1,Reference Can, Tanboğa and Demircan2
Pulmonary vascular endothelial dysfunction in pulmonary artery hypertension can cause platelet activation and local thrombosis. In addition, systemic inflammation in pulmonary artery hypertension patients may cause platelet activation and can increase markers of platelet activation. Inflammatory response is an important feature of pulmonary artery hypertension, and increased levels of circulating cytokines, including interleukin-6, have been reported in patients with pulmonary artery hypertension and cytokine elevation has been negatively associated with survival. Cytokines such as interleukin-3 or interleukin-6 have been demonstrated to affect megakaryocytes and may lead to the production of relatively more reactive and larger platelets.Reference Soon, Holmes and Treacy11 Therefore, increased interleukin-6 in pulmonary artery hypertension patients may cause an increase in mean platelet volume values by stimulating megakaryocytes.Reference Debili, Masse and Katz12 Pulmonary pressure increase in single ventricle patients is different from primary pulmonary artery hypertension; however, the two conditions may be similar with respect to platelet characteristics. Pathogenesis of pulmonary artery hypertension may be similar to that of primary pulmonary artery hypertension, especially in patients with a single ventricle with increased pulmonary blood flow.Reference Vizioli, Muscari and Muscari13,Reference Nakonechnicov, Gabbasov, Chazova, Popov and Belenkov14
In our study, when we grouped patients with respect to Glenn shunts and pulmonary bands applied at the first palliation, we found that the mean platelet volume value of the group with shunt application was higher than the value of the group with band application. We attributed this to the use of foreign body (shunt graft) in patients who underwent shunt operation and the higher inflammatory response due to the non-physiological flow dynamics of the shunt. However, we could not obtain significant statistical relationships between platelet activation markers and pulmonary pressures in either group.
In patients with cyanosis, erythropoiesis is stimulated to increase oxygen delivery to the tissues, and the number of red blood cells increases, but the number of platelets decreases. The lower the oxygen in the blood, the greater the increase in haemoglobin will be. Inversely, there will be a decrease in platelet level. Thus, haemoglobin and platelet level can indirectly provide data about the severity of cyanosis. Although the platelet count is decreased in these patients, thrombogenic events are common. Additionally, it should be noted that previous studies have associated mean platelet volume values with increased aggregation, but no significant increase in mean platelet volume values is observed among cyanotic patients.Reference Matter, Ragab, Roushdy, Ahmed, Aly and Ismail15–Reference Laskine-Holland, Kahr and Crawford-Lean17 Mean platelet volume is a simple and easy method of evaluating platelet function obtained from routine postoperative haemogram results and reflects the rate and stimulation of platelet production.Reference Park, Schoene and Haris18
In the study conducted by Varol et al, they showed that mean platelet volume was significantly higher in adult primary pulmonary artery hypertension patients.Reference Varol, Uysal and Ozaydin8 In our study, we found no correlation between mean platelet volume and pulmonary pressures in the early postoperative period after Glenn surgery in the paediatric patient group. We attributed this to the fact that there was no change in mean platelet volume in the early postoperative period and the number of patients was limited, especially considering that primary pulmonary artery hypertension pathogenesis is a chronic process. In addition, we believe that the paediatric age of the patients in our study also affected the results.
Although platelet count and activation markers are suggestive parameters in idiopathic pulmonary hypertension, in our retrospective study, no significant relationship was found between pulmonary pressures and platelet activation markers, with regard to increased inflammation and surgical stress in the postoperative period after cardiac surgery.Reference Badesch, Champion and Sanchez1 However, in our study, platelet distribution width and mean platelet volume increased while total mass of platelets in the blood and plateletcrit decreased in the postoperative period compared to the preoperative period. We think this was due to increased inflammation and increased consumption.
Pulmonary artery hypertension that develops in the early postoperative period after Glenn shunt surgery is not only associated with inflammation and endothelial dysfunction, it has been associated with various causes and is considered a multifactorial development. The processes in the development of postoperative pulmonary artery hypertension in single ventricle patients are different from primary pulmonary artery hypertension. Therefore, platelet activation markers used in the diagnosis of primary pulmonary artery hypertension are of limited use in postoperative patients and may be misleading. In our study, the correlations between early postoperative pulmonary pressures and platelet activation markers were statistically non-significant. We believe that one of the reasons for this situation was the transfer of blood into a foreign surface (during cardiopulmonary bypass), causing formation of an inflammatory response, and consequently, altering platelet activation markers.
In conclusion, patients with pulmonary increased blood flow before Glenn surgery were found to have higher mean platelet volume values. In addition, even if platelet activation markers provide information about the pulmonary bed, they may be misleading due to other reasons that trigger inflammatory processes in the early postoperative period.
Acknowledgements
None.
Financial support
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest
None.
Ethical statement
The ethics committee approved the study protocol and all steps of the study were conducted in accordance with the principles of the Declaration of Helsinki. (2020/14/411).
