Platelet Indices as Predictive Markers of Prognosis in Critically Ill Patients: A Prospective Study

INTRODUCTION

Platelets (PLTs) are dynamic blood molecules which perform multiple physiological functions, such as thrombosis, coagulation, enhance host defense against microbes, inflammation and along with coagulation factors initiate hemostasis and therefore prevent excess bleeding.¹ Platelet indices are biomarkers of PLT activation and are reliable predictors of the PLT size, morphology, and proliferation kinetics and assist in assessment of its derangements.² The routinely utilized PLT indices include PLT count, mean platelet volume (MPV), platelet distribution width (PDW), and plateletcrit (PCT). The MPV is defined as the ratio of PCT to PLT count and is the index which measures the volume of the average circulating PLT. The PDW is a PLT index which measures the volume of PLT dispersion.³ Platelet distribution width is defined numerically as the coefficient of PLT volume variation.⁴ Platelet is defined as the arithmetic product of PLT volume and PLT count.

Platelet indices have been applied in diagnosing hematological disorders but recent studies have found a relationship between the changes in PLT indices and the activation of the coagulation system, severe infection, trauma, systemic inflammatory reaction syndrome, and thrombotic diseases.⁵ Platelet indices provide a more comprehensive picture of the etiology of the illness and its severity. Studies have shown that low PLT count is an independent risk factor for mortality in patients in intensive care units (ICUs) and the rising or declining trend of PLTs has an impact on the overall survival of the patient.⁶ In mortality scoring system, such as acute physiology and chronic health evaluation IV (APACHE IV), includes thrombocytopenia as an independent risk factor for mortality. In a recent research, it was reported that abnormally low PLT, high MPV value, and high PDW value are associated with more severe illness in ICU patients.⁶ In addition, MPV, PDW, and PLT large cell ratio are strong, independent prognostic factors in acute myocardial infarction (MI).⁷ In addition, increase in MPV, PDW in patients with cirrhosis and ascites were accurate diagnostic predictors for ascitic fluid infection.⁸ There is a paucity of Indian studies which investigate whether PLT indices are related with all-cause mortality and the relation of these indices with ICU scoring systems for morbidity like APACHE IV in patients in intensive care. Thus, we conducted a prospective study, among patients admitted to our ICU from September 2017 to April 2019, to study whether PLT indices (PLT, MPV, PDW, and PCT) are related with all-cause mortality, APACHE IV, diabetes mellitus (DM), and length of stay in critically ill patients in ICU.

MATERIALS AND METHODS

It is a prospective observational study conducted in ICU of our hospital from September 2017 to April 2019 after permission from the institutional ethical committee and conducted in accordance with the Declaration of Helsinki. The primary objectives were to compare PLT indices with the clinical condition of the patient using APACHE IV and to compare mortality rate in patients with normal and abnormal PLT indices. The secondary objectives were to study the effect of DM on PLT indices in ICU patients and to correlate PLT indices with duration of stay in the ICU.

Patients aged above 18 years with length of ICU stay %3E;24 hours were included whereas pregnant and lactating women; patients with active hemorrhage; hematological and rheumatological diseases, diagnosed chronic liver disease were excluded. Also patients who were infused with PLT concentrate up to 48 hours prior to their admission and have used drugs known to cause thrombocytopenia or have received radiotherapy or chemotherapy or bone marrow transplantation 1 month prior to admission were excluded from the study.

All patients admitted to the ICU who satisfied the inclusion and exclusion criteria were recruited for the study and after informed consent, basic information was collected from medical records, and blood was sent for investigations and APACHE IV was calculated within first 24 hours of ICU admission and the patient were followed up during their ICU stay.

Platelet indices were analyzed using Beckham Coulter Unicel DXH 800 analyzer. The normal range for PLT count was 150,000–450,000, for MPV was 7–11 fL, while for PDW –17 and PCT is 0.108–0.282%. The data collected were analyzed using IBM SPSS Statistics 25. Categorical variables was presented as numerical data and percentages and statistical comparisons was performed using chi-square (χ²) test. Comparisons between groups were performed using Student’s t test. Sensitivity and specificity of each PLT index in predicting mortality were calculated using receiver operating characteristic (ROC) and the area under the curves (AUC) was compared. Kaplan–Meier method was used to construct ICU survival curve. Regression analysis was performed to study the effect of DM on PLT indices and APACHE. The p value <0.05 was considered to indicate statistical significance.

RESULTS

During the study period from September 2017 to April 2019, there were 345 hospitalizations in the multispecialty ICU among which 170 subjects satisfied the study criteria. The clinical characteristics of the survival group and the non-survivor group were summarized in Table 1.

Among the 170 patients admitted in ICU, majority were males 96 patients and females 74 patients, and their mortality rates were 33.3 and 25.6%, respectively. Around 62 patients were hospitalized in the ICU because of sepsis, whereas 38 and 33 patients were admitted, respectively, because of respiratory and neurological etiologies. The other indications for hospitalization included surgical and miscellaneous (9 each), metabolic (8), gastroenterology (5), genitourinary (3), cardiovascular (2), and trauma (1).

In our study, non-survivors had higher APACHE IV and acute physiology scores (p < 0.001) than survivors. Among the PLT indices, PLT and PCT were found to be significantly lower in non-survivors (p < 0.001 and p = 0.001, respectively) while MPV and PDW were higher in the non-survivors (p = 0.014 and p = 0.004, respectively) (Table 1).

DISCUSSION

In our study, it was observed that a patient in ICU who had a low PLT and PCT and a high MPV and PDW had a higher APACHE IV score and a comparatively poor prognosis including higher risk of mortality. Additionally, PDW is the only PLT index which has a statistically significant effect on APACHE when adjusted to DM. Platelet indices are easily accessible parameters which are being increasingly recognized as markers of inflammation and thrombosis. In pathological processes like sepsis, disseminated intravascular coagulation which is commonly encountered in ICUs, there is an excessive consumption of PLTs with increased PLT destruction which is reflected as a simultaneous reduction of both PLT and PCT. The bone marrow compensates for this by producing excess new PLTs which change from biconcave to spherical shape with an increase in formation of pseudopods which lead to PLTs which are large in size and volume.⁹ This change is reflected as an increase in both MPV and PDW. There have been studies of thrombocytopenia in ICU but there is a paucity of studies involving the other PLT indices in the ICU and to the best of our knowledge ours is the first study in the Indian Subcontinent to explore the relationship of these indices with APACHE IV, mortality, length of ICU stay, and DM.

The relationship of PLT indices to APACHE which is used for assessing the clinical condition of ICU patients yielded similar results in a recent study which showed an elevation in APACHE II was related with PLT and PCT in the low tertile and MPV and PDW in the high tertile.⁶ It was also seen that APACHE had a statistically significant negative correlation with PLT count and PCT and a statistically significant positive relation with MPV and PDW. To the best of our knowledge, ours is the only study to use APACHE IV to assess PLT indices in ICU.

In our study, it was observed that among the 170 patients, 51 patients did not survive among whom 86% of the patients did not survive beyond first 10 days of ICU stay. Among the 51 patients, around 47.1% had thrombocytopenia which was statistically significant (p = 0.004). Similarly, a statistically significant low PCT was found in 31.3% patients who did not survive. A statistically significant association was not obtained between abnormal PLT indices and mortality. It may be because of the following reasons, majority of our patients both in the survivor and non-survivor group had values in the normal ranges and hence a statistically significant relationship could not be obtained because of low sample size and previous studies have shown that the positive and negative association of MPV varies depending on the underlying pathological process.⁷

In our study, thrombocytopenia, low PCT, high MPV and high PDW was significantly observed in non-survivors. This is similar to a recent study in 1,556 patients in ICU where it was observed that MPV and PDW were significantly elevated in non-survivors and PDW %3E;17% and MPV >11.3 fL were independent risk factors for mortality.³ A lower PCT was also associated with increased risk of mortality in these patients.

In our study, no significant association was obtained between the length of ICU stay and the PLT indices and neither was this parameter studied in previous studies. Thrombocytopenia when associated with other critical illness might prolong the ICU stay.

Diabetes mellitus was considered as a confounding factor as it is known to have an impact on the PLT indices and also has an effect on the scoring system in APACHE and hence might lead to an altered value of these indices. Hyperglycemia and insulin resistance are known to produce hyper-reactivity of PLTs which in turn also cause an increase in coagulation with impairment in endothelial function and fibrinolysis which has been implicated in the pathophysiology of development of complications in diabetics. This PLT hyper-reactivity can be observed as changes in PLT parameters.

In our study, in univariate regression analysis, it was observed that all the four PLT indices individually adjusted to DM had a significant effect on APACHE but in multivariate analysis only PDW had a statistically significant effect on APACHE when adjusted to DM as was seen in the above study. In a recent study, it was observed that only MPV, PDW, and PLT–large cell ratio were significantly higher in diabetic individuals with high HbA1c and also microvascular complications when compared with diabetics without complications.¹⁰

Our study included patients with a wide variety of etiologies for ICU admission irrespective of their PLT count and at the same time tried to avoid any possible exogenous factor which might cause an alteration in the PLT morphology by a strict exclusion criteria to ensure that the PLT indices were accurately calculated across both genders and in all adults who were admitted in our ICU, so that these indices could be used to assess their clinical condition, mortality, and length of ICU stay.

The limitations of our study include that majority of the cases included in our study were patients who were admitted in the ICU due to sepsis and very few surgical patients were included in the study. All the etiologies of ICU admission were considered together and their influence on PLT indices were studied. Each pathological process has its own varying degree of inflammation and eventual one marrow stimulation and the individual effect of different processes could not be studied.

Further studies can be performed to study the causal relationship between PLT indices and different pathological processes and to estimate probable cutoffs for the same and in surgical patients not in sepsis to identify whether PLT indices can be used for prognosis in them too.

CONCLUSION

In our study, it was observed that a patient in ICU who had a low PLT count and PCT and a high MPV and PDW had a higher APACHE IV score and a comparatively poor prognosis. Also, ICU patients who had a low PLT count and PCT and a high MPV and PDW had a higher risk of mortality. No relation was observed between days of ICU stay and the PLT indices. Platelet distribution width is the only PLT index which has a statistically significant effect on APACHE when adjusted to DM.

CLINICAL SIGNIFICANCE

Platelet indices which are routinely available can be effectively used as a morbidity and mortality indicators in critically ill patients.

REFERENCES

1. Golebiewska EM, Poole AW. Platelet secretion: from hemostasis to wound healing and beyond. Blood Rev 2015;29(3):153–162. DOI: 10.1016/j.blre.2014.10.003.

2. Hoffbrand AV, Moss PAH, Pettit JE. Essential Hematology.Carlton, Australia: Blackwell publishing Ltd; 2006. pp. 106–110.

3. Zhang Z, Xu X, Ni H, Deng H. Platelet indices are novel predictors of hospital mortality in intensive care unit patients. J Crit Care 2014;29(5):885.e1–885.e6. DOI: 10.1016/j.jcrc.2014.04.020.

4. Osselaer JC, Jamart J, Scheiff JM. Platelet distribution width for differential diagnosis of thrombocytosis. Clin Chem 1997;43(6 Pt 1):1072–1076. DOI: 10.1093/clinchem/43.6.1072.

5. Thaulow E, Erikssen J, Sandvik L, Stormorken H, Cohn PF. Blood platelet count and function are related to total and cardiovascular death in apparently healthy men. Circulation 1991;84(2):613–617. DOI: 10.1161/01.CIR.84.2.613.

6. Zhang S, Cui YL, Diao MY, Chen DC, Lin ZF. Use of platelet indices for determining illness severity and predicting prognosis in critically ill patients. Chin Med J (Engl) 2015;128(15):2012–2018. DOI: 10.4103/0366-6999.161346.

7. Rechcinski T, Jasinska A, Forys J, Pakula MK, Drabik KW, Plewka M, et al. Prognostic value of platelet indices after acute myocardial infarction treated with primary percutaneous coronary intervention. Cardiol J 2013;20(5):491–498. DOI: 10.5603/CJ.2013.0134.

8. Abdel-Razik A, Eldars W, Rizk E. Platelet indices and inflammatory markers as diagnostic predictors for ascitic fluid infection. Eur J Gastroenterol Hepatol 2014;26(12):1342–1347. DOI: 10.1097/MEG.0000000000000202.

9. Catal F, Tayman C, Tonbul A, Akca H, Kara S, Tatli M, et al. Mean platelet volume (MPV) may simply predict the severity of sepsis in preterm infants. Clin Lab 2014;60(7):1193–1200. DOI: 10.7754/Clin.Lab.2013.130501.

10. Walinjkar RS, Khadse S, Kumar S, Bawankule S, Acharya S. Platelet indices as a predictor of microvascular complications in type II diabetes. Indian J Endocr Metab 2019;23(2):206–210. DOI: 10.4103/ijem.IJEM_13_19.