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\begin{document}


\def\RunningAuthor{Jaywant S Thorat et al.}
\firstPage{2088}
\articleType{Original Article}
\receivedDate{28 Apr 2021}
\acceptedDate{07 Jun 2021}
\revisedDate{02 Jun 2021}
\journalVolume{2021, 12}
\journalIssue{3}
\journalDoi{ijrps.v12i3.4819}
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\title{\textbf{Effect of vitamin C supplementation on hematological parameters in smokeless tobacco chewers}}
\author{Jaywant~S~Thorat\textsuperscript{*},  
            Anand~G~Joshi, 
            Kanchan~C~Wingkar~\\[5pt]{Department of Physiology, Krishna Institute of Medical Sciences Deemed to be University, Karad {\textendash} 415 110, Maharashtra, India}}

\begin{abstract}
The present study was aimed to evaluate the effect of Vitamin C (VC) supplementation on hematological parameters in Smokeless Tobacco (ST) chewers. A total of 338 subjects aged between 31 to 60 years (168 ST chewers and 170 ST non-chewers) participated in the present study. ST chewers were further divided into 3 subgroups with respect to ST chewing duration in years. Subjects of both the groups were examined at the baseline study and after 45 days of supplementation of 1 g of Vitamin C (VC) for hematological parameters. WBC count (p=0.04), granulocytes \% (p=0.0007), HCT (p=0.01) and MCV (p=0.04) were significantly increased whereas, monocytes \% (p=0.002) and platelet count (p{\textless}0.0001) were significantly decreased in ST chewers as compared to controls. After supplementation of VC, WBC count (p{\textless}0.001) and granulocytes \% (p{\textless}0.0001) were significantly decreased and lymphocytes \% (p=0.008), monocytes \% (p{\textless}0.0001), RBC count (p=0.01) and Hb content (p=0.006) were significantly increased in ST chewers as compared to their baseline values. In conclusion\textbf{, } the use of ST had deleterious effects on hematological parameters; however, supplementation of 1 g of VC showed protective effects on hematological parameters. 
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Granulocytes,\newline Monocytes,\newline Lymphocytes,\newline Platelets
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Jaywant~S~Thorat~\\ Phone:\ +91- 9823727827~\\  Email:\ jaywantviews@gmail.com
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
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\section{Introduction}
According to World Health Organization (WHO), Smokeless Tobacco (ST) is the single greatest cause of preventable death all over the world \unskip~\citep{1136260:22508803}. The various forms of tobacco are smoked, chewed, sniffed, sucked and applied to teeth and gums \unskip~\citep{1136260:22508813}. Forms of chewing tobacco include crushed tobacco leaves mixed with slaked lime paste, khaini, gutkha, mishri (a roasted and powdered tobacco), mawa (a mixture of sliced areca nut, lime, kiwam and tobacco leaves), pan (piper betel leaf filled with sliced areca nut, lime and tobacco leaves) and dry snuff or tapkeer (use for inhalation) \unskip~\citep{1136260:22508799}. ST largely used in South Asia and mainly in India as compared to the Western world \unskip~\citep{1136260:22508795}. In India, millions of people die every year due to tobacco use \unskip~\citep{1136260:22508811}. The majority of cardiovascular diseases (CVD), cancers and lung diseases are directly credited to tobacco use \unskip~\citep{1136260:22508811}.

ST use is documented in 120 nations of the world \unskip~\citep{1136260:22508812}. India has the largest number of ST users in the world. Out of the 346 million worldwide tobacco users, India alone has 152.4 million people and out of that, 80.8 million ST users \unskip~\citep{1136260:22508794} and there has been a considerable rise in ST users among all age groups \unskip~\citep{1136260:22508783}. The financial burden due to tobacco-related diseases in India was US\$ 22.4 billion in the year 2011- 2012 \unskip~\citep{1136260:22508814,1136260:22508808}. The economic burden was more in females as compared to males due to ST use \unskip~\citep{1136260:22508794}.

In view of the various pharmacological actions of nicotine and its wide use in many regions of the world, chronic consumption of ST may affect the status of hematological parameters. However, there are limited studies available on the effect of ST use on hematological parameters in humans. The present study was undertaken to find out whether `smokeless tobacco' causes any adverse effect on hematological parameters as well to evaluate the beneficial effects of vitamin C supplementation.
    
\section{Materials and Methods}
The present interventional study has an experimental approach and the case-control design was carried out in the Krishna Institute of Medical Sciences, Karad, during 2015{\textendash}2019. The study protocol was approved by the Institutional Ethical Committee of KIMSDU, Karad (Ref. No: KIMSDU/IEC/01/2015). A total of 338 subjects aged between 31 to 60 years (168 ST chewers and 170 ST non-chewers) participated in the study. Experimental protocol and study objectives were explained to the participants and their written informed consent were obtained according to the Helsinki declaration \unskip~\citep{1136260:22508798}.

\textbf{Inclusion Criteria}

Healthy adults aged between 31 to 60 years with at least last one or more years of history of ST chewing ( dried tobacco leaves mixed with slaked lime) were selected as ST chewers. Age and sex-matched healthy adults with no history of tobacco use in any form were selected as controls.

\textbf{Exclusion Criteria}

Individuals with any type of CVD, autonomic, endocrine, metabolic dysfunction, liver disease, cancer, any type of long term and regular medication and alcoholic individuals were excluded from the present study.

EDTA anticoagulated blood was used for estimation of hematological parameters on SYSMEX XT- 1800 fully auto analyzer. Subjects of both groups were examined at the study baseline for hematological parameters. All study participants, ST chewers and controls were asked to consume 1gm of VC (Celin, Glaxo SmithKline) daily after a meal, respectively, for 45 days. 

Regular follow up were taken twice in a week and subjects were advised to maintain their normal diet and continue their habitual physical activity. Subjects of both groups were examined at the end of the study (after supplementation of VC) for hematological parameters. Participants of the ST chewers group were further divided with respect to ST chewing duration in years. The data obtained from both study groups were analyzed and compared by using a suitable statistical test.
    
\section{Results and Discussion}

\begin{table*}[!htbp]
\caption{\boldmath {Comparison of hematological parameters between controls and ST chewers} }
\label{tw-ffb2455df255}
\centering 
\begin{threeparttable}

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\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Parameters & \cAlignHack Controls & \cAlignHack ST Chewers & \cAlignHack Unpaired  & \cAlignHack p-value\\
\rowcolor{kwdboxcolor}\cAlignHack  & \cAlignHack N= 170 & \cAlignHack N= 168 & \cAlignHack `t' test & \cAlignHack \\
\tblmidrule 
\cAlignHack WBC (1000/ cumm) &
  \cAlignHack 7568\ensuremath{\pm}1369 &
  \cAlignHack 7851\ensuremath{\pm}1204 &
  \cAlignHack 2.01 &
  \cAlignHack 0.04\\
\cAlignHack Lymphocytes (\%) &
  \cAlignHack 27.28\ensuremath{\pm}4.70 &
  \cAlignHack 25.90\ensuremath{\pm}4.81 &
  \cAlignHack 2.70 &
  \cAlignHack 0.07\\
\cAlignHack Monocytes (\%) &
  \cAlignHack 6.00\ensuremath{\pm}1.07 &
  \cAlignHack 5.57\ensuremath{\pm}1.09 &
  \cAlignHack 3.78 &
  \cAlignHack 0.002\\
\cAlignHack Granulocytes (\%) &
  \cAlignHack 66.70\ensuremath{\pm}4.68 &
  \cAlignHack 68.52\ensuremath{\pm}5.14 &
  \cAlignHack 3.40 &
  \cAlignHack 0.0007\\
\cAlignHack RBC (million/cumm) &
  \cAlignHack 5.20\ensuremath{\pm}0.46 &
  \cAlignHack 5.27\ensuremath{\pm}0.50 &
  \cAlignHack 1.33 &
  \cAlignHack 0.18\\
\cAlignHack Hb (g/dl) &
  \cAlignHack 14.86\ensuremath{\pm}1.164 &
  \cAlignHack 14.98\ensuremath{\pm}0.91 &
  \cAlignHack 1.05 &
  \cAlignHack 0.29\\
\cAlignHack HCT (\%) &
  \cAlignHack 44.67\ensuremath{\pm}4.03 &
  \cAlignHack 45.70\ensuremath{\pm}3.81 &
  \cAlignHack 2.41 &
  \cAlignHack 0.01\\
\cAlignHack MCV (fl) &
  \cAlignHack 84.86\ensuremath{\pm}5.01 &
  \cAlignHack 85.92\ensuremath{\pm}4.74 &
  \cAlignHack 1.99 &
  \cAlignHack 0.04\\
\cAlignHack MCH (pg) &
  \cAlignHack 29.14\ensuremath{\pm}2.11 &
  \cAlignHack 29.35\ensuremath{\pm}1.92 &
  \cAlignHack 0.51 &
  \cAlignHack 0.60\\
\cAlignHack MCHC (g/dl) &
  \cAlignHack 32.35\ensuremath{\pm}1.53 &
  \cAlignHack 32.54\ensuremath{\pm}1.31 &
  \cAlignHack 1.22 &
  \cAlignHack 0.21\\
\cAlignHack Platelets (lakh/ cumm) &
  \cAlignHack 2.63\ensuremath{\pm}0.55 &
  \cAlignHack 2.31\ensuremath{\pm}0.64 &
  \cAlignHack 4.93 &
  \cAlignHack {\textless}0.0001\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{WBC- White Blood Cells, RBC- Red Blood Cells, Hb-Hemoglobin HCT- Hemtocrit, MCV- Mean corpuscular Volume, MCH- Mean Corpuscular Hemoglobin, MCHC- Mean Corpuscular Hemoglobin Concentration. cumm- Cubicmillimeter, \%- percentage, g/dl-grams per deciliter, fl- femtoliter(10\ensuremath{^{-15}}), pg- picogram}
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Comparison of hematological parameters with respect to ST chewing duration in ST chewer groups as compared to controls} }
\label{tw-ed5a91662699}
\centering 
\begin{threeparttable}

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\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Parameters & \cAlignHack Controls & \multicolumn{3}{p{\dimexpr(.4869\linewidth-2\tabcolsep)}}{\cAlignHack ST chewers (tobacco chewing duration in years)} & \cAlignHack ANOVA\\
\rowcolor{kwdboxcolor}\cAlignHack  & \cAlignHack  & \cAlignHack 1-10 years & \cAlignHack 11-20 years & \cAlignHack 21-30 years & \cAlignHack F-value\\
\rowcolor{kwdboxcolor}\cAlignHack  & \cAlignHack N=170 & \cAlignHack N= 50 & \cAlignHack N= 81 & \cAlignHack N= 37 & \cAlignHack (p-value)\\
\tblmidrule 
\cAlignHack WBC (1000/ cmm) &
  \cAlignHack 7568\ensuremath{\pm}1369 &
  \cAlignHack 7729\ensuremath{\pm}1176 &
  7838\ensuremath{\pm}1204 &
  \cAlignHack 7986\ensuremath{\pm}1071 &
  \cAlignHack 1.55\\
 &
   &
   &
   &
   &
  \cAlignHack (0.19)\\
\cAlignHack Lymphocytes (\%) &
  \cAlignHack 27.28\ensuremath{\pm}4.70 &
  \cAlignHack 26.83\ensuremath{\pm}5.13 &
  25.78\ensuremath{\pm}4.62 &
  \cAlignHack 25.09\ensuremath{\pm}4.97 &
  \cAlignHack 3.12\\
 &
   &
   &
   &
   &
  \cAlignHack (0.02)\\
\cAlignHack Monocytes (\%) &
  \cAlignHack 6.00\ensuremath{\pm}1.07 &
  \cAlignHack 5.84\ensuremath{\pm}1.08 &
  5.49\ensuremath{\pm}1.02 &
  \cAlignHack 5.38\ensuremath{\pm}0.98 &
  \cAlignHack 5.48\\
 &
   &
   &
   &
   &
  \cAlignHack (0.001)\\
\cAlignHack Granulocytes (\%) &
  \cAlignHack 66.70\ensuremath{\pm}4.68 &
  \cAlignHack 68.13\ensuremath{\pm}5.64 &
  \cAlignHack 68.51\ensuremath{\pm}5.19 &
  \cAlignHack 68.92\ensuremath{\pm}4.90 &
  \cAlignHack 3.75\\
 &
   &
   &
   &
   &
  \cAlignHack (0.01)\\
\cAlignHack RBC (million/cmm) &
  \cAlignHack 5.20\ensuremath{\pm}0.46 &
  \cAlignHack 5.21\ensuremath{\pm}0.48 &
  \cAlignHack 5.28\ensuremath{\pm}0.56 &
  \cAlignHack 5.30\ensuremath{\pm}0.52 &
  \cAlignHack 1.91\\
 &
   &
   &
   &
   &
  \cAlignHack (0.12)\\
\cAlignHack Hb (g/dl) &
  \cAlignHack 14.86\ensuremath{\pm}1.164 &
  \cAlignHack 14.89\ensuremath{\pm}1.03 &
  \cAlignHack 15.02\ensuremath{\pm}0.91 &
  \cAlignHack 15.05\ensuremath{\pm}0.89 &
  \cAlignHack 0.70\\
 &
   &
   &
   &
   &
  \cAlignHack (0.54)\\
\cAlignHack HCT (\%) &
  \cAlignHack 44.67\ensuremath{\pm}4.03 &
  \cAlignHack 45.81\ensuremath{\pm}3.68 &
  \cAlignHack 45.74\ensuremath{\pm}3.98 &
  \cAlignHack 45.55\ensuremath{\pm}4.03 &
  \cAlignHack 2.00\\
 &
   &
   &
   &
   &
  \cAlignHack (0.11)\\
\cAlignHack MCV (fl) &
  \cAlignHack 84.86\ensuremath{\pm}5.01 &
  \cAlignHack 85.86\ensuremath{\pm}5.13 &
  \cAlignHack 85.90\ensuremath{\pm}4.68 &
  \cAlignHack 86.04\ensuremath{\pm}4.58 &
  \cAlignHack 1.32\\
 &
   &
   &
   &
   &
  \cAlignHack (0.26)\\
\cAlignHack MCH (pg) &
  \cAlignHack 29.14\ensuremath{\pm}2.11 &
  \cAlignHack 29.18\ensuremath{\pm}1.83 &
  \cAlignHack 29.30\ensuremath{\pm}1.98 &
  \cAlignHack 29.27\ensuremath{\pm}2.05 &
  \cAlignHack 0.170\\
 &
   &
   &
   &
   &
  \cAlignHack (0.84)\\
\cAlignHack MCHC (g/dl) &
  \cAlignHack 32.35\ensuremath{\pm}1.53 &
  \cAlignHack 32.57\ensuremath{\pm}1.39 &
  \cAlignHack 32.51\ensuremath{\pm}1.28 &
  \cAlignHack 32.53\ensuremath{\pm}1.42 &
  \cAlignHack 0.62\\
 &
   &
   &
   &
   &
  \cAlignHack (0.53)\\
\cAlignHack Platelets &
  \cAlignHack 2.63\ensuremath{\pm}0.55 &
  \cAlignHack 2.35\ensuremath{\pm}0.70 &
  \cAlignHack 2.33\ensuremath{\pm}0.60 &
  \cAlignHack 2.29\ensuremath{\pm}0.74 &
  \cAlignHack 7.049\\
\cAlignHack (lakh/ cmm) &
   &
   &
   &
   &
  \cAlignHack ({\textless}0.0001)\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{*p{\textless}0.05, **p{\textless}0.01, ***p{\textless}0.001 significant as compared with controls}
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Comparison of hematological parameters before and after supplementation of VC in controls and ST chewers} }
\label{tw-2e00be64be09}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.19265714285714285\linewidth-2\tabcolsep}p{\dimexpr.13695714285714285\linewidth-2\tabcolsep}p{\dimexpr.14875714285714292\linewidth-2\tabcolsep}p{\dimexpr.12264285714285721\linewidth-2\tabcolsep}p{\dimexpr.1518571428571429\linewidth-2\tabcolsep}p{\dimexpr.11742857142857146\linewidth-2\tabcolsep}p{\dimexpr.12970000000000002\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Parameters & \multicolumn{3}{p{\dimexpr(.40835714285714296\linewidth-2\tabcolsep)}}{\cAlignHack Tobacco non-chewers (controls)} & \multicolumn{3}{p{\dimexpr(.39898571428571444\linewidth-2\tabcolsep)}}{\cAlignHack Tobacco chewers (subjects)}\\
\rowcolor{kwdboxcolor}\cAlignHack  & \multicolumn{3}{p{\dimexpr(.40835714285714296\linewidth-2\tabcolsep)}}{\cAlignHack N =170} & \multicolumn{3}{p{\dimexpr(.39898571428571444\linewidth-2\tabcolsep)}}{\cAlignHack N =168}\\
\rowcolor{kwdboxcolor}\cAlignHack  & \cAlignHack Before VC & \cAlignHack After VC & \cAlignHack Paired t (p-value) & \cAlignHack Before VC & \cAlignHack After VC & \cAlignHack Paired t \mbox{}\protect\newline (p-value)\\
\tblmidrule 
\cAlignHack WBC  &
  \cAlignHack 7568\ensuremath{\pm}1369 &
  \cAlignHack 7420\ensuremath{\pm}1124 &
  \cAlignHack 2.56 &
  \cAlignHack 7851\ensuremath{\pm}1204 &
  \cAlignHack 7456\ensuremath{\pm}1137 &
  \cAlignHack 8.47\\
\cAlignHack (1000/ cumm) &
   &
   &
  \cAlignHack (0.01) &
   &
   &
  \cAlignHack ({\textless}0.001)\\
\cAlignHack Lymphocytes  &
  \cAlignHack 27.28\ensuremath{\pm}4.70 &
  \cAlignHack 27.32\ensuremath{\pm}4.43 &
  \cAlignHack 009 &
  \cAlignHack 25.90\ensuremath{\pm}4.70 &
  \cAlignHack 27.81\ensuremath{\pm}4.20 &
  \cAlignHack 2.65\\
\cAlignHack (\%) &
  \cAlignHack  &
  \cAlignHack  &
  \cAlignHack (0.92) &
  \cAlignHack  &
  \cAlignHack  &
  \cAlignHack (0.008)\\
\cAlignHack Monocytes &
  \cAlignHack 6.00\ensuremath{\pm}1.07 &
  \cAlignHack 6.12\ensuremath{\pm}1.14 &
  \cAlignHack 1.58 &
  \cAlignHack 5.57\ensuremath{\pm}1.09 &
  \cAlignHack 5.98\ensuremath{\pm}0.90 &
  \cAlignHack 5.69\\
\cAlignHack (\%) &
  \cAlignHack  &
  \cAlignHack  &
  \cAlignHack (0.11) &
  \cAlignHack  &
  \cAlignHack  &
  \cAlignHack ({\textless}0.001)\\
\cAlignHack Granulocytes &
  \cAlignHack 66.70\ensuremath{\pm}4.68 &
  \cAlignHack 66.56\ensuremath{\pm}4.54 &
  \cAlignHack 0.50 &
  \cAlignHack 68.52\ensuremath{\pm}5.14 &
  \cAlignHack 66.19\ensuremath{\pm}4.58 &
  \cAlignHack 6.562\\
\cAlignHack (\%) &
  \cAlignHack  &
  \cAlignHack  &
  \cAlignHack (0.61) &
  \cAlignHack  &
  \cAlignHack  &
  \cAlignHack ({\textless}0.001)\\
\cAlignHack RBC  &
  \cAlignHack 5.20\ensuremath{\pm}0.46 &
  \cAlignHack 5.24\ensuremath{\pm}0.44 &
  \cAlignHack 1.65 &
  \cAlignHack 5.27\ensuremath{\pm}0.50 &
  \cAlignHack 5.35\ensuremath{\pm}0.44 &
  \cAlignHack 2.576\\
\cAlignHack (million/cumm) &
  \cAlignHack  &
  \cAlignHack  &
  \cAlignHack (0.10) &
  \cAlignHack  &
  \cAlignHack  &
  \cAlignHack (0.01)\\
\cAlignHack Hb (g/dl) &
  \cAlignHack 14.86\ensuremath{\pm}1.164 &
  \cAlignHack 14.96\ensuremath{\pm}0.96 &
  \cAlignHack 3.00 &
  \cAlignHack 14.98\ensuremath{\pm}0.91 &
  \cAlignHack 15.24\ensuremath{\pm}0.84 &
  \cAlignHack 2.72\\
\cAlignHack  &
  \cAlignHack  &
  \cAlignHack  &
  \cAlignHack (0.003) &
  \cAlignHack  &
  \cAlignHack  &
  \cAlignHack (0.006)\\
\cAlignHack HCT (\%) &
  \cAlignHack 44.67\ensuremath{\pm}4.03 &
  \cAlignHack 44.89\ensuremath{\pm}3.26 &
  \cAlignHack 1.16 &
  \cAlignHack 45.70\ensuremath{\pm}3.81 &
  \cAlignHack 45.86\ensuremath{\pm}2.95 &
  \cAlignHack 0.43\\
\cAlignHack  &
  \cAlignHack  &
  \cAlignHack  &
  \cAlignHack (0.24) &
  \cAlignHack  &
  \cAlignHack  &
  \cAlignHack (0.66)\\
\cAlignHack MCV (fl) &
  \cAlignHack 84.86\ensuremath{\pm}5.01 &
  \cAlignHack 85.07\ensuremath{\pm}4.30 &
  \cAlignHack 0.93 &
  \cAlignHack 85.92\ensuremath{\pm}4.74 &
  \cAlignHack 86.30\ensuremath{\pm}3.95 &
  \cAlignHack 0.79\\
\cAlignHack  &
  \cAlignHack  &
  \cAlignHack  &
  \cAlignHack (0.35) &
  \cAlignHack  &
  \cAlignHack  &
  \cAlignHack (0.45)\\
\cAlignHack MCH (pg) &
  \cAlignHack 29.14\ensuremath{\pm}2.11 &
  \cAlignHack 29.12\ensuremath{\pm}1.65 &
  \cAlignHack 1.06 &
  \cAlignHack 29.35\ensuremath{\pm}1.92 &
  \cAlignHack 29.21\ensuremath{\pm}1.57 &
  \cAlignHack 0.80\\
\cAlignHack  &
  \cAlignHack  &
  \cAlignHack  &
  \cAlignHack (0.28) &
  \cAlignHack  &
  \cAlignHack  &
  \cAlignHack (0.42)\\
\cAlignHack MCHC (g/dl) &
  \cAlignHack 32.35\ensuremath{\pm}1.53 &
  \cAlignHack 32.41\ensuremath{\pm}1.02 &
  \cAlignHack 1.30 &
  \cAlignHack 32.54\ensuremath{\pm}1.31 &
  \cAlignHack 32.52\ensuremath{\pm}0.91 &
  \cAlignHack 1.70\\
\cAlignHack  &
  \cAlignHack  &
  \cAlignHack  &
  \cAlignHack (0.19) &
  \cAlignHack  &
  \cAlignHack  &
  \cAlignHack (0.09)\\
\cAlignHack Platelets &
  \cAlignHack 2.63\ensuremath{\pm}0.55 &
  \cAlignHack 2.60\ensuremath{\pm}0.48 &
  \cAlignHack 0.53 &
  \cAlignHack 2.31\ensuremath{\pm}0.64 &
  \cAlignHack 2.30\ensuremath{\pm}0.62 &
  \cAlignHack 0.14\\
\cAlignHack (lakh/ cumm) &
  \cAlignHack  &
  \cAlignHack  &
  \cAlignHack (0.59) &
  \cAlignHack  &
  \cAlignHack  &
  \cAlignHack (0.88)\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Correlations of serum CTN and serum VC with hematological parameters in controls and ST chewers} }
\label{tw-e1dd88bbdc5b}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.134\linewidth-2\tabcolsep}p{\dimexpr.11\linewidth-2\tabcolsep}p{\dimexpr.1091\linewidth-2\tabcolsep}p{\dimexpr.1155\linewidth-2\tabcolsep}p{\dimexpr.11650000000000002\linewidth-2\tabcolsep}p{\dimexpr.1118\linewidth-2\tabcolsep}p{\dimexpr.10080000000000002\linewidth-2\tabcolsep}p{\dimexpr.098\linewidth-2\tabcolsep}p{\dimexpr.1043\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack  & \multicolumn{4}{p{\dimexpr(.4511\linewidth-2\tabcolsep)}}{\cAlignHack Tobacco non-chewers (controls) N=170} & \multicolumn{4}{p{\dimexpr(.4149\linewidth-2\tabcolsep)}}{\cAlignHack ST chewers (subjects) N= 168}\\
\rowcolor{kwdboxcolor}\cAlignHack  & \multicolumn{2}{p{\dimexpr(.2191\linewidth-2\tabcolsep)}}{\cAlignHack Sr. CTN} & \multicolumn{2}{p{\dimexpr(.23200000000000003\linewidth-2\tabcolsep)}}{\cAlignHack Sr. VC} & \multicolumn{2}{p{\dimexpr(.2126\linewidth-2\tabcolsep)}}{\cAlignHack Sr. CTN} & \multicolumn{2}{p{\dimexpr(.2023\linewidth-2\tabcolsep)}}{\cAlignHack Sr. VC}\\
\rowcolor{kwdboxcolor}\cAlignHack  & \cAlignHack r-value & \cAlignHack p-value & \cAlignHack r-value & \cAlignHack p-value & \cAlignHack r-value & \cAlignHack p-value & \cAlignHack r-value & \cAlignHack p-value\\
\tblmidrule 
\cAlignHack WBC \mbox{}\protect\newline 1000/cumm &
  \cAlignHack -0.01 &
  \cAlignHack 0.88 &
  \cAlignHack 0.06 &
  \cAlignHack 0.40 &
  \cAlignHack 0.55 &
  \cAlignHack 0.04* &
  \cAlignHack -0.51 &
  \cAlignHack 0.05*\\
\cAlignHack Lymphocytes \% &
  \cAlignHack -0.43 &
  \cAlignHack 0.58 &
  \cAlignHack -0.09 &
  \cAlignHack 0.22 &
  \cAlignHack -0.05 &
  \cAlignHack 0.44 &
  \cAlignHack -0.41 &
  \cAlignHack 0.60\\
\cAlignHack Monocytes \% &
  \cAlignHack -0.01 &
  \cAlignHack 0.81 &
  \cAlignHack 0.10 &
  \cAlignHack 0.17 &
  \cAlignHack 0.05 &
  \cAlignHack 0.48 &
  \cAlignHack 0.20 &
  \cAlignHack 0.008**\\
\cAlignHack Granulocytes \% &
  \cAlignHack 0.04 &
  \cAlignHack 0.54 &
  \cAlignHack 0.07 &
  \cAlignHack 0.36 &
  \cAlignHack 0.04 &
  \cAlignHack 0.57 &
  \cAlignHack -0.03 &
  \cAlignHack 0.65\\
\cAlignHack RBC \mbox{}\protect\newline Millions/cumm &
  \cAlignHack 0.10 &
  \cAlignHack 0.16 &
  \cAlignHack 0.10 &
  \cAlignHack 0.15 &
  \cAlignHack -0.03 &
  \cAlignHack 0.66 &
  \cAlignHack 0.11 &
  \cAlignHack 0.12\\
\cAlignHack Hb \mbox{}\protect\newline g/dl &
  \cAlignHack 0.18 &
  \cAlignHack 0.07 &
  \cAlignHack 0.14 &
  \cAlignHack 0.06 &
  \cAlignHack 0.06 &
  \cAlignHack 0.37 &
  \cAlignHack 0.04 &
  \cAlignHack 0.59\\
\cAlignHack HCT \mbox{}\protect\newline \% &
  \cAlignHack 0.01 &
  \cAlignHack 0.82 &
  \cAlignHack 0.08 &
  \cAlignHack 0.28 &
  \cAlignHack 0.05 &
  \cAlignHack 0.46 &
  \cAlignHack 0.11 &
  \cAlignHack 0.13\\
\cAlignHack MCV \mbox{}\protect\newline Fl &
  \cAlignHack -0.01 &
  \cAlignHack 0.87 &
  \cAlignHack -0.01 &
  \cAlignHack 0.83 &
  \cAlignHack -0.07 &
  \cAlignHack 0.31 &
  \cAlignHack 0.01 &
  \cAlignHack 0.85\\
\cAlignHack MCH \mbox{}\protect\newline Pg &
  \cAlignHack 0.13 &
  \cAlignHack 0.08 &
  \cAlignHack -0.01 &
  \cAlignHack 0.82 &
  \cAlignHack 0.007 &
  \cAlignHack 0.93 &
  \cAlignHack 0.01 &
  \cAlignHack 0.85\\
\cAlignHack MCHC \mbox{}\protect\newline g/dl &
  \cAlignHack 0.14 &
  \cAlignHack 0.06 &
  \cAlignHack 0.08 &
  \cAlignHack 0.27 &
  \cAlignHack -0.10 &
  \cAlignHack 0.19 &
  \cAlignHack -0.01 &
  \cAlignHack 0.80\\
\cAlignHack Platelets \mbox{}\protect\newline Lakh/cumm &
  \cAlignHack -0.24 &
  \cAlignHack 0.06 &
  \cAlignHack -0.005 &
  \cAlignHack 0.95 &
  \cAlignHack -0.22 &
  \cAlignHack 0.004** &
  \cAlignHack 0.08 &
  \cAlignHack 0.27\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{*p{\textless}0.05, **p{\textless}0.01, ***p{\textless}0.001 significant correlations of serum CTN and serum VC with hematological parameters}
\end{tablenotes}
\end{threeparttable}

\end{table*}
The present study showed that tobacco chewers had significantly deranged hematological parameters. In the present study, we observed that, WBC count (p=0.04), granulocytes \% (p=0.0007), HCT (p=0.01) and MCV (p=0.04) were significantly increased whereas, monocytes \% (p=0.002) and platelet count (p{\textless}0.0001) was significantly decreased in ST chewers as compared to controls (Table~\ref{tw-ffb2455df255}). Selected hematological parameters showed increased derangement with respect to increased ST chewing duration in years (Table~\ref{tw-ed5a91662699}). Lymphocytes \% (p=0.02) and monocytes \% (p=0.001) were significantly decreased with respect to increased ST chewing duration whereas granulocytes \% (p=0.01) and platelets count (p{\textless}0.0001) were significantly decreased with respect to increased ST chewing duration. 

In the present study, monocytes \% (p= 0.008) shows a significant positive correlation with serum VC. WBC count shows a significant positive correlation with serum CTN (p=0.04) and a negative correlation with serum VC (p=0.05). However, platelet count (p=0.004) shows a significant negative correlation with serum CTN in ST chewers (Table~\ref{tw-e1dd88bbdc5b}).

In previous similar studies, it was concluded that Hb level and WBC count were increased whereas monocytes and basophils count were decreased in gutkha consumers as compared to controls \unskip~\citep{1136260:22508804,1136260:22508809,1136260:22508791}. 

In another previous study \unskip~\citep{1136260:22508782} observed that Hb, RBC and WBC count were significantly increased, whereas; lymphocytes, monocytes and platelet count were significantly decreased in tobacco chewers as compared to controls. The findings of Ukoha indicated that chronic tobacco consumption might put the body at some risk of adverse hematological and haemostatic conditions \unskip~\citep{1136260:22508781}. Roan Mukherjee reported that the adverse effects of gutkha on hematological parameters are not less than smoking \unskip~\citep{1136260:22508788}.

Nicotine present in tobacco might affect the suprarenal glands to release more catecholamine, which may influence leukocytosis causing damage and inflammation to tissues \unskip~\citep{1136260:22508790}. In the present study, WBC count was significantly increased in tobacco chewers as compared to controls. A similar significant increase in WBC count was also seen in previous studies \unskip~\citep{1136260:22508809,1136260:22508787}. 

The granulocytes, mainly neutrophils \%, significantly increased in the present study, may be linked with continuous inflammation of tissues. Neutrophils are well known to produce cytotoxic material which harmful to lung functions \unskip~\citep{1136260:22508796,1136260:22508810}. 

In our study, monocytes \% was significantly decreased in tobacco chewers than controls; this variation of monocytes \% might be due to placid adverse effects on lungs \unskip~\citep{1136260:22508806}.

However, lymphocytes \% did not show any significant change in tobacco chewers in the present study. According to previous studies, inadequate pulmonary function in tobacco and gutkha chewers might be responsible for stimulating erythropoiesis for fulfilling the demands of oxygen to the tissues \unskip~\citep{1136260:22508786}.

Blood indices such as MCV, MCHC, and MCH relate to individual RBCs as well as indicators of anemia. A lowered level of MCV related to iron deficiency anemia and increased levels are related to vitamin deficiency anemia \unskip~\citep{1136260:22508797}. 

In the present study, the MCV level (p=0.04) was significantly increased in tobacco chewers as compared to controls. A similar increase in the MCV level was found in the previous study \unskip~\citep{1136260:22508801}. 

However, after VC supplementation, the MCV level was decreased. It suggested that tobacco chewers had vitamin deficiency due to nicotine-induced oxidative stress. Whereas another study reported a significant decrease in the level of MCV in tobacco users \unskip~\citep{1136260:22508791,1136260:22508805}. 

In the present study, MCH and MCHC level did not show a significant change in tobacco chewers as compared to controls. However, some previous studies reported that the MCH level was found to be significantly increased in their studies \unskip~\citep{1136260:22508791,1136260:22508801,1136260:22508805}.\textbf{\space }

We studied the effect of VC supplementation in controls as well as in tobacco chewers independently for hematological parameters (Table~\ref{tw-2e00be64be09}). 

In the control group, WBC count (p=0.01) significantly decreased and Hb content (p{\textless}0.003) was significantly increased after supplementation of VC as compared to their baseline values. 

Whereas, in tobacco chewers group WBC count (p{\textless}0.001) and granulocytes \% (p{\textless}0.0001) were significantly decreased and lymphocytes \% (p=0.008), monocytes \% (p{\textless}0.0001), RBC count (p=0.01) and Hb content (p=0.006) were significantly increased after supplementation of VC as compared to baseline values. 

Vitamin C enhances the absorption of iron which is helpful to improve hemoglobin level in girls \unskip~\citep{1136260:22508815}. Vitamin C involves a hydrogen transfer rather than electron transfer and neutralizes harmful free radicals and reverted hemotoxicity \unskip~\citep{1136260:22508784}.  

In the previous study, Hounkpatin reported the protective effect of VC supplementation on deranged hematological parameters in Wistar rats \unskip~\citep{1136260:22508793}. 

Ibitoroko reported that hemotoxicity caused by gasoline was reversed by supplementation VC in Albino rats \unskip~\citep{1136260:22508792}, the similar result reported in rabbits \unskip~\citep{1136260:22508807}, in Herring gulls and Atlantic puffins \unskip~\citep{1136260:22508800}, in African catfish \unskip~\citep{1136260:22508785} and in Wistar rats \unskip~\citep{1136260:22508802}. 

Soronnadi reported that platelet count was significantly decreased after supplementation of VC \unskip~\citep{1136260:22508789}. This suggested that oral VC supplementation has beneficial effects on haemostatic dysfunction in chronic tobacco users. 
    
\section{Conclusion}
ST has adverse effects on hematological parameters such as an increase in WBC count, granulocytes \%, HCT and MCV and decreases monocytes \% and platelets count whereas, insignificant changes were observed in lymphocytes \%, RBC count, Hb, MCH and MCHC. Increased tobacco chewing duration produce increased adverse effects on health. In addition, it was concluded that long term supplementation with 1 g/day of vitamin C may help in improving deranged hematological parameters in ST chewers. 

\textbf{Funding Support}

The authors would be like to thank Krishna Institute of Medical Sciences, ``Deemed to be Uiversity," for funding the research. 

\textbf{Conflict of Interest}

The authors declare that they have no conflict of interest.
    

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