Original Article Correlative Analysis of Red Blood Cell ...

ABSTRACT

INTRODUCTION: Iron deficiency Anemia (IDA) is one of the world's most common and

potentially treatable health problems. In IDA, there is an increased risk of thrombotic events due to

microthrombosis-related hypercoagulability.

AIMS AND OBJECTIVES: To compare and analyze blood cell(RBC) and platelet parameters in

Iron Deficiency Anemia (IDA) patients with individuals without anemia and to establish the

correlation between platelet size parameters especially mean Platelet Volume (MPV), Platelet

Distribution Width (PDW) with RBC parameters.

MATERIAL AND METHODS: Totally 150 subjects (75 with IDA and 75 without anemia) were

included. Blood samples analyzed for RBC parameters with iron profile and platelet parameters.

RESULTS: The difference in mean hemoglobin (Hb), RBC count, hematocrit (HCT), Mean

corpuscular volume (MCV), Mean corpuscular hemoglobin (MCH), Mean corpuscular hemoglobin

concentration (MCHC), Red cell Distribution Width (RDW), Serum iron, serum ferritin levels and

similarly the difference in mean Platelet count, Plateletcrit (PCT), MPV and PDW between patients

with IDA and those without anemia were statistically significant (p<0.05). Significant direct linear

relationship between PDW, MPV and RDW and a significant inverse linear relationship between

Platelet count with Hb, RBC count, HCT, MCH, MCHC, serum iron and serum ferritin, MPV with

HCT, MCH, MCHC, serum iron and PCT with MCH, MCHC. The following parameters were

noticed and were statistically significant(p<0.05)

CONCLUSION : Our study demonstrates a significant association between RBC and platelet

parameters in IDA. We speculate that platelets in IDA are increased, more aggregableand hence an

increased risk of thrombosis owing to increased MPV and PDW. This insight should pave the way

for pathophysiology-directed therapy, thus contributing to the avoidance of thrombosis associated

with IDA and the importance of close monitoring in these patients.

KEYWORDS : Anemia, Iron deficiency, Red blood cell indices, Platelet indices, thrombosis

Address for correspondence:

Dr. Lavanya Rajagopal, F4, Trisquare Prestige Appartment,Vivekanandanagar, Sambakulam, Moondrumavadi,

K.Pudur, Madurai - 625007, Tamilnadu, Email id:[email protected], Mobile : 08754131339

1 2 5Assistant Professor, Assistant Professor, Professor and HOD, Department of Pathology, SRM Medical College Hospital and Research Centre, Kattankulathur, Chennai.

4Dean (Medical), Professor, Department of Pathology, SRM Medical College Hospital and Research Centre,Kattankulathur, Chennai.

3Faculty Of Applied Medical Sciences, Medical Laboratory Department, Jazan University, Jazan, Saudi Arabia.

Correlative Analysis of Red Blood Cell and Platelet Parameters Predicts

the Risk of Thrombosis in Patients with Iron Deficiency Anemia1 2 3Lavanya Rajagopal , Veena Raja , Saleh Mohammed Abdullah ,

4 5Sundaram Arunachalam , Shivashekar Ganapathy

16

http://dx.doi.org/10.31975/NJBMS.2018.9103

Original Article

National Journal of Basic Medical Sciences | Volume 9 | Issue 1 | 2018

17

Moreover, several recent studies and meta-analyses

suggest that higher MPV and PDW values indicate

platelets, which are metabolically and

enzymatically more active with a great

prothrombotic potential and can be used as an 22alternative marker for platelet activity. The

relationship between platelet counts MPV, PDW

and risk of thrombosis has been of special interest 16,23-27in IDA and healthy individuals in literature.

Although the exact mechanism of alterations in

platelet parameters associated with iron deficiency

is unknown, iron is postulated to play a key role in

the synthesis of platelets and in the regulation of 28thrombopoiesis. This study demonstrates the

effect of iron deficiency on platelet parameters and

provides an insight into the pathogenesis of

alterations in platelet parameters associated with

iron deficiency.

There are only few reports in literature regarding

the correlation of platelet parameters with red 29blood cell parameters. The objective of this study,

therefore, was to compare and analyze red blood

cell (RBC) and platelet parameters in IDA patients

with individuals without anemia and furthermore to

establish the correlation between platelet size

parameters especially MPV, PDW with RBC

parameters.

METHODS :

This descriptive analytical cross-sectional study

was carried out in department of pathology over a

period from august 2016 to August 2017, at SRM

Medical College Hospital & Research Centre,

Kattankulathur, Tamilnadu, India and approved by

institutional ethical committee. Totally 150

subjects aged more than 20 years of both genders

(75 with IDA and 75 without anemia) were

INTRODUCTION:

ron deficiency is one of the world's most

common and potentially treatable health Iproblems, nevertheless little is known about its

relationship with platelet parameters. The first

observations were reported in 1904, when the effect

of severe hemorrhage on the number of platelets 1was tested in rabbits. In Iron deficiency anemia

(IDA), several changes in platelets have been

reported. So, a relationship between iron

metabolism and thrombopoiesis should be 2,3considered. Several research reports linked

thrombosis, thrombocytosis and iron deficiency

and the suggested relationship between the two 4-10assumes clinical importance.

A biphasic pattern of platelet response was noted in

patients with IDA. Moderate IDA is usually 11-13

associated with reactive thrombocytosis.

Thrombocytopenia can be seen in patients with 3,14-16severe IDA. Both thrombocytosis and

thrombocytopenia may disappear af ter 12-15

irontherapy.

Erythropoietin (Epo) is the primary growth factor

for the red cell lineage, regulating the survival,

proliferation and differentiation of erythroid

precursors but treatment with recombinant human

Epo (rHuEpo) has been shown to increase platelet 17-19counts. A recent study conducted in dogs

showed that EPO not only st imulates

erythropoiesis but also affects platelet quality by 20increasing platelet reactivity.

Iron deficiency can cause hypercoagulability,

reactive thrombocytosis, anemia, and increased

viscosity due to red cell deformability related to 21microcytosis. In IDA, there is an increased risk of

thrombotic events due to microthrombosis-related

hypercoagulability.

Lavanya Rajagopal et.al : Red Blood Cell and Platelet Parameters predicts Thrombosis in IDA


18

included in this study. Their blood samples (5 ml)

were analyzed for red cell parameters [hemoglobin

(Hb), RBC count (RBC), hematocrit (HCT), Mean

corpuscular volume (MCV), Mean corpuscular

hemoglobin (MCH), Mean corpuscular

hemoglobin concentration (MCHC), Peripheral

smear, Serum iron and Ferritin levels] and Platelet

parameters [Platelet count, Plateletcrit (PCT),

Mean Platelet Volume (MPV) and Platelet

Distribution Width (PDW)]. History of underlying

hematologic disorder, chronic kidney disease,

diabetes, pregnant woman and patients on

antiplatelet drugs, hematinics were excluded from

this study. Informed consent was obtained from all

the subjects. Medical history recorded.

The anemic patients were selected based on their

hemoglobin levels (Hb<13 gm% in males and <12

gm% in females) based on definition of World

Health Organization (WHO) and those with

predominantly microcytic red cell indices

(MCV<76 fl), hypochromic red cell indices

(MCH<27 pg/cell and MCHC<32 gm/dl) and on

their peripheral smear (microcytic hypochromic)

were considered to have IDA which was confirmed

by low serum iron (<59 μg/dl in males and <37

μg/dl in females) & low serum ferritin (<15 ng/ml

in males and <9 ng/ml in females).

Red cell and platelet parameters were estimated by

SYSMEX XT-1800i automated Hematology

analyzer. Serum ferritin (Bio-Rad Quanimune

Ferritin IRMA, Bio-Rad lab) & Serum iron (TPTZ)

method.

STATISTICAL ANALYSIS

The data are presented as mean ± SD for continuous

variables. A student's t- test was applied for

comparison of group means. Pearson's co-efficient

was calculated to determine correlation between

two variables. P value <0.05 was considered

statistically significant.

RESULTS

Table-1: Comparison of red cell parameters

between anemic (IDA) and not anemic

individuals.

In this study the difference in mean Hb, RBC count,

Hct, MCV, MCH, MCHC, RDW, Serum iron and

ferritin between patients with IDA and those

without anemia was statistically significant

(p<0.05).

Table-2: Comparison of platelet parameters

between anemic (IDA) and not anemic

individuals.

Similarly, the difference in mean platelet count,

PDW, MPV and PCT between patients with IDA

and those without anemia was statistically

significant (p<0.05).



19

Table 3: Correlation between red cell and

platelet parameters among anemic (IDA) and

not anemic individuals.Significant* (p < 0.05).

In patients with IDA, when Pearson's correlation

test was performed, inverse correlation between

platelet count, PCT and Hb, RBC count, HCT,

MCV, MCH, MCHC, Serum iron, serum ferritin

and linear correlation between platelet count, PCT

and RDW was determined.

The observations derived from the present study

also shows inverse correlation between PDW and

Hb, RBC count, Hct, MCH, MCHC; linear

correlation between PDW and MCV,RDW, serum

iron and serum ferritin. Similarly, inverse

correlation between MPV and HCT, MCH, MCHC,

serum iron and serum ferritin; linear correlation

between Hb, RBC count, RDW was determined.

In the stepwise logistic regression test, a

statistically significant direct linear relationship

between PDW, MPV and RDW (p<0.05) was

seen.Similarly, a statistically significant inverse

linear relationship between the following

parameters was noticed.

I. Platelet count with Hb, RBC count, Hct, MCH,

MCHC, serum iron and serum ferritin (p<0.05).

ii. MPV with Hct, MCH, MCHC, serum iron

(p<0.05).

iii. PCT with MCH, MCHC (p<0.05).

No association of statistical significance was seen

between other platelet and RBC parameters in

patients with IDA.In individuals without anemia,

we observed no significant correlation between

RBC and platelet parameters except for Hb and

MPV.

DISCUSSION :

The ontogeny of human hematopoietic cells has

been an area of constant research and immense

interest.Here we addressed the hypothesis that iron

deficiency is also relevant for IDA-associated

thrombocytosis and also a risk factor for

thrombosis. This study is the first to underline the

relevance of iron deficiency in this setting.

The uniquely anuclear red blood cell is one of the 30

most highly specialized of cells. Platelets are

small anuclear cell fragments that are derived from

mature megakaryocytes. An increase in the

circulating number of platelets may occur in

circumstances such as neoplastic proliferative

diseases (i.e. essential thrombocytosis) or reactive

thrombocytosis secondary to IDA, malignancy 31-33

etc.

Some of the features that are similar to both RBCs

and platelets are: I) both develop from a common 34Megakaryocyte/Erythroid progenitor cell (MEP).

A population of probable erythrocytic and

megakaryocytic cell lineage precursors co-35

expressed glycophorin A and glycoprotein IIIa.

Such a bipotentery megakaryocytic progenitor has 36been characterized in human bone marrow,

ii)Both red blood cells and platelets are anucleate 37form in the peripheral blood, iii) Both the cells

have an immature peripheral blood stage called as

reticulocyte for RBCs and reticulated platelets for 38

platelets.



20

Erythropoietin and thrombopoietin share a high

degree of amino acid sequence homology (first 155

amino acids are common). Based on this theory,

thrombocytosis in children with iron deficiency 39

anemia was explained by Bilic E et al. Munker M

et al suggest that both thrombopoietin and

ery thropoie t in be longing to the same

hematopoietic growth factor subfamily, are

majorly produced in the kidney and act similarly

by activating the JAK/STAT pathway and Ras 40

signal transduction on their respective precursors.

GATA-1, a transcription factor is expressed in

p r imi t i ve and de f in i t e e ry th ro id and

megakaryocytic cells and expression of both

lineages are dependent on the presence of an intact 41GATA site. Thus a large body of data supports the

concept that megakaryocytic and erythrocytic cell 4 2l ineages share a common progenitor.

Megakaryocytes have been shown to express

erythroid-specific transcription factors, such as 43 44

GATA factors, a specific DNA-binding protein

or a nuclear factor involved in the regulation of 45

globin transcription.

Iron Deficiency (ID) is the world's most

widespread nutritional disorder, irrespective of

age, gender and socioeconomic status, affecting

both industrialized and developing countries.

Approximately one-third of patients with anemia 46

exhibit iron deficiency. The annual incidence rate

of iron deficiency anemia (IDA) is 7.2-13.96 per 47

1,000 people per year. Although few studies have

linked IDA with altered platelet parameters, the

relationship between them has long been a topic of

debate in the literature.

Our study results show a statistical significant

increase in platelet count and platelet crit in patients

with IDA when compared with individuals without

anemia(Table 2). This coincides with the results of 48 49 50 Yuce S et al, Kodikoylu G et al, Park MJ et al but

28contradicts with results of Gupta et al, Perlman

14 51MK et al, Morris VK et al.

The mechanism leading to thrombocytosis in cases

of iron deficiency anemia remains unclear. The

duration and the degree of IDA may play a role in

determining the mechanism of platelet production.

In moderate IDA, the causes of thrombocytosis

may be: 1) shortening of megakaryocyte

maturation 2) increased rate of influx of precursor

cells into the megakaryocyte compartment with an

increased rate of efflux 3) stimulator effect of

transferrin on megakaryopoiesis 4) inhibition of 52-54

iron on megakaryocyte maturation. However,

when iron deficiency becomes very severe,

m e g a k a r y o c y t e n u m b e r s d e c r e a s e d ,

megakaryocyte size increased, and platelet counts

tended to normalize. This may be due to the

shortening of megakaryocyte maturation. This

could, however, also be consistent with the

previously described diphasic pattern of increased 52,53stimulation by endogenous Epoprecursors.

Bilic and Bilic reported that an amino acid

sequence homology between erythropoietin and

thrombopoietin may explain thrombocytosis in 39

children with IDA.

Our study results show a statistically significant

increase in MPV in patients with IDA when

compared with individuals without anemia (Table 50

2). This coincides with the results of Park MJ et al 48but contradicts with results ofYuce S et al.

Similarly a statistically significant increase in

PDW in patients with IDA (Table 2). This coincides 55

with the results of Timuragaogluet al. Our study

results show a statistically significant direct linear



21

relationship between MPV, PDW and RDW in

patients with IDA (Table 3). This coincides with the 56 29

results of Wiwanitkit V et al and Saouli Z et al.

Although thrombotic and bleeding events are much

less likely to occur in association with reactive

t h r o m b o c y t o s i s t h a n a u t o n o m o u s 57thrombocytosis, thrombotic complications were

58-59occasionally reported in iron deficiency anemia.

Previous studies have shown that elevation of

collagen and ADP during IDA may lead to 60increased thrombocyte aggregation. However,

other studies have not found increased collagen and 61,62ADP during IDA. Malhotra RK et al studied

platelet aggregation with ADP, adrenaline and

collagen before and after iron therapy in IDA

patients. He found that in untreated patients platelet

aggregation with all three reagents was reduced,

and it became normal on iron repletion, with 63normalization of hemoglobin.

Larger platelets are younger, more reactive and

aggregable, contain denser granules, secrete more

serotonin and β-thromboglobulin, and produce

more thromboxane A2 than smaller platelets. All

these can produce a pro-coagulant effect and cause 64

thrombotic vascular complications. Several

recent studies and meta-analyses suggest that

higher MPV and PDW values indicate platelets,

which are metabolically and enzymatically more

active with a great prothrombotic potential and can

be used as an alternative marker for platelet 65activity. The activated platelets differ in size from

non-activated ones mainly due to a change from a

discoid to a spherical shape and pseudopodia

formation, leading to a change in the Platelet 66Distribution Width (PDW). The differences in

platelet volume vividly correlates with differences

in density, platelet aggregation to adenosine di-

phosphate and serotonin uptake and release,

supporting the relevance of the Mean Platelet 67,68Volume (MPV) as a measure of platelet function.

Thus Platelet size has become an important marker

of platelet function and also a physiological 69

variable of hemostatic importance.

Table 4: Comparison of present study with

different studies.

Another important clinical implication of this

inverse relationship would be in voluntary

plateletpheresis. The American Association of

Blood Banks (AABB) demonstrated that higher

donor platelet counts reflected a decrease in MCV,

thus projecting a higher likelihood of donor iron 70deficiency in high plateletpheresis yields. Higher

RDW has also been shown to concurrently occur

with higher platelet counts in advanced cancer 71stages, particularly in lung cancer.

LIMITATIONS OF THE STUDY :

There are few limitations in our study such as small

sample size and qualitative platelet disorders were

not assessed.



22

CONCLUSION :

Our study clearly demonstrates a significant

association between red cell and platelet

parameters in IDA. This study has indicated that

IDA could induce thrombocytosis. We speculate

that platelets of IDA patients become more reactive

and more aggregabledue to red cell deformability

related to microcytosis and hence an increased risk

of thrombosis owing to increased MPV and PDW.

This insight should pave the way for

pathophysiology-directed therapy, thus

contributing to the avoidance of several deleterious

effects like thrombosis associated with IDA and the

importance of close monitoring in these patients.

Further studies with larger samples are needed to

clarify these relations in terms of the pathogenesis.

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Received on : 17-02-2018 Revised on : 08-03-2018 Accepted on : 16-07-2018



Original Article Correlative Analysis of Red Blood Cell ...

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