Are mean platelet volume and splenomegaly subclinical inflammatory marker in children with familial mediterranean fever ?

The present study aimed to investigate the correlation of MPV and splenomegaly as inflammation activity of FMF patients at the attacks free period. We retrospectively reviewed the medical records of 43 patients with FMF. This study was performed at the attack free period as clinical and laboratory. For this study, patients were divided into two groups. Patients with splenomegaly is called group 1 (n = 12) and patients with no splenomegaly is called group 2 (n = 31). Groups were compared respect to age, gender, platelet counts, acute phase reactants and MPV. The mean MPV (fl) were significantly higher in group 1 (8.9 ± 0.8) than in group 2 (8.4 ± 0.5, p < 0.05). This study suggested that increased MPV and splenomegaly without amyloidosis could be a sign of chronic inflammation in children with FMF even in attack free period.


INTRODUCTION
Familial Mediterranean fever (FMF) is a recessive disorder characterized by attacks of periodic fever and inflammation [1].The FMF patients are asymptomatic, acute phase reactants (C-reactive protein, ESR) are normal in the attacs free period, but serum amyloid A (SAA) and some cytokines are constantly higher [2,3].Subclinical inflammation continues in attack-free period in FMF patients [3,4].
It has been reported that IL-6 /HPRT is significantly higher than control in attack free period of FMF (3).IL-6 has been shown to promote megakaryocyte maturation in the absence of other growth factors.It possibly stimulates megakaryocyte proliferation.Administration of IL-6 has been shown to result in a significant increase in the platelet count [5].Also it is a cytokine that can induce the formation of SAA and C-reactive protein (CRP) [6][7][8].Erythrocyte sedimentation rate, CRP and SAA correlate closely with clinical disease activity in FMF patients [4].
The spleen acts as a reservoir for platelets; one-third of the circulating platelet mass is temporarily sequestered within a normal sized spleen, and up to 90 percent may be found within a markedly enlarged spleen.The etiology of splenomegaly may relate to an increase in a normal splenic process (e.g.hemolysis) or may be due to infiltrative, infectious, or vascular disorders [9].Involvement of the reticuloendothelial system in FMF is rare mentioned in the literature [10,11].Splenomegaly in patients with FMF may be related to the rate of platelet destruction.The changes of peripheral platelet volume depend on the rate of splenic sequestration and bone marrow production.The platelet survival is directly related to the lowest platelet count and inversely related to both the highest mean platelet volume and duration of the thrombocytopenia [12].If the rate of platelet destruction is equal or higher than the rate of platelet production, mean platelet volume is increase because of increased peripheral immature platelets.If the rate of platelet destruction is lover than the rate of platelet production, mean platelet volume is normal or decrease [12,13].
Mean platelet volume (MPV) is a parameter generated by full blood count analyzers as part of the routine complete blood count (CBC) test which is usually overlooked by clinicians.MPV correlates with the platelet function and activation.An association between FMF activity and MPV has not been investigated yet.
The present study aimed to investigate the correlation of MPV and splenomegaly as the inflammatory activity of FMF patients at the attacks free period.

PATIENTS AND METHODS
We retrospectively reviewed the medical records of 43 patients with FMF who were followed up in our Pediatric Nephrology and Rheumatology Unite.The diagnosis of FMF was made according to the diagnostic criteria which described by Livneh et al. and DNA analyses [14,15].This study was performed at the attack free period.The attack free period was accepted if the clinically patient had no symptoms and in the laboratory, ESR and CRP were normal.Patients were divided into two groups according to splenomegaly.Patients with splenomegaly is called group 1 (n = 12) and patients with no splenomegaly is called group 2 (n = 31).Groups were compared respect to age, gender, platelet counts, acute phase reactants (ESR and CRP) and MPV.None of the patients had abnormal urinalysis for proteinuria.Splenomegaly has been established by physical examination and confirmed by abdominal ultrasound (USG).In USG examination, we used age and height dependant standarts for splenomegaly [16].

STATISTICAL ANALYSIS
All tests were performed using SPSS for Windows 15.0.The parameters with normal distribution were expressed as mean ± SD and the parameters with abnormal distribution were expressed as median (minimum-maximum).Comparisons of means were performed with unpaired t-test.Comparisons of medians were performed with Mann-Whitney U-test.Comparisons of proportions were performed with Pearson-chi-squared test.A P value < 0.05 was accepted as statistically significant.

RESULTS
The results of genotype of the patients with FMF were showed in Table1.Table 2 shows epidemiological and laboratory findings of the patients with FMF.While the group 1 included two girls and ten boys, the group 2 included 15 girls and 16 boys.The mean age of the group 1 and group 2 were 11.0 ± 4.4 and 10.1 ± 3.5, respectively.The mean platelet counts of the group 1 and group 2 were 248500 ± 67654 and 281000 ± 51847, respectively.There was no significant difference between group 1 and group 2 according to age and platelet counts (p > 0.05).The mean MPV (fl) were significantly higher  in group 1 (8.9 ± 0.8) than in group 2 (8.4 ± 0.5, p < 0.05) (Table 2).

DISCUSSION
Involvement of the reticuloendothelial system in FMF is seldom mentioned in the literature [10,11].Enlargement of the spleen without amyloid deposition has been reported in 30.7% of patients with FMF [17].Aharoni et al. [18] detected splenomegaly in 27.5%, 13.3% of patients with FMF at the attack and at attack free period, respectively.In our study, splenomegaly was detected by physical examination and abdominal ultrasound in 27.9% of FMF patients at the attacks free period.
In literature, so far, it has not been reported study that investigates association between MPV and disease activity in patients with FMF.There are few studies about the association between MPV and the clinical activity of rheumatoid arthritis.Milovanovic et al. [19] have reported that in active disease IL-6 but not thrombopoietin (TPO) is related to platelet count.Thus, IL-6 raises platelet count in reactive thrombocytosis and the neutrophil count.In rheumatoid arthritis, MPV and myeloperoxidase also mirror the disease activity [19].In the other study has been reported that cytokines and IL-6, IL-11 and growth factors (e.g.TPO) may also contribute to the pathologic megakaryocytopoiesis of RA [20].Kisacik et al. [21] have been shown the correlation between MPV and the clinical activity of rheumatoid arthritis and ankylosing spondylitis.They suggest the assessment of MPV that may provide additional information about inflammation in AS and RA.
Up now, there are two study that has been shown the association with splenomegaly and genotype in patients with FMF in the literature [22,23].Kone et al. [22] showed that homozygosity for the M694V mutation correlated with splenomegaly.But, Inal et al. [23] didn't detect the association with splenomegaly and genotype in patients with FMF.In our study, since the the number of the patients is small to do the correlation with the genotype and splenomegaly, we do not find the result statistically significant.
In conclusion, the diagnosis of FMF is based mainly on the clinical criteria and laboratory examinations.We found the correlation of MPV and splenomegaly as the inflammatory activity of FMF patients at the attacks free period.These could help to diagnosis of the FMF and may be applible for clinical chronic inflammatory condition score marker that related to prognosis or the possibility that development of amiloidosis.Further and including much more number patients studies are needed to confirm.

Table 1 .
Shows genotyping distribution of patients with FMF.

Table 2 .
Epidemiological and laboratory findings of the patients with FMF.