Immune Thrombocytopenia among Children Living at a High Altitude Region: A Hospital-Based Retrospective Study

Med. J. Cairo Univ., Vol. 82, No. 2, December: 87-93, 2014 www.medicaljournalofcairouniversity.net Immune Thrombocytopenia among Children Living at a High Altitude Region: A Hospital-Based Retrospective Study ALI AL-SUHEEL, M.D.*; AYED SHATI, M.D.*; SULTAN A. ALMEDHESH, M.D.**; DHAFER B. ALSHEHRI, M.D.** and MOHAMED ALZAHRANI, M.D.** The Department of Child Health, College of Medicine, King Khalid University, Abha*, KSA and Najran University, Najran**, KSA Abstract Objective: To identity the pattern of immune thrombocytopenia (ITP) and to describe presenting features, laboratory characteristics and outcome of the ITP among Saudi children living at a high altitude area. Methodology: A retrospective descriptive study design was followed at the Pediatric Medical Department of Aseer Central Hospital, during the period from January 2011 till December 2013. All data of children aged 6 months till 12 years with the diagnosis of ITP during the study period (n=46) were included into this study. Results: More than half of patients were females (58.7%). Most of them were diagnosed before the age of 6 years (86.9%). More than half of patients had their ITP attack after infection (58.7%). Only one patient had positive family history (2.2%). The most common symptoms were skin rash (93.5%) and epistaxis (41.3%), which was significantly more among male children. The most common signs were ecchymosis (87%), purpura (76.1%), petechial rash (60.9%), bleeding in mucous membranes (58.7%) and pallor (32.6%). Splenomegaly was present in 6.5% of patients. Platelet count of most children (80.4%) was less than 20x10 3 /ml, 37% had low hemoglobin level (5-12gm/dL). ESR was >30mm/hour in almost one fourth of patients. Peripheral blood smears showed isolated thrombocytopenia in 82.6% of patients, megakaryocytes in 15.2% and pancytopenia in 2.2% of patients. Bone marrow aspiration was performed for 28 cases (60.9%) to confirm diagnosis (50%), to start steroids treatment (4.3%), for pancytopenia (4.3%) or splenomegaly (2.2%). On discharge, the condition of 63% of children with ITP was completely resolved, with a higher cure rate among boys than girls (84.1% and 48.1%, respectively), 34.8% had chronic ITP, with a lower proportion among boys than girls (15.8% and 48.1%, respectively). One child died (2.2%), who was a girl. Differences between male and female children with ITP regarding their outcome at discharge were statistically significant (p=0.042). Conclusions: There are higher predilection of ITP and significantly lower cure rates among girls than boys. These findings need further epidemiological, biochemical and hematological studies to be explained. Correspondence to: Dr. Ali Al-Suheel, The Department of Child Health, College of Medicine, King Khalid University, Abha, KSA Key Words: Immune thrombocytopenia Children High altitude Saudi Arabia Retrospective study. Introduction IMMUNE thrombocytopenic purpura (ITP) is no longer considered idiopathic [1]. ITP is an acquired hematological disorder that is developed as a result of the production of auto-antibodies against platelets leading to isolated thrombocytopenia, in the absence of other causes of thrombocytopenia such as drugs, preceding infection, malignancy, or other autoimmune diseases [2,3]. The International Working Group [4] noted that the term purpura is not accurate since many patients do not present with bleeding symptoms and even thrombocytopenia could be discovered incidentally during a routine clinic visit. However, the acronym ITP continued to be used and will stand for the new proposed name, i.e., immune thrombocytopenia. Moreover, the platelet count threshold to establish the diagnosis was set at a new level (i.e., 100x10 9 /L) instead of the previous limit of (150x10 9 /L). The report proposed further definitions to the phases of the disease as follows: Newly diagnosed ITP (within 3 months from diagnosis), persistent ITP (between 3 to 12 months from diagnosis; this includes patients that do not reach spontaneous remission or do not maintain complete response off therapy), and chronic ITP (lasting for more than 12 months). Cases of ITP have been identified several centuries ago. In the l0th century, the Muslim philosopher and physician Abu Ali Al-Hussain, Ibn Abdullah Ibnsina (Avicenna) described a chronic form of purpura that matches the diagnosis of ITP [5]. In 1735, the German poet and physician Paul Gottlieb Werlhof gave a classical description of ITP. He described a disease in a 16-year old girl 87

88 Immune Thrombocytopenia among Children Living at a High Altitude Region who had cutaneous and mucosal bleeding and called it morbus maculosus haemorragicus. The condition was then called after him as Werlhof disease [5,6]. In 1951, Evans was able to identify the plasma factor as antiplatelet antibody [7]. In the same year, Wintrob was the first to use steroids for the treatment of ITP [8]. In 1983, the use of anti-d in ITP was described by Salama et al., [9]. The use of rituximab was introduced by the end of 20t h century for the treatment of patients with chronic and refractory ITP [10-12]. Recently, the use of thrombopoietin (TPO) agonists to enhance platelets production showed promising results in severe refractory chronic ITP [13-15]. ITP in children typically affects a previously healthy child who is between two to seven years of age. The diagnosis of ITP in children is essentially one of exclusion. The CBC shows isolated thrombocytopenia with normal WBC and normal hemoglobin levels. The peripheral blood smear shows no evidence of abnormal cells [8,16]. Laboratory investigations in ITP include complete blood count (CBC) and peripheral blood smear, which are essential to establish the diagnosis of ITP. CBC shows isolated thrombocytopenia with normal WBC and normal hemoglobin levels. Anemia is present only if there is severe bleeding [17-20]. Bone marrow aspiration (BMA) is not required to establish the diagnosis of ITP and also is not necessary prior to steroid treatment in typical cases of ITP. However, BMA should be done if there is bone pain, lymphadenopathy, hepatosplenomegaly, anemia that is not explained by blood loss, or abnormally high or low WBC. Antiplatelet antibodies measurement does not assist in the diagnosis of ITP. It is usually done for research purposes [12-18]. The aim of this study is to identity the pattern of immune thrombocytopenia (ITP) and to describe presenting features, laboratory characteristics and outcome of the ITP among Saudi children living at a high altitude area. Patients and Methods Following a retrospective descriptive study design, the researchers reviewed and analyzed all medical records of patients admitted to the Pediatric Medical Department of Aseer Central Hospital, during the period from January 2011 till December 2013. Aseer Central Hospital is a tertiary care hospital with 570 beds capacity, while the Pediatric Medical Department is 40-bed capacity. It serves the com- munity of Aseer Region in the southwestern part of Saudi Arabia, which is a mountainous region with high altitude, about 3000 meters above the sea level. The Saudi population inhabiting Aseer Region belongs almost entirely to ancient tribes native to the area. All data of children aged 6 months till 12 years with the diagnosis of ITP during the study period (n=46) were included into this study. These data comprised patient's nationality, age at diagnosis, exposure to infections before onset of ITP, family history of ITP, symptoms, signs, laboratory findings and patient's condition on discharge form hospital. The Statistical Package for Social Sciences (SPSS version 22.0) was used for data entry and statistical analysis. Descriptive statistics (frequency and percentage) and chi square test of significance (x 2 -test) were applied. A difference was considered as statistically significant at p<0.05. Results Table (1) shows that more than half of our cases were females (58.7%). Most of cases were diagnosed before the age of 6 years (86.9%). More than half of patients had their ITP attack after infection (58.7%). Only one patient had positive family history (2.2%). Table (1): Characteristics of ITP patients (n=46). Characteristics No. % Gender: Male 19 41.3 Female 27 58.7 Age at diagnosis: <2 years 14 30.4 2-6 years 26 56.5 >6 years 6 13.0 Infection before the ITP attack: No 19 41.3 Yes 27 58.7 Positive family history of ITP 1 2.2 Table (2) shows that the most common symptoms were skin rash (93.5%) and epistaxis (41.3%), which was significantly more among male children. The most common signs were ecchymosis (87%), purpura (76.1%), petechial rash (60.9%), bleeding in mucous membranes (58.7%) and pallor (32.6%). Splenomegaly was present in 6.5% of patients. Apart from epistaxis, all other clinical findings were not significantly different between males and female children.

Ali Al-Suheel, et al. 89 Table (3) shows that platelet count of most children (80.4%) was less than 20x10 3 /ml. More than one third of patients (37%) had low hemoglobin level (5-12gm/dL). ESR was >30mm/hour in almost one fourth of patients. The MPV of more than half of patients (54.3%) was 8-10 fl. Antinuclear antibody was performed for 7 cases, of whom, 3 children were positive (6.5%). Peripheral blood Table (2): Clinical criteria of ITP patients according to their gender. Clinical criteria Male (n=19) Gender smears showed isolated thrombocytopenia in 82.6% of patients, megakaryocytes in 15.2% and pancytopenia in 2.2% of patients. Bone marrow aspiration was performed for 28 cases (60.9%) to confirm diagnosis (50%), to start steroids treatment (4.3%), for pancytopenia (4.3%) or splenomegaly (2.2%). Results of all laboratory findings were not significantly different between males and female patients. Female (n=27) Total (n=46) p-value Symptoms: Skin rash 18 (94.7%) 25 (92.6%) 43 (93.5%) 0.772 Hematuria 2 (10.5%) 1 (3.7%) 3 (6.5%) 0.561 CNS symptoms 1 (5.3%) 1 (3.7%) 2 (4.3%) 0.798 Gastrointestinal bleeding 3 (15.8%) 5 (18.5%) 8 (17.4%) 0.810 Epistaxis 12 (63.2%) 7 (25.9%) 19 (41.3%) 0.010 Signs: Petechial rash 9 (47.4%) 19 (70.4%) 28 (60.9%) 0.137 Purpura 14 (73.7%) 21 (77.8%) 35 (76.1%) 0.749 Echymosis 15 (78.9%) 25 (92.6%) 40 (87.0%) 0.213 Pallor 6 (31.6%) 9 (33.3%) 15 (32.6%) 0.901 Bleeding in the MM 11 (57.9%) 16 (59.3%) 27 (58.7%) 0.926 Splenomegaly 1 (5.3%) 2 (7.4%) 3 (6.5%) 0.772 MM: Mucous membranes. Table (3): Laboratory criteria of ITP patients according to their gender. Laboratory tests Male (n=19) Gender Female (n=27) Total (n=46) p-value Platelets (x10 3 /ml): <_20 14 (73.7%) 23 (85.2%) 37 (80.4%) 20-50 3 (15.8%) 3 (11.1%) 6 (13.0%) 0.558 50-100 2 (10.5%) 1 (3.7%) 3 (6.5%) Hemoglobin (gm/dl): 5-12 >_ 12 6 (31.6%) 13 (68.4%) 11 (40.7%) 16 (59.3%) 17 (37.0%) 29 (63.0%) ESR (mm/hour): <_30 14 (73.7%) 21 (77.8%) 35 (76.1%) 30-100 4 (21.1%) 5 (18.5%) 9 (19.6%) >_ 100 1 (5.3%) 1 (3.7%) 2 (4.3%) 0.941 MPV (fl): 8-10 10 (52.6%) 15 (55.6%) 25 (54.3%) >_ 10 9 (47.4%) 12 (44.4%) 21 (45.7%) 0.845 Antinuclear antibody: Positive 0 (0.0%) 3 (11.1%) 3 (6.5%) Negative 1 (5.3%) 3 (11.1%) 4 (8.7%) Not done 18 (94.7%) 21 (77.8%) 39 (84.8%) 0.231 Peripheral blood smear: Megakaryocytes 4 (21.1%) 3 (11.1%) 7 (15.2%) Isolated thrombocytopenia 15 (78.9%) 23 (85.2%) 38 (82.6%) Pancytopenia 0 (0.0%) 1 (3.7%) 1 (2.2%) 0.477 Indications for BMA: Not indicated 17 (36.8%) 26 (40.7%) 43 (39.1%) Splenomegaly 1 (5.3%) 0 (0.0%) 1 (2.2%) Pancytopenia 1 (5.3%) 1 (3.7%) 2 (4.3%) 0.311 BMA: Bone marrow aspiration. 0.555

90 Immune Thrombocytopenia among Children Living at a High Altitude Region Table (4) shows that on discharge, the condition of 63% of children with ITP was completely resolved, with a higher cure rate among boys than girls (84.1% and 48.1%, respectively). On the other hand, 34.8% of cases had chronic ITP, with a lower proportion among boys than girls (15.8% and 48.1%, respectively). One child died (2.2%), who was a girl. Differences between male and female children with ITP regarding their outcome at discharge were statistically significant (p=0.042). Table (4): Outcome of ITP patients on discharge from hospital. Resolved Chronic Death Male (n=19) 16 (84.1%) 3 (15.8%) 0 (0.0%) Female (n=27) 13 (48.1%) 13 (48.1%) 1 (3.7%) Discussion Total (n=46) p value 29 (63.0%) 16 (34.8%) 1 (2.2%) 0.042 Immune thrombocytopenia (ITP) is a common worldwide hematologic disorder [21], which usually runs a benign, self-limiting course, with or without treatment [16]. In this retrospective hospital-based study, a total of 46 children with ITP were seen at the Pediatric Medical Department, of the tertiary care Aseer Central Hospital, during a period of 3 years. Results of this study showed a higher proportion for ITP among girls (58.7%). This finding is in agreement with that of Watts [22], who found that childhood ITP affected girls more than boys. However, Al Fawaz [23] reported that during a 7-year period, 49 children with ITP were seen at King Khalid University Hospital, Riyadh, Saudi Arabia, with higher male to female ratio (30 boys and 19 girls). In Qatar, Al-Mulla et al., [24] reported that ITP was more prevalent among boys (64.5%) than girls. Also in Iran, Saeidi et al., [25] reported that childhood ITP was higher in males than females. However, Yong et al., [26] stated that ITP in children affects males and females equally. The variable male to female ratios among children with ITP in different studies have been explained by Fogarty and Segal [27] who reported that a higher male to female ratio exists during infancy with a gradually decreasing trend afterwards. This study showed that most children presented with ITP before the age of 6 years (86.9%). This finding is in agreement with that of Ahn and Horstman [28], who observed a higher incidence of the ITP among children aged 2 to 4 years. In addition, Al-Mulla et al., [24] reported that most children diagnosed with ITP were under the age of 5 years (60%). Findings of the present study revealed that more than half of children had their ITP attack after infection (58.7%). Rosthoj et al., [29] stated that among approximately two thirds of cases, the onset of acute ITP was preceded by an infectious illness, most often an upper respiratory tract infection. Similarly, Al-Mulla et al., [24] reported that childhood ITP is commonly preceded, few weeks earlier, by an infection in almost two-thirds of their cases (63.2%). In Iran, Saeidi et al., [25] reported that 80.8% of children had infection prior to the onset of ITP. In this study, only one child had positive family history of ITP. Similarly, Al-Mulla et al., [24] reported that they did not observe any case of childhood ITP with a positive family history in their clinical experience of Qatar. However, contrary to this, Rischewski et al., [30] emphasized that familial predisposition has been reported for cases of ITP, suggesting a genetic susceptibility. The most commonly presenting symptoms among our patients were skin rash, epistaxis which was significantly more among boys. On the other hand, the most common signs were ecchymosis, purpura, petechial rash, bleeding in mucous membranes and pallor. Splenomegaly was present in 3 children (6.5%). Apart from epistaxis, which was significantly higher among male patients, all clinical findings were not significantly different between males and female patients. These findings are in agreement with those reported by several studies. Bolton-Maggas [31] stated that onset of ITP is usually abrupt with bruises and petechial rashes affecting almost all patients. Epistaxis may occur in about one third of patients. Al-Mulla et al., [24] reported that the most common clinical features for ITP among their cases were petechiae, bruising and bleeding. Blanchette and Bolto-Maggs [32] stated that physical examination at presentation is remarkable only for the cutaneous manifestations of severe thrombocytopenia with bruising or a petechial rash present in almost all cases. A spleen tip may be palpable in 5-10% of cases. Epistaxis is a presenting symptom in approximately one quarter of affected children frequently. In Iran, Saeidi et al., [25] reported that 60.5% of their ITP patients had petechiae while 61% of the patients had purpura and ecchymosis.

Ali Al-Suheel, et al. 91 The significantly higher incidence of epistaxis among boys may be explained by the fact that boys are more active than girls, which raises the possibility of being exposed to trauma and bleeding. This study showed that most children had very low platelet count (<20x10 3 /ml). More than one third of patients had low hemoglobin levels (5-12 gm/dl). The ESR of almost one fourth of patients was >_30mm/hour. The MPV of more than half of patients was 8-10 fl. Out of 7 cases, who underwent antinuclear antibody testing, 3 children were positive. Peripheral blood smears showed isolated thrombocytopenia in most patients, megakaryocytes in 15.2% and pancytopenia in one patient. In accordance with our laboratory findings among children with ITP, Blanchette and Bolto- Maggs [31] stated that the key laboratory finding in children with ITP is isolated, and often severe, thrombocytopenia. In more than half of cases, platelet counts at presentation are less than 20x 10 3 /ml. Other hematologic abnormalities are consistent with a diagnosis of childhood acute ITP only if they can be explained easily (e.g., low hemoglobin level). The blood smear shows a marked decrease in platelets with some platelets that are large (megathrombocytes). A bone marrow aspirate typically shows normal to increased numbers of megakaryocytes, many of which are immature. Lowe and Buchanan [33] added that a positive antinuclear antibody is common in children who have ITP. Provan et al., [18] added that complete blood count and peripheral blood smear are essential to establish the diagnosis of ITP. Anemia is present only if there is severe bleeding. Several researchers reported similar laboratory findings for their series of childhood ITP. Al-Mulla et al., [24] reported that 68% of their studied children with ITP showed a platelet count below 20x10 3 /ml. This study showed that bone marrow aspiration was performed for 3 cases only. Indications were presence of pancytopenia or splenomegaly. This finding is in agreement with that stated by Neunert et al., [34], who stressed that bone marrow aspiration is not required to establish the diagnosis or treatment in typical cases of ITP. However, it should be done if there is bone pain, lymphadenopathy, hepatosplenomegaly, or pancytopenia. In the series of ITP patients of Watts [22], bone marrow aspiration was performed in 72% but altered the diagnosis or treatment in none of his patients. Regarding the outcome on discharge from hospital, the condition of 63% of our cases was completely resolved with a higher cure rate among boys than girls. On the other hand, 34.8% had chronic ITP, with a lower proportion of chronicity among boys than girls. One female child with ITP died. Differences between boys and girls regarding their outcome were statistically significant. The relatively high cure rate and low case fatality observed in our study support the findings of Belletrutti et al., [35], who stated that ITP usually runs a benign, self-limiting course. Complete remission usually occurs within six months from diagnosis in the majority of children with ITP. However, about one third of children continue to have chronic ITP with persistent low platelets count and bleeding symptoms beyond six months from diagnosis. Watts [22] stated that the overall prognosis in childhood ITP is excellent. Most cases can be managed by pediatricians even without hematology referral. Chronic cases usually present at an older age with higher platelet counts. Nevertheless, up to 50% of cases of chronic ITP will resolve with ongoing follow-up. Finally, Lehmann et al., [36] noted that prolonged exposure to high altitude disturbs platelet functions. It activates platelets, which leads to platelet aggregation, platelet consumption, and decreased platelet count. That is why this study was performed aiming at exploring the pattern of ITP among children living at the high altitude Aseer Region. Our results were compared with patterns reported for ITP patients living in areas at sea-level in Saudi Arabia, i.e., Riyadh; nearby countries, i.e., Qatar and Iran; in addition to other studies in western countries. In conclusion, this study revealed that clinical findings, laboratory results and outcome of children with ITP living at high altitude are generally similar to those of others in different parts of the world. However, the peculiar findings that this study reached are the slightly higher predilection of ITP and the significantly lower cure rates among girls compared with boys. These two findings need further epidemiological, biochemical and hematological studies to be explained. 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