Abstract
Introduction: Pancytopenia is a clinical problem which is a common and wide differential diagnostic spectrum. and may occur with various mechanisms. In this study we aimed to determine the most common etiologic causes in patients with pancytopenia.
Materials and Methods: The records of patients aged 18 years and older, who applied to the Health Sciences University Bakirkoy Dr. Sadi Konuk Training and Research Hospital between 2012 and 2017 and who were diagnosed with pancytopenia according to WHO criteria were retrospectively reviewed.
Statistical Method: Mann-Whitney-U test was used for 2 groups and Kruskal-Wallis test was applied for 3 and more groups. Since no normal distribution was provided as a descriptive statistic, median and change interval values were given for continuous data.
Results: A total of 766 patients, 475 (62%) women and 291 (38%) men, were included in the study. In these patients, non-hematologic causes were found in 77.7% and hematologic causes in 22.3% of patients with pancytopenia. Hematological etiologies were 72.2% benign and 27.8% malignant. Nonhematological causes were divided into groups as renal diseases (6.1%), rheumatological diseases (2.4%), infective diseases (10.8%), endocrinological diseases (3.9), hypersplenism (14.5%), immunosuppressive drug use (17.5%), solid organ cancers (10.8%) and unidentified reasons (34.3%).
Conclusion: Pancytopenia should be evaluated carefully and the etiology should be detected quickly and corrected by appropriate treatment. It is an appropriate approach to exclude, first the non-hematological causes (especially immunosuppressive drug use, hypersplenism, infection and solid organ cancers, respectively) and the benign causes of hematological reasons.
Keywords: Pancytopenia; Anemia; Bisitopenia
Introduction
The definition of pancytopenia adopted by the World Health Organization (WHO) includes the combination of all three parameters: Hemoglobin (Hb) - for non-pregnant women - ‹12g/ dl and ‹13g/dl for men, absolute neutrophil count ‹ 1800 /microl, platelet count ‹150000 /mm3 [1]. In healthy adults, hematopoiesis occurs in the marrow where mature blood cells migrate to other regions with the circulatory system. The balance between blood cell production, distribution in other organs, and ongoing cellular destruction determines the levels of circulating blood cells [2-5]. Pancytopenia may occur with various mechanisms. The etiologic classification consists of bone marrow infiltration (hematological malignancies, metastatic cancers, myelofibrosis and infectious diseases, tuberculosis, fungal infections, etc.), bone marrow aplasia (vitamin B12 or folate deficiency, aplastic anemia, infectious diseases such as HIV, viral hepatitis, parvovirus B19 and drugs) and blood cell destruction or sequestration (disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, ineffective erythropoiesis - myelodysplastic syndrome, megaloblasitis disorders, hypersplenism). Although pancytopenia is a common clinical problem with a wide differential spectrum, there is not enough information about the incidence of causes except for a few studies [6-8]. In our study, the aim was to determine the most common etiologies in patients with pancytopenia and to contribute to the shortening of the transition period for appropriate treatment by making a rapid diagnosis.
Materials and Methods
The records of patients 18 years and older, who applied to the Health Sciences University Bakirkoy Dr. Sadi Konuk Training and Research Hospital Internal Medicine outpatient clinics from, 2012 to 2017 and who were diagnosed with pancytopenia according to WHO criteria were retrospectively analyzed. Gender, age, Hemoglobine (Hb), hematocrit (Hct), white blood cell count, platelet count, mean corpuscular volume (MCV), reticulocyte count, lactate dehydrogenase (LDH), vitamin B12, folic acid, serum iron, ferritin levels, TSH, fT4, fT3, drug (immunosuppressive) use, presence of hepatomegaly and/or splenomegaly, bone marrow aspiration and biopsy results and diagnoses leading to pancytopenia after the analyzes were recorded. The patients were divided into 2 groups according to hematological and non-hematological etiologies, which primarily led to pancytopenia. Hematologic etiology group was further divided into two groups as benign and malignant causes. The non-hematologic etiological group was further divided into subgroups as; infectious, rheumatologic, endocrinological, renal diseases, hypersplenism, immunosuppressive drug use, solid organ cancers and others (undetectable).
Statistical method
The normality tests were performed for each variable in the study and Kolaporov-Smirnov and Shapiro-Wilk tests were performed. Since the variables were not normally distributed due to p ‹0.05, non-parametric methods were preferred in the analyzes. Mann- Whitney-U test was used for 2 groups and Kruskal-Wallis test was applied for 3 and more groups. Since no normal distribution was provided as a descriptive statistic, median and change interval (maxmin) values were given for continuous data. Frequency (frequency) distribution tables for categorical data were interpreted. Data are presented as percentage and number. The analyzes were performed with SPSS 22.0 statistical analysis program and significance level was considered as p ‹0.05.
Results
A total of 766 patients, 475 (62%) women and 291 (38%) men, were included. The mean age of men was 60.6 years, the mean age of women was 55.5 years, and the average age of all patients was 57.5 years. Non-hematological causes were found in 77.7% and hematological causes in 22.3% of patients with pancytopenia. Gender distribution among both groups is shown in Graphic 1. Hematological etiologies were 72.2% benign and 27.8% malignant. Gender distribution in hematological subgroups is shown in Graphic 2. Non-hematological causes were divided into groups as renal diseases (6.1%), rheumatological diseases (2.4%), infective diseases (10.8%), endocrinological diseases (3.9), hypersplenism (14.5%), immunosuppressive drug use (17.5%), solid organ cancers (10.8%) and unidentified reasons (34.3%). Gender and etiology distribution of non-hematological group is shown in Table 1. Differences between the hematological and non-hematological groups (Table 2) and benign and malignant groups from the hematological subgroups (Table 3) were shown in the tables below. Age (p=0.024), LDH (p=0.000), serum iron (p=0.032), ferritin (p=0.000) and vitamin B12 (p=0.000) levels were significantly higher in the non-hematological group. According to the comparison between hematological groups; Hb (p=0.000), Hct (p=0.000), white blood cell count (p=0.000) and platelet count (p=0.002) were significantly higher in benign hematological group. Serum iron (p=0.001), ferritin (p=0.000) and vitamin B12 (p=0.004) levels were significantly higher in the malignant hematological group. Fifty-five (17.2%) out of 319 patients with abdominal ultrasonography had hepatomegaly and 92 (28.8%) had splenomegaly. Bone marrow aspiration and biopsy was performed in only 33 (4.3%) of all patients. Because in other patients there was a non-haematological cause and no need to performe bone marrow biopsy.
Graphic 1:: Gender distribution among groups.
Graphic 2: Gender distribution between hematological subgroups.
Etiology
Male
Female
Total / %
Infectious causes
22
42
64 / 10,7
Rheumatological
0
14
14 / 2,3
Hypersplenism
33
53
86 / 14,4
Endocrinological causes
5
18
23 / 3,8
Immunosuppressive drug use
49
55
104 / 17,4
Renal causes
18
18
36 / 6,05
Solid organ cancers
38
26
64 / 10,7
Other reasons
71
133
204 / 34,2
Total
236
359
595 / 100
Table 1: Nonhematological group sex - etiology distribution.
Group
N
Average row
Mann-Whitney-U statistics
p
Age
hematologic
171
352.41
45556
0.024*
non-hematologic
595
392.44
Total
766
Hb
hematologic
171
373.93
49236
0.521
non-hematologic
595
386.25
Total
766
Hct
hematologic
171
389.82
49791
0.671
non-hematologic
595
381.68
Total
766
White Blood Cell Count
hematologic
171
372.79
49040
0.472
non-hematologic
595
386.58
Total
766
Platelet Count
hematologic
171
384.25
50745
0.96
non-hematologic
595
383.29
Total
766
LDH
hematologic
171
302.59
37036
0.000*
non-hematologic
595
406.75
Total
766
MCV
hematologic
171
369.5
48478
0.346
non-hematologic
595
387.52
Total
766
TSH
hematologic
171
144.42
8183.5
0.319
non-hematologic
595
155.95
Total
766
Ft4
hematologic
171
124.73
5179.5
0.975
non-hematologic
595
125.07
Total
766
Serum iron
hematologic
171
155.59
10917.5
0.032*
non-hematologic
595
176.03
Total
766
Ferritin
hematologic
171
137.38
9006.4
0.000*
non-hematologic
595
181.61
Total
766
Folate
hematologic
171
119.68
5863.5
0.853
non-hematologic
595
117.97
Total
766
Vitamin B12
hematologic
171
140.6
9447.1
0.000*
non-hematologic
595
194.14
Total
766
Table 2: Differences between hematological and non-hematological groups of variables, Mann-Whitney-U test results.
Group
N
Average row
Mann-Whitney-U statistics
p
Age
benign
122
79.88
2242.5
0.023*
malign
47
98.29
Total
169
Hb
benign
122
93.73
1802
0.000*
malign
47
62.34
Total
169
Hct
benign
122
93.43
1839
0.000*
malign
47
63.13
Total
169
White Blood Cell Count
benign
122
93.23
1862.5
0.000*
malign
47
63.63
Total
169
Platelet Count
benign
122
92.3
1977
0.002*
malign
47
66.06
Total
169
LDH
benign
122
81.65
2458.5
0.151
malign
47
93.69
Total
169
MCV
benign
122
81.36
2422.5
0.113
malign
47
94.46
Total
169
TSH
benign
122
39.47
1567.8
0.584
malign
47
36.52
Total
169
Ft4
benign
122
24.29
1254.9
0.304
malign
47
28.65
Total
169
Serum iron
benign
122
46.73
1796.3
0.001*
malign
47
68.47
Total
169
Ferritin
benign
122
46.7
1952.2
0.000*
malign
47
72.23
Total
169
Folate
benign
122
34.58
1162.1
0.378
malign
47
39.38
Total
169
Vitamin B12
benign
122
50.52
1836.3
0.004*
malign
47
70.15
Total
169
Table 3: Differences between benign and malign hematological groups, Mann-Whitney-U test results.
Discussion
Pancytopenia can be fatal if it cannot be diagnosed early [9]. Therefore, rapid detection of the underlying cause is extremely important in terms of coping with the disease and prognosis. It is important to investigate the the most common pancytopenia etiologies and which may be less frequent but more serious, in the differential diagnosis. Gayathri BN et al. reported a mean age of 41 years and male gender as a dominant in a prospective study of 104 pancytopenia patients aged between 2 and 80 years in India. Also, splenomegaly was more common than hepatomegaly in their study [10]. M. Premkumar et al. found that the mean age was 32.8 / year and male gender was dominant in their study which evaluating the hematological etiology with 140 pancytopenia patients. As the etiological frequency; Megaloblastic anemia (60.7%), infectious causes (16.4%), aplastic anemia (7.8%) and leukemia (9.2%) were detected [11]. In a study conducted by Imbert et al. with 213 adult pancytopenia patients in France, it was observed that malign hematological causes were more frequent that was not compatible with our study. According to this study, malignant myeloid disorders (acute myeloid leukemia, MDS and myelofibrosis) 42% and malignant lymphoid disorders 18% accounted for 60% of all hematological etiologies. The group containing the benign etiologies such as megaloblastic anemia was found to be 17% [8]. It was thought that this difference could be related with adequate nutrition and sociocultural level of the patient population. Dr. Atif Sitwat Hayat et al. Found that 72.94% of the patients were male and 27.05% were female. In the etiological evaluation, they found that non-cancerous causes were more frequent with a rate of 63.52% [12]. Bhagwan Singh Yadav et al., found the mean age of 35.15 ± 12.6 years and an equal female / male ratio in gender distribution, in their study with 58 pancytopenia patients above the age of 18 [13]. In the study of T. N. Dubey et al., which included 70 patients over 13 years of age, the male / female ratio was 1.4/1. In the etiological evaluation, megaloblastic anemia was in the first place with a rate of 41.4%. Aplastic anemia with the ratio of 22.9%, hypersplenism 15.7% and leukemic diseases 14.2% were also found in the etiology [14].
In our study, the mean age was 57.5 year and different from the literature the female gender was dominant. The difference in mean age was considered to be related only to the inclusion of the adult population in our study. We also showed that non hematological causes more common than hematological ones and similar to literature, we showed that benign causes (72.8%) were more frequently in the hematological etiology.
Conclusion
Pancytopenia should be evaluated carefully and the etiology should be detected quickly and corrected by appropriate treatment. In studies conducted, gender dominance is different for each study, so it is not true to say that pancytopenia is more common in male or female sex. According to our study, it is an appropriate approach to exclude, first the non-hematological causes (especially immunosuppressive drug use, hypersplenism, infection and solid organ cancers, respectively) and the benign causes of hematological reasons. When family physicians encounter patient with pancytopenia, they should be calm and after diagnosis treat the benign causes. If there is no benign cause than they should refer the patients to advanced center immediately.
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