|Year : 2021 | Volume
| Issue : 3 | Page : 283-291
Clinicopathological study of new onset pancytopenia: An experience of largest study from a tertiary care center of western India
Ganesh Pendkur1, Paresh Singhal1, Venkatesan Somasundaram1, SK Raghavendra2, Sanjeevan Sharma3
1 Department of Pathology, Armed Forces Medical College, Pune, Maharashtra, India
2 Department of Community Medicine, Adichunchanagiri Institute of Medical Sciences, B.G Nagara, Karnataka, India
3 Hematology Unit, Command Hospital, Pune, Maharashtra, India
|Date of Submission||10-Apr-2020|
|Date of Decision||14-Jul-2020|
|Date of Acceptance||24-Jul-2020|
|Date of Web Publication||12-Feb-2021|
Department of Pathology, Armed Forces Medical College, Pune - 411 040, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Pancytopenia is characterized by decreased hemoglobin (adult males <13 g/dl, pregnant females <10 g/dl, nonpregnant females and children <11 g/dl), total leukocyte count (<4 × 109/L), and platelet count (<100 × 109/L). Depending on the severity, patients can present with varied symptoms. Vast majority of conditions causing pancytopenia are known. Hence, a systematic approach is a mandatory requirement to identify the cause of pancytopenia for appropriate management. Aim: Clinicopathological study of new onset pancytopenia and to determine the frequency of different etiologies causing pancytopenia. Materials and Methods: A prospective study of 451 consecutive cases who had pancytopenia and presented in outpatient or emergency room of a tertiary care center of Western India, from July 2017 to September 2019. The clinical data of the patients were obtained and hematological investigations were analyzed in the hematopathology section of the pathology department. Bone marrow (BM) aspirates and biopsies were performed in 355 cases. Data were analyzed using SPSS software. Results: Patients age ranged from 6 months to 84 years with mean standard deviation of 45.89 ± 19.21 years. Overall male to female ratio was 1.87:1. Hematolymphoid malignancy was the most common cause (n = 137, 30.37%) followed by nutritional anemia (n = 97, 21.5%), infections (n = 68, 15.07%), BM failure (n = 66, 14.63%), hypersplenism (n = 55, 12.19%), and autoimmune disorder (n = 11, 2.44%). Conclusion: Pancytopenia is a common hematological entity with the multifactorial etiologies. It can present as a life-threatening condition or can be merely transient. Hematolymphoid malignancy was found to be the most common underlying cause in our study. An accurate etiological break will further assist in appropriate management of these patients.
Keywords: Bone marrow failure, hematolymphoid malignancy, hypersplenism, nutritional anemia, pancytopenia
|How to cite this article:|
Pendkur G, Singhal P, Somasundaram V, Raghavendra S K, Sharma S. Clinicopathological study of new onset pancytopenia: An experience of largest study from a tertiary care center of western India. Med J DY Patil Vidyapeeth 2021;14:283-91
|How to cite this URL:|
Pendkur G, Singhal P, Somasundaram V, Raghavendra S K, Sharma S. Clinicopathological study of new onset pancytopenia: An experience of largest study from a tertiary care center of western India. Med J DY Patil Vidyapeeth [serial online] 2021 [cited 2021 May 13];14:283-91. Available from: https://www.mjdrdypv.org/text.asp?2021/14/3/283/309177
| Introduction|| |
Cytopenia is a common hematological abnormality which causes cessation or reduction in one or the major formed elements of blood, i.e., red blood cells or white blood cells or platelets. Pancytopenia may be due to variety of underlying etiologies in which all three major blood elements are decreased as compared to the normal range. Pancytopenia is one of the common indication for bone marrow (BM) examination, to rule out bone underlying marrow pathology, although marrow pathology may not be always detected.
The etiological spectrum in pancytopenia varies widely from a benign course of transient BM suppression to more serious and life-threatening condition due to marrow infiltration by neoplastic cells.
A comprehensive medical history, meticulous clinical examination, and careful analysis of complete blood count (CBC) and peripheral blood smear (PBS), forms the corner stone of first line investigation in pancytopenia patients. Inputs from first-line investigations provide valuable information and assist in further planning of diagnostic workup in form of BM aspiration (BMA), BM biopsy (BMB), immunophenotyping, cytogenetics, or molecular studies. The present study was conducted with aim to dwell on the clinical and hematological aspects of various etiological causes of pancytopenia from a tertiary care center.
| Materials and Methods|| |
Ethical clearance was obtained to conduct this study from Institutional Ethical Clearance committee (IEC S. No.: IEC/2020/78 dated May 5, 20). All patients who presented to the emergency room or outpatient department with findings of pancytopenia, defined as Hemoglobin in adult males <13 g/dl, pregnant females <10 g/dl, nonpregnant females and children <11 g/dl; leukocytes ≤4.0 × 109/L or absolute neutrophils count ≤1.5 × 109/L and platelets count ≤100 × 109/L2; from July 2017 to September 2019. The inclusion criteria were pancytopenia in peripheral blood, based on the above defined criteria. The exclusion criteria were: (1) history of chemotherapy/radiation therapy for hematological or nonhematological malignancies and (2) history of blood or components transfusion.
A detail history, clinical examination, and CBC including PBS followed by BMA/BMB were performed, wherever clinically indicated, at the time of initial presentation. In all the age groups, BMA/BMB was performed under aseptic precautions at posterior iliac crest using disposable Jamshidi BMB needle. Ancillary studies such as immunohistochemistry (IHC) and immunophenotyping were performed for diagnostic confirmation wherever indicated.
CBC included hemoglobin, red blood cell indices; total, differential and absolute leucocytes count and platelet counts. This was conducted on fully automated hematology counter. Smears from peripheral blood, BMA smears were stained using a fully automated stainer with Leishman-Giemsa stain. Special staining for myeloperoxidase, Periodic acid–Schiff, Ziehl–Neelsen stain, and congo red were done on BMA/BMB, as per the manufacturer's instructions. IHC was performed on BMB using rabbit monoclonal antibody. All hematological malignancies were classified according to the World Health Organization 2016 nomenclature.
Data were analyzed using SPSS (Statistical Package for the Social Sciences). The association between age and diagnosis was assessed using Chi-square test; statistical association having P < 0.05 was taken as statistically significant.
| Results|| |
Four hundred and fifty-one cases [Table 1] of pancytopenia of which 28 were children (<12 years) included in this prospective study. BM study was performed in 355 cases including 24 children. Age ranged from 6 months to 84 years (mean standard deviation age: 45.89 ± 19.21). There were 294 cases of male with m: f ratio of 1.87:1. Majority (19.51%) of the cases were from 41 to 50 years, followed by second peak (18.62%) in 61–70 years [Diagram 1]. The most common presenting complaints were generalized weakness (86.03%) and fever (78.2%) among adults and children respectively. Pallor was the commonest sign (100%) in all age groups. Details of other signs and symptoms are tabulated in [Table 2].
Hematolymphoid malignancies were the most common cause of pancytopenia (n = 137, 30.37%) [Table 1] in both children (n = 12) and adults population (n = 125). Age range in this category was from 6 months to 72 years. The mean age was 48.46 ± 21.7. In acute leukemia, common clinical presentations were fever (n = 44,88%), weight loss (n = 39,78%), weakness (n = 43,86%), lymphadenopathy (n = 17,34%), and splenomegaly (n = 39,78%). Acute myeloid leukemia (AML) was the most common one (n = 30, 6.65%) in acute leukemia category [Figure 1]a and [Figure 1]b. Majority of the cases were above 20 years (n = 26, 86.66%). AML with minimally differentiation (n = 14), AML without maturation (n = 9), acute monoblastic leukemia (n = 5) were common subtypes. Two cases of acute promyelocytic leukemia [Figure 2] were also diagnosed in which t (15;17) was confirmed by karyotyping and reverse transcription polymerase chain reaction. Unlike adults, B-acute lymphoblastic leukemia (ALL) was the most common hematolymphoid neoplasm seen predominantly in pediatric population (n = 10). B-ALL (n = 18) was more common than T-ALL.
|Figure 1: (a) Acute myeloid leukemia peripheral blood smear showing Myeloid blasts with Auer rods More Details (×1000); (b) CD34 monoclonal antibody highlights blasts on biopsy (×200)|
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|Figure 2: Acute promyelocytic leukemia peripheral blood smear showing promyelocytes with auer rods (×1000)|
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Forty-five cases of myelodysplastic syndrome (MDS) were recorded, which was most common above 50 years. Age ranged from 7 to 84 years with male preponderance (m: f = 1.5:1) among whom pallor (n = 45,100%), dyspnea (n = 29,64.44%), and generalized weakness (n = 43,95.55%) were frequent clinical findings. The mean age of MDS was 58.44 ± 15.81 years. MDS with multilineage dysplasia (MDS-MLD), MDS with excess blasts 1 (MDS-EB-1) and MDS-EB-2 were the most common category seen in 21, 19, and 4 cases respectively [Figure 3]. An isolated case of childhood MDS was seen in 7 years' old child, who presented with fever, BM study had dyspoiesis in all three cell lines with 6% blasts and monosomy 7 on cytogenetic evaluation. Myeloproliferative neoplasm was seen in eight cases who presented with pancytopenia, showed specific morphology of primary myelofibrosis (PMF) in BMB.
|Figure 3: (a) Myelodysplastic syndrome excess blasts bone marrow aspiration showing blasts with dyspoietic neutrophils and erythroid series showing megaloblastic maturation (×1000); (b) CD34 highlights blasts in small clusters (×1000)|
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Mature B-cell neoplasms were seen in 31 cases. Of which, plasma cell neoplasm was the most common, other causes are tabulated in [Table 1]. Three cases showed the involvement of marrow by Hodgkin lymphoma and 14 cases by non-Hodgkin lymphoma (NHL), which was confirmed by IHC on BMB. In lymph node biopsy proven cases of classical Hodgkin lymphoma-lymphocyte predominant subtype, BMB revealed infiltration by CD15, CD30, and PAX5 positive while CD45-negative Reed Sternberg cells. Similarly, in Follicular lymphoma cases (n = 9), BMB showed uniform positivity for CD19, CD20, CD10, and Bcl6 while negative for CD3, CD5, and Cyclin D1 in atypical lymphoid cells; whereas in marginal zone lymphoma (n = 4), BMB showed CD19, CD20 and CD22 positivity and CD3, CD5 and Cyclin D1 negativity in lymphoma deposits.
Nutritional anemia was the second most common cause (n = 97, 21.5%) of pancytopenia in the present study. Age ranged from 6 to 78 years with mean of 48.61 ± 16.01. Most common clinical presentations were pallor (n = 97, 100%), generalized weakness (n = 89, 91.75%) and dyspnea (n = 38, 39.17%). Megaloblastic anemia (MA) (n = 68, 15.07%) was more common in males (n = 46, 67.65%). MA was diagnosed based on sequential steps: Macrocytosis (Mean corpuscular volume >100 fl), hypersegmented neutrophils (>5% of 5 lobed or single 6 lobed) on PBS, megaloblasts on marrow aspiration and re-evaluation of clinical and hematological profile after replacement therapy. Hemogram showed raised MCV (>100 fl) in (n = 65, 67.01%), PBS revealed macrocytic red blood cells (RBC's), macro-ovalocytes and hypersegmented neutrophils (n = 59, 60.82%). BM study was performed on all the cases which revealed megaloblastic maturation. Serum B12 and folic acid assay could not be performed in all the cases; hence data could not be reproduced. Dimorphic anemia was recorded (n = 29, 6.43%) with low MCV (<100 fl) on hemogram along with morphological evidence of microcytes and macrocytes on PBS. Dimorphic anemia was more common in females (n = 15,3.32%) as compared to MA. All of the patients with dimorphic anemia had component of megaloblastic maturation on BM study and was followed by reticulocytosis on replacement therapy.
Infectious etiology (n = 68, 15.07%) was third most common causes of pancytopenia, with HIV being commonest (n = 26, 5.76%) [Table 1]. Age ranged from 3 to 80 years with m: f = 2.05:1. The mean age was 43.42 ± 17.44. Common clinical presentations were fever (n = 62, 91.17%), generalized weakness (n = 57, 83.82%), and dyspnea (n = 43, 63.23%). BM study was performed in all cases of HIV; findings are tabulated in [Table 3].
Of the 24 (5.32%) cases of Pyrexia of Unknown Origin (PUO), 14 cases were later diagnosed with enteric fever, which were confirmed on Widal serology and blood culture. While 10 cases were labeled as septicemia; BMB was done in septicemia cases, which revealed nonspecific reactive marrow in 8 cases and 2 cases had features of hemophagocytosis [Table 3]. Four cases each of pulmonary tuberculosis (PTB) (n = 10, 2.21%) had marrow involvement by epithelioid granulomas and hemophagocytosis [Figure 4]; and 1 case each of nonspecific reactive and inconclusive marrow. All patients of serologically proven dengue fever (1.77%) were in stage of dengue shock syndrome. BM was not performed in cases of dengue and enteric fever, due to known fact of transient nature of disease.
|Figure 4: Bone marrow aspiration shows marrow macrophages (green arrow head) with evidence of hemophagocytosis engulfing normal hematopoietic elements (×1000)|
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Sixty-six patients presented with evidence of BM failure (BMF) amongst which idiopathic aplastic anemia (IAA) (n = 59, 13.08%) was the most common. Age ranged from 4 to 78 years with mean age of 44.36 ± 18.37. Common clinical features were bleeding (n = 56, 84.84%), fever (n = 53, 80.30%), and pallor (n = 66, 100%). Most of the patients with IAA (n = 52, 88.13%) were above 20 years. In IAA, peripheral blood showed relative lymphocytosis in 56 cases; whereas BMB demonstrated hypoplastic changes and no features of dyspoiesis in 59 cases of IAA. Methotrexate and anti-tubercular treatment lead to iatrogenic BMF in 4 and 1 case, respectively. Hypocellular BMB with necrosis was seen in 2 cases of antiphospholipid lupus anticoagulant (APLA) syndrome.
Although hypersplenism (n = 55, 12.19%) was less common cause of pancytopenia in adults, it was second most common cause among children (n = 7, 25%) in the present study. Age ranged from 0.5 to 82 years with mean of 39.29 ± 21.08. Common clinical features were pallor (n = 55, 100%), generalized weakness (n = 49, 89.09%), and splenomegaly (n = 55, 100%). Viral hepatitis was the most common underlying cause affecting 26 patients, out of which 23 were carrier of Hepatitis B virus and remaining were positive for hepatitis C virus. As expected, glycogen storage disorder was seen only in pediatric age and confirmed on liver biopsy [Figure 5], with cellular reactive marrow. Remaining causes of hypersplenism are tabulated [Table 1].
|Figure 5: Glycogen storage disease Tru-cut liver biopsy higher magnification shows swollen and mosaic pattern of hepatocytes with compression of sinusoids (×200)|
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Other less common cause of pancytopenia, was autoimmune disorder (n = 11, 2.44%). Age ranged from 23 to 63 years, with mean of 41.46 ± 13.12. Most common clinical features were pallor (n = 11, 100%), fever (n = 6, 54.54%), and weight loss (n = 8, 72.72%). Females were commonly affected and presented with systemic lupus erythematosus (SLE), where BMB revealed hypocellularity in 5 cases, 2 cases had features of hemophagocytosis and a case of marrow necrosis. Primary amyloidosis was seen in 2 cases and a case of graft versus host disease.
Of the 17 cases in the miscellaneous group, three cases were of chronic pancreatitis and five cases of chronic kidney disease. Pancytopenia was detected in 8 cases, on OPD reporting, who presented with generalized weakness but unfortunately were lost to follow-up and further work up could not be done. Solitary case of metastatic deposit of carcinoma prostate had pancytopenia.
| Discussion|| |
This prospective study was conducted in a post graduate teaching institute of western India, which gives multispecialty medical facilities to serving and veterans defense personnel and their family members. Review of literature shows that there are many studies on the subject but to the best of our knowledge, the present study is the largest comprehensive data on pancytopenia from this part of India.
Pancytopenia is a common clinical phenomenon which is a reflection on peripheral blood of an underlying marrow disorder which may be subtle and transient to a more complicated and life-threatening illness. The wide variation in the etiological break up among different group can be attributed to varied diagnostic criteria, diet, age groups, genetic predisposition, geographical distribution, and laboratory quality checks and accreditation.,
The present study had shown male preponderance in all the sub categories of pancytopenia etiology except the autoimmune cause [Table 1] with overall gender ratio of 1.87:1, which is consistent with other studies.,, This can be explained not only due to well-known fact of male dominant Indian society but also their increased exposure to environmental factors like smoking, alcohol and occupational chemicals; and recently studied various biological factors. In our study, majority of the patients were in 5th (19.51%) and 7th (18.62%) decades, which is in concurrence with other studies.
Acute leukemia was the most frequent etiology (n = 50, 11.08%), followed by MDS (n = 45, 9.98%). In contrast to most of the Indian studies,,,, wherein MA, aplastic anemia, hypersplenism, and infections were predominant causes; our findings corresponds to the western literature,,,, who in their studies found malignant myeloid neoplasms and MDS as the most common cause. This could possibly be attributed to the balanced nutrition, healthy life style in defense set up and also being a referral center, hematolymphoid malignancies are referred for management by hematologist, whereas less serious causes of pancytopenia could have been managed by general physician at a lower echelon. AML with minimum differentiation was the commonest subtype in our cohort. Peripheral blood blasts in AML and precursor lymphoid neoplasms ranged from 2% to 14% and 3%–9% respectively, and BMB was hypercellular for age 100% cases with suppressed erythroid and megakaryocytes. AML was commonly manifested above 20 years of age whereas ALL was common in pediatric age, which is in accordance with other studies.
MDS was diagnosed as per revised definition of the WHO, seen in 45 cases. As expected, more than 70% of patients were above 5th decade of life which was statistically significant also (P value: <0.001). Blast count on BMA ranged from 2% to 4%, 6%–8%, and 11%–17% seen in MDS-MLD, MDS-EB-1 and MDS-EB-2 respectively with mean blast count of 5.6%. MDS-MLD and MDS-EB were the commonest subtype of MDS in our study, which was also seen in study by Weinzierl and Arber.
Paradoxically, myeloproliferative neoplasms which presented with pancytopenia in the current study was PMF see in 8 cases (1.77%). All the patients had leukoerythroblastic picture on PBS and grade-3 marrow fibrosis which has resulted into pancytopenia.
Mature B-cell neoplasms accounted for 31 cases (6.87%) which has resulted into pancytopenia, and the most common subtype was plasma cell neoplasm (3.55%), which was similarly noted in another study. Other B-cell neoplasms were follicular lymphoma (1.99%), marginal zone lymphoma (0.9%), and hairy cell leukemia (0.22%), which were also reported by other studies as lesser common cause of pancytopenia.,, All patients in this category were adults with mean age of 58.16 ± 15.5 years. Hodgkin lymphoma (0.67%) was lesser common cause of pancytopenia as compared to NHL in our study, seen in adults with mean age of 41.33 ± 9.01 years.
Nutritional category was the second most common cause, predominantly due to MA which contributed to 21.5% cases of pancytopenia. Pallor (n = 97, 100%), generalized weakness (n = 93, 95.87%), and dyspnea (n = 26, 26.80%) were common clinical presentations, while in other similar studies, these clinical features varied from 15% to 66%., MA was seen more commonly in males, which may be explained due to frequent association of iron deficiency in female population, as result of which MCV was not raised to macrocytic range, which is also seen in study by Maktouf et al. Macrocytosis with raised MCV was seen in 67% (65/97) and hypersegmentation in 60.82% (59/97), which was higher than that of study by Gayathri and Rao. All the cases revealed erythroid hyperplasia with megaloblastic maturation (n = 97, 100%).
Infections were third most common cause of pancytopenia, seen in 68 cases. The prevalence of HIV was marginally higher than PUO, seen in 26 (38.32%) cases. Pathogenesis of cytopenias in HIV is multifactorial which may be due to viral load, antiretroviral therapy, opportunistic infections, or infiltrative pathology. Devi et al. found HIV in 6% cases of pancytopenia, the prevalence of HIV-induced pancytopenia was slightly lower in our study which may be due to different diagnostic criteria for pancytopenia and stage of infection., Out of 24 patients with initial presentation of PUO and pancytopenia; 14 were diagnosed as enteric fever on blood culture hence BM study was not done, whereas 10 had culture negative septicemia. BM study in latter cases revealed cellular reactive marrow in 8 cases and evidence of hemophagocytosis in remaining cases. In comparison with other Indian studies by Jain and Naniwadekar, Premkumar et al.,, infections were less common cause of pancytopenia in our cohort. This could be explained as our patients have an early medical intervention in armed forces set up which prevents development of complications.
We found hemophagocytosis [Figure 4] in eight cases, four due to underlying PTB, and two cases each of HIV and PUO. Hemophagocytosis can lead to pancytopenia even in noninfectious etiologies such as hematolymphoid malignancies, BM metastasis, and hemophagocytic lymphohistiocytosis (HLH); infectious agents are more common underlying cause of hemophagocytosis induced pancytopenia, thus efforts should be made to search for its evidence, which may alter further management. BM study was not done in dengue, pancytopenia can be explained again due to transient marrow failure or hemophagocytosis.
Bone marrow failure
In the present study, BMF was the fourth leading cause of pancytopenia and presented most commonly as IAA (59/66). BMB was performed in all cases which revealed hypoplasia. As compared to other studies by Dasgupta et al., Varma and Dash¸ Zeb Jan et al., where they found younger age was commonly affected;,, however, in our study, IAA was more common in adult population above 40 years of age which is statistically significant also (P < 0.001) and in concurrence with bimodal age distribution.
Methotrexate was found to be the most common iatrogenic-induced pancytopenia in our study followed by ATT, and thus the treating physicians should be have high index of suspicion about drug-induced cytopenias to minimize their morbidity and mortality with appropriate dosages in correct time frame., Although thrombocytopenia is the commonest hematological manifestation in APLA syndrome, there are rare cases of marrow necrosis in setting of APLA syndrome which may even cause pancytopenia.
Hypersplenism was seen in 12.19% cases which is less common cause of pancytopenia as compared to other Indian studies.,, Peripheral pooling and destruction of cells inside reticuloendothelial system of spleen results in cytopenia. Among adults, chronic viral hepatitis was more prevalent 26 (49.05%) in our study followed by alcoholic liver disease, 8 (15.09%) which is in concurrence with other studies. In children, storage disorder was more common cause of hypersplenism (n = 3, 0.67%), which was also seen in study by Naseem et al., as cause of pancytopenia in pediatric population.
In our study, 11 cases were due to autoimmune pathology, among which majority cases were due to SLE. Hypocellularity was the most common findings in marrow examination in SLE which was followed hemophagocytosis which is in agreement with Bashal. Two cases of secondary amyloidosis due to underlying interstitial lung disease were also seen which was further confirmed on Congo red stain [Figure 6].
|Figure 6: Apple green birefringence under the polarized microscope (×200)|
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In this category, all five patients with chronic renal failure were in end stage renal disease, and thus further detailed hematological work up could not be performed due to poor general condition of patients. Studies done by Jain and Naniwadekar have seen pancytopenia in other chronic conditions including pancreatitis, possibly due to marrow fibrosis., Loss to follow up cases had dimorphic picture of RBCs (normocytic and macrocytic), hence, it was assumed that the underlying etiology may be due to nutritional factors. Metastatic deposit has been reported as cause of pancytopenia in few studies, which was seen in solitary case of ours.
Limitations of study
The present study should be considered in light of certain limitations. The study was conducted at a tertiary care level hence representation from lower medical echelon has not been reflected. Although BM study was performed in around 80% cases, it would have been ideal to study in all the cases for further insights of underlying pathology. Nutritional anemia was diagnosed on the basis of RBCs indices and cellular morphology; serum vitamin assays could have further correlated the hematological findings. Nevertheless, the study highlights different etiologies of pancytopenia, where accurate diagnosis will have impact on appropriate management and timely intervention especially for treatable and reversible causes.
| Conclusion|| |
Pancytopenia is a common hematological problem encountered in day-to-day practice not only by clinical hematologist but also by general practitioner. We found hematolymphoid malignancy as the most common cause of pancytopenia followed by nutritional factors. There is plethora of other causes we found in this study which at times was extremely challenging enough to diagnose accurately with a painstaking examination of PBS and BM smears; even in presence of a sharp clinical acumen. Hence, we further reiterate that the meticulous examination of peripheral blood and BM still remains the corner stone to identify various underlying causes, especially for more cryptic pathology like hemophagocytosis. An important message can be conveyed to our population about balanced diet, healthy sanitation, and hygiene practices which could definitely curtail the preventable cause of pancytopenia.
Informed consent was obtained from the patients for publication of this article.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 1], [Table 2], [Table 3]