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Full Research Article

Hemophagocytic Syndrome Associated with Infectious Diseases in Pancytopenic Dogs

M
M. Ranjithkumar1,#,*
V
V. Arvind1,#
N
N. Pazhanivel1
R
Rajat Sagare1
A
A.S. Pandian1
R
R. Ramprabhu1
1Department of Veterinary Clinical Medicine, Madras Veterinary College, Tamil Nadu Veterinary and Animal Sciences University, Chennai-600 007, Tamil Nadu, India. 

ABSTRACT

#These authors contributed equally to this work.

Background: Pancytopenia, characterized by a reduction in the number of peripheral blood cells, encompasses various etiologies, including infectious, immune-mediated diseases, sepsis and drug-related causes. The primary diagnostic tool for pancytopenia is bone marrow aspiration. The objective of this study was to elucidate bone marrow changes in naturally occurring pancytopenic cases with hemoprotozoan and immune mediated etiologies.

Methods: Animals confirmed as pancytopenic through hematological analysis underwent bone marrow cytology, PCR analysis and flow cytometry to identify the underlying pathology. Over the three-year study period, bone marrow samples were collected from 44 cases.

Result: Marrow findings revealed hypoplasia in 19 dogs (44.18%), hyperplasia in 15 dogs (34.09%), normocellular patterns in 4 dogs (9%) and a mixed cell type in 6 dogs (13.6%). Dogs affected by E. canis were in the initial stage of the disease, showing erythroid hyperplasia (n = 5), followed by myeloid hypoplasia due to chronic infection (n = 4). In B. gibsoni-infected dogs, erythroid hypoplasia (n = 9) and marrow necrosis (n = 1) due to severe infection were notable findings. Bone marrow cytology revealed erythroid hypoplasia as the most common finding, followed by erythroid hyperplasia. A significant correlation was observed between the myeloid-to-erythroid ratio and the peripheral monocyte count at a 99% confidence level (p≤0.01), suggesting that activated monocytes, likely induced by infection, play a major role in pancytopenic cases.

INTRODUCTION

Pancytopenia is characterized by a decrease in myeloid, erythroid and megakaryocytic marrow-derived cell lines, accompanied by a decline in peripheral blood (Kearns and Ewing, 2006; Brazzell and Weiss, 2006). Canine pancytopenia is commonly associated with monocytic ehrlichiosis, parvoviral enteritis, sepsis, drug usage, neoplastic myelophthisis, myelodysplastic and hemophagocytic syndromes, myelofibrosis, myelonecrosis and immune-mediated diseases, leading to bone marrow hypoplasia/aplasia (Mylonakis et al., 2006). Canine hemoprotozoan diseases viz. ehrlichiosis and babesiosis are mostly associated with critical anemia and thrombocytopenia with pancytopenic changes, leading to multi-organ failure. These infections are pre-dominant in Indian subcontinent (Yadav et al., 2025; Sharma et al., 2026). Bone marrow cytology is recommended when abnormalities in peripheral blood cell counts cannot be explained by clinical history, physical examination, or other diagnostic tests (Stacy and Harvey, 2017). It serves as the primary diagnostic tool for pancytopenia (Townsend III, 2004). To identify the medullary quantitative changes and their influence on pancytopenia, myelogram and CBC were essential (Girardi et al., 2017). Canine hemophagocytic syndrome (HPS) is a rare, severe, life-threatening benign proliferative disorder of activated macrophages characterized by the proliferation of non-neoplastic macrophages in the bone marrow and marked by bi-or pancytopenia/multiple cytopenias in the blood (Weiss, 2007; Frezoulis et al., 2018). HPS has associated with a variety of viral, bacterial, fungal and parasitic infections, as well as collagen-vascular diseases and malignancies (Fisman, 2000). Babesiosis can trigger secondary hemophagocytic lymphohistiocytosis in humans (Jacob et al., 2025). Identification of secondary HPS in dogs, particularly when associated with immune-mediated or infectious diseases, may facilitate early recognition and appropriate therapeutic intervention. Therefore, the present study aimed to characterize bone marrow changes in naturally occurring pancytopenic dogs associated with hemoprotozoan infections and immune-mediated diseases, determine the occurrence of HPS and evaluate the correlation between the myeloid-to-erythroid (M:E) ratio and peripheral blood cell counts in pancytopenic dogs.

MATERIALS AND METHODS

Study place
 
The study focused on naturally occurring pancytopenic dogs that were presented to the critical care unit, during the period of 2023-2025 at Madras Veterinary College, Chennai. The investigation involved clinically assessing dogs with a history of bleeding tendencies, including episcleral, petechial and ecchymotic hemorrhage, melena, anemia, splenomegaly and signs indicative of sepsis. Although the clinical signs associated with pancytopenia are often nonspecific, pallor and bleeding tendencies, particularly petechiae, are among the most common manifestations (Kearns and Ewing, 2006). The identified cases were initially screened for pancytopenia based on hematological examination, as described previously (Weiss et al., 1999). Dogs diagnosed with pancytopenia subsequently underwent further investigations, including PCR, bone marrow cytological examination and flow cytometric analysis, to determine the underlying etiologies. All the study animals were natural clinical cases and did not require ethical approval.
 
Blood analysis
 
Two milliliters of whole blood was aseptically collected from sick dogs via venous puncture into EDTA-coated tubes and analyzed in automated anlyzers (Exigo Eos, Sweden). Pancytopenic cases were examined for Ehrlichia canis, Babesia canis, Babesia gibsoni and Anaplasma platys through multiplex PCR analysis as demonstrated already (Sathish et al., 2021). The flow cytometry analysis was carried out as per earlier study (Kucinskiene et al., 2005) from EDTA sample.
 
Bone marrow aspiration and biopsy
 
Pancytopenic animals were sedated prior to bone marrow aspiration. The aspiration site was aseptically prepared before the procedure. The bone marrow was aspirated as per earlier technique (Raskin and Messick, 2012; Jain et al., 2023). A total of 44 samples were collected out of 66 identified pancytopenic cases. Smears were prepared and stained by using a combination of Leishman and Giemsa stains. In possible cases biopsy also carried out. The myeloid:erythroid ratio was calculated according to the method outlined earlier (De Tommasi et al., 2014; Stacy and Harvey, 2017) from 500 cells in each smear. The cellularity, M:E ratio, hemophagocytic macrophages, correlation with the severity of cytopenias were evaluated.
       
Data obtained from the study were subjected to appropriate statistical analyses. One-way analysis of variance (ANOVA) was performed to compare the hematological and biochemical parameters among the study groups. Pearson’s correlation analysis and multiple linear regression analysis were performed to evaluate the relationships between the bone marrow myeloid-to-erythroid (M:E) ratio and peripheral blood neutrophil, monocyte and erythrocyte counts. All statistical analyses were performed using SPSS Statistics version 22 (IBM Corporation, New York, NY, USA).

RESULTS AND DISCUSSION

During the study period, 66 dogs were diagnosed with pancytopenia. The identified etiologies included hemoprotozoan infections in 62% (41 dogs), immune-mediated diseases in 24% (16 dogs) and canine distemper in 1% (1 dog). Together, these accounted for 89% of all pancytopenia cases. There was a significant reduction in cell counts in the hemoprotozoan and immune-mediated groups, with RBC counts of 2.75±0.21 and 2.16±0.18, WBC counts of 3000.00±412.13 and 2723.08±509.29 and platelet counts of 22,347.06±3379.65 and 27,000.00± 3891.14, respectively, compared to the control (Table 1) group. In the study, hemoprotozoan diseases associated with pancytopenia were diagnosed in descending order: Ehrlichiosis 44% (n=18), Babesiosis (B.gibsoni) 24% (n=10), Anaplasmosis 7% (n=3) and concurrent infections of Ehrlichiosis, Babesiosis and Anaplasmosis 24% (n=10), as determined through PCR analysis. Among the dogs with immune-mediated etiologies, 8 dogs had immune-mediated thrombocytopenia, 4 dogs were diagnosed with evans syndrome and immune-mediated hemolytic anemia individually.

Table 1: Mean±S.E values of hematological parameters in pancytopenic animals and healthy control.


       
Out of 44 cases from this study, the cytological findings (Table 2) of marrow were hypoplastic in 19 (44.18%) dogs, hyperplastic in 15 (34.09%) dogs, normocellular in 4 (9%) dogs and mixed cell type in 6 dogs (13.6%). The mixed cells include erythroid hypoplasia with plasma cell infiltration in 2 dogs, myeloid hypoplasia with plasma cell infiltration in 2 dogs and 2 dogs had marrow necrosis. Two more animals had neutrophilic infiltration, one with myeloid hyperplasia and another with erythroid hypoplasia. None of the animals in the study were diagnosed with myelofibrosis, including through biopsy. Of the hypoplastic bone marrow the erythroid hypoplasia was observed in nine dogs (47%), myeloid hypoplasia was observed in four dogs (21%) and megakaryocytic hypoplasia was observed in four dogs (21%). Of the hyperplastic bone marrow, erythroid hyperplasia in 5 dogs (33.3%), myeloid hyperplasia in five dogs (33.3%) and megakaryocytic hyperplasia in two dogs (13.3%). 

Table 2: Details of cytology examination with relation to etiology.


       
The cytological findings in E. canis affected dogs were erythroid hyperplasia (Fig 1) in five cases and myeloid hypoplasia (Fig 2) in four cases. Erythroid hypoplasia (Fig 3) was observed in nine cases of B. gibsoni. and five dogs with co-infection of E.canis, B.giboni, A.platys, had myeloid hyperplasia. One co-infection animal had marrow necrosis (Fig 4) and another two dogs had myeloid hypoplasia with plasma cell infiltration.

Fig 1: Erythroid hyperplasia.



Fig 2: Myeloid hypoplasia.



Fig 3: Erythroid hypoplasia-Adipose tissue infiltration-Hypoplastic bone marrow.



Fig 4: Necrosis of marrow.


       
The bone marrow changes in dogs with immune-mediated disease (n = 11) included erythrophagocytosis (Fig 5) of erythroid cell lines in six dogs, erythroid hypoplasia in two dogs and erythroid hyperplasia in three dogs. Megakaryocytic hyperplasia with concurrent erythroid hyperplasia was observed in two dogs (18.1%), while megakaryocytic hypoplasia was noted in four dogs (36.3%). Hemophagocytic syndrome was identified in four dogs (9%) in the overall cytological examination (Fig 6). Of these four, one dog was infected with Babesia gibsoni and the remaining three had immune-mediated diseases.

Fig 5: Erythrophagocytosis.



Fig 6: Hemophagocytosis by macrophage (Black arrow-RBC, Blue arrow-Platelet, Green and red arrow-WBC).


       
The multilinear regression analysis revealed a significant correlation (p = 0.003; Table 3) between the myeloid-to-erythroid (M:E) ratio and the peripheral monocyte count at the 99% confidence level (p≤0.01). Additionally, pearson’s correlation (two-tailed model) also showed a significant association (p = 0.001; Table 4). This suggests a meaningful relationship between the peripheral monocyte count and the M:E ratio in bone marrow.

Table 3: Multi linear regression coefficientsa.



Table 4: Pearsons’s correlation of myeloid: Erythroid ratio value.


       
Canine hemoprotozoan diseases, viz. ehrlichiosis, anaplasmosis and babesiosis, are commonly associated with severe anemia and thrombocytopenia, often accompanied by pancytopenic changes that can lead to multi-organ failure (Yadav et al., 2025; Sharma et al., 2026). The multiplex PCR assay could simultaneously detect natural co-infections of hemoprotozoan parasites in dogs, emphasizing the need for the assay in epidemiological studies (Senthil and Chakravarthi, 2023; Pati et al., 2025). Notably, the observation of a normal myeloid: erythroid ratio with no medullary changes in 9% of the dogs with pancytopenia suggests that the cytopenia’s origin may be attributed to peripheral destruction, sequestration, or ineffective hematopoiesis, as mentioned earlier (Stokol, 2010).
       
The study identified that dogs affected by E. canis were in the initial stage of the disease, showing erythroid hyperplasia (n = 5), followed by myeloid hypoplasia due to chronic infection (n = 4) as notable findings. Dogs with erythroid hyperplasia were commonly associated with diagnoses such as blood-loss anemia and hemolytic anemia (Stacy and Harvey, 2017; Weiss, 2006). Although transient pancytopenia can accompany acute E. canis infection, it typically associates with bone marrow hypercellularity (Mylonakis et al., 2003). The observed erythroid hyperplasia in E. canis infection may be attributed to an increased demand for peripheral erythrocytes, as seen in cases of hemolysis (Girardi et al., 2017). Myeloid hyperplasia was noted in five dogs with concurrent infections of E. canis, B. gibsoni and A. platys, suggesting the presence of chronic infection, known to increase medullary compartments and bone marrow cellularity (Ikeda-Garcia et al., 2007). Increases in granulopoietic cells (myeloid hyperplasia) are often related to an inflammatory response (Travlos, 2006).
       
The study observed erythroid hypoplasia in nine B. gibsoni cases, myeloid hypoplasia in four E. canis cases and megakaryocytic hypoplasia in four immune-mediated cases. The destruction of stem cells and progenitor cells is a well-established cause of marrow hypoplasia or aplasia and many toxins and infectious agents exert marrow-suppressive effects (Kearns and Ewing, 2006). Various factors, including infections such as ehrlichiosis and parvoviral infection, have been associated with myeloid or erythroid hypoplasia of the bone marrow. Chronic Ehrlichiosis can lead to a marked reduction of hematopoietic tissue, occupying less than 25% of the marrow flecks, usually consisting of adipocytes, endothelial and stromal cells (Mylonakis et al., 2019). Granulocytic hypoplasia is commonly associated with chemotherapy and septicemia (Weiss, 2006). Earlier study by Girardi et al., (2017) had similar results in their report, noting that two cases of E. canis showed myeloid hypoplasia. The observed erythroid hypoplasia in nine dogs with B. gibsoni suggests that babesiosis can lead to the development of septic shock and an unfavorable outcome (Matijatko et al., 2012).
       
The observed erythroid hypoplasia and erythrophagocytosis in dogs with immune mediation suggest the presence of precursor-targeting immune-mediated anemia. Bone marrow hypoplasia, along with lymphocytosis or plasma-cell hyperplasia, is characteristic of immune-mediated anemia and immune-mediated thrombocytopenia (Weiss et al., 1999). Megakaryocytic hyperplasia indicates increased platelet consumption, possibly due to immune mediation secondary to infectious etiologies such as E. canis, aligning with previous study (Harvey, 2001). Thrombocytopenia with megakaryocytic hyperplasia can be seen in immune-mediated platelet destruction, increased peripheral utilization and hypersplenism (Stacy and Harvey, 2017). The observed megakaryocytic hypoplasia and hyperplasia, along with erythroid hypoplasia, are consistent with earlier reports.
       
In the study, plasma cell proliferation in the marrow, particularly in cases of ehrlichiosis, was observed, suggesting a potential chronic infectious etiology. Chronic infectious diseases, especially ehrlichiosis, can lead to marked plasma cell proliferation in the marrow. The presence of myelonecrosis in certain cases could be attributed to various factors such as trauma, inflammation and thromboembolism (Raskin and Messick, 2012). Myelonecrosis and neutrophilic infiltration observed in the study might be associated with septicemia, reflecting the impact of infectious processes on the bone marrow.
       
Hemophagocytic syndrome was diagnosed in four cases (9%), indicating a relatively high incidence that might be associated with secondary immune-mediated disease. Hemophagocytic syndromes can develop secondary to infection (Weiss, 2007). It was reported in humans that HPS occur more often in the summer and follow seasonal pattern (Chen et al., 1991) more in south east Asian tropical counties probably because of endemic malarial species (Sung et al., 2011) and Dengue infections (Mizutani et al., 2023). Although babesiosis, parvovirus, Epstein-Barr virus, malaria, COVID-19 and other infections have been reported as causes of secondary HPS in humans, no comparable studies have been conducted in veterinary medicine. Hemophagocytosis is achieved mostly by monocytes and macrophages and in nonviral pathogens by host lymphocytes and monocytes. Excessive activation of monocytes in HPS may be due to stimulation by high levels of activating cytokines (Fisman, 2000). The significant correlation between the myeloid-to-erythroid ratio and monocyte count suggests that a majority of pancytopenic cases in the study were likely of infectious origin. Erythroid suppression, along with lymphocytic, monocytic and macrophage hyperplasia in the bone marrow, was observed in dogs affected by vector-borne pathogens (De Tommasi et al., 2014). Monocytes play a crucial role in the innate immune system and elevated levels may be indicative of various diseases, especially those involving phagocytosis (Pierini et al., 2020). Although bone marrow cytology provided valuable insights into the underlying medullary quantitative changes in pancytopenic dogs, multicentric studies involving larger populations are warranted to further elucidate the pathogenesis and spectrum of bone marrow abnormalities associated with pancytopenia. Such studies may also contribute to the development of evidence-based therapeutic strategies, particularly in determining the appropriate use of immunosuppressive therapy in dogs with hemophagocytic syndrome.

CONCLUSION

Infectious diseases (89%) contribute significantly to pancytopenia in dogs. Erythroid hypoplasia as the most common finding, followed by erythroid hyperplasia. A significant correlation was observed between the myeloid-to-erythroid ratio and the peripheral monocyte count at a 99% confidence level (p≤0.01), suggesting that activated monocytes, likely induced by infection, play a major role in pancytopenic cases.

ACKNOWLEDGEMENT

The authors thank the administration of Tamilnadu Veterinary and Animal Sciences University for their support in conducting this research.
 
Disclaimers
 
The views and conclusions expressed in this article are solely those of the authors and do not necessarily represent the views of their affiliated institutions. The authors are responsible for the accuracy and completeness of the information provided, but do not accept any liability for any direct or indirect losses resulting from the use of this content.
 
Animal ethics
 
All the study animals were natural clinical cases and did not require ethical approval. However, owner’s written consent was obtained before bone marrow aspiration or biopsy.

CONFLICT OF INTEREST

The authors declare that they have no conflict of interest.

REFERENCES


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    Full Research Article

    Hemophagocytic Syndrome Associated with Infectious Diseases in Pancytopenic Dogs

    M
    M. Ranjithkumar1,#,*
    V
    V. Arvind1,#
    N
    N. Pazhanivel1
    R
    Rajat Sagare1
    A
    A.S. Pandian1
    R
    R. Ramprabhu1
    1Department of Veterinary Clinical Medicine, Madras Veterinary College, Tamil Nadu Veterinary and Animal Sciences University, Chennai-600 007, Tamil Nadu, India. 

    ABSTRACT

    #These authors contributed equally to this work.

    Background: Pancytopenia, characterized by a reduction in the number of peripheral blood cells, encompasses various etiologies, including infectious, immune-mediated diseases, sepsis and drug-related causes. The primary diagnostic tool for pancytopenia is bone marrow aspiration. The objective of this study was to elucidate bone marrow changes in naturally occurring pancytopenic cases with hemoprotozoan and immune mediated etiologies.

    Methods: Animals confirmed as pancytopenic through hematological analysis underwent bone marrow cytology, PCR analysis and flow cytometry to identify the underlying pathology. Over the three-year study period, bone marrow samples were collected from 44 cases.

    Result: Marrow findings revealed hypoplasia in 19 dogs (44.18%), hyperplasia in 15 dogs (34.09%), normocellular patterns in 4 dogs (9%) and a mixed cell type in 6 dogs (13.6%). Dogs affected by E. canis were in the initial stage of the disease, showing erythroid hyperplasia (n = 5), followed by myeloid hypoplasia due to chronic infection (n = 4). In B. gibsoni-infected dogs, erythroid hypoplasia (n = 9) and marrow necrosis (n = 1) due to severe infection were notable findings. Bone marrow cytology revealed erythroid hypoplasia as the most common finding, followed by erythroid hyperplasia. A significant correlation was observed between the myeloid-to-erythroid ratio and the peripheral monocyte count at a 99% confidence level (p≤0.01), suggesting that activated monocytes, likely induced by infection, play a major role in pancytopenic cases.

    INTRODUCTION

    Pancytopenia is characterized by a decrease in myeloid, erythroid and megakaryocytic marrow-derived cell lines, accompanied by a decline in peripheral blood (Kearns and Ewing, 2006; Brazzell and Weiss, 2006). Canine pancytopenia is commonly associated with monocytic ehrlichiosis, parvoviral enteritis, sepsis, drug usage, neoplastic myelophthisis, myelodysplastic and hemophagocytic syndromes, myelofibrosis, myelonecrosis and immune-mediated diseases, leading to bone marrow hypoplasia/aplasia (Mylonakis et al., 2006). Canine hemoprotozoan diseases viz. ehrlichiosis and babesiosis are mostly associated with critical anemia and thrombocytopenia with pancytopenic changes, leading to multi-organ failure. These infections are pre-dominant in Indian subcontinent (Yadav et al., 2025; Sharma et al., 2026). Bone marrow cytology is recommended when abnormalities in peripheral blood cell counts cannot be explained by clinical history, physical examination, or other diagnostic tests (Stacy and Harvey, 2017). It serves as the primary diagnostic tool for pancytopenia (Townsend III, 2004). To identify the medullary quantitative changes and their influence on pancytopenia, myelogram and CBC were essential (Girardi et al., 2017). Canine hemophagocytic syndrome (HPS) is a rare, severe, life-threatening benign proliferative disorder of activated macrophages characterized by the proliferation of non-neoplastic macrophages in the bone marrow and marked by bi-or pancytopenia/multiple cytopenias in the blood (Weiss, 2007; Frezoulis et al., 2018). HPS has associated with a variety of viral, bacterial, fungal and parasitic infections, as well as collagen-vascular diseases and malignancies (Fisman, 2000). Babesiosis can trigger secondary hemophagocytic lymphohistiocytosis in humans (Jacob et al., 2025). Identification of secondary HPS in dogs, particularly when associated with immune-mediated or infectious diseases, may facilitate early recognition and appropriate therapeutic intervention. Therefore, the present study aimed to characterize bone marrow changes in naturally occurring pancytopenic dogs associated with hemoprotozoan infections and immune-mediated diseases, determine the occurrence of HPS and evaluate the correlation between the myeloid-to-erythroid (M:E) ratio and peripheral blood cell counts in pancytopenic dogs.

    MATERIALS AND METHODS

    Study place
     
    The study focused on naturally occurring pancytopenic dogs that were presented to the critical care unit, during the period of 2023-2025 at Madras Veterinary College, Chennai. The investigation involved clinically assessing dogs with a history of bleeding tendencies, including episcleral, petechial and ecchymotic hemorrhage, melena, anemia, splenomegaly and signs indicative of sepsis. Although the clinical signs associated with pancytopenia are often nonspecific, pallor and bleeding tendencies, particularly petechiae, are among the most common manifestations (Kearns and Ewing, 2006). The identified cases were initially screened for pancytopenia based on hematological examination, as described previously (Weiss et al., 1999). Dogs diagnosed with pancytopenia subsequently underwent further investigations, including PCR, bone marrow cytological examination and flow cytometric analysis, to determine the underlying etiologies. All the study animals were natural clinical cases and did not require ethical approval.
     
    Blood analysis
     
    Two milliliters of whole blood was aseptically collected from sick dogs via venous puncture into EDTA-coated tubes and analyzed in automated anlyzers (Exigo Eos, Sweden). Pancytopenic cases were examined for Ehrlichia canis, Babesia canis, Babesia gibsoni and Anaplasma platys through multiplex PCR analysis as demonstrated already (Sathish et al., 2021). The flow cytometry analysis was carried out as per earlier study (Kucinskiene et al., 2005) from EDTA sample.
     
    Bone marrow aspiration and biopsy
     
    Pancytopenic animals were sedated prior to bone marrow aspiration. The aspiration site was aseptically prepared before the procedure. The bone marrow was aspirated as per earlier technique (Raskin and Messick, 2012; Jain et al., 2023). A total of 44 samples were collected out of 66 identified pancytopenic cases. Smears were prepared and stained by using a combination of Leishman and Giemsa stains. In possible cases biopsy also carried out. The myeloid:erythroid ratio was calculated according to the method outlined earlier (De Tommasi et al., 2014; Stacy and Harvey, 2017) from 500 cells in each smear. The cellularity, M:E ratio, hemophagocytic macrophages, correlation with the severity of cytopenias were evaluated.
           
    Data obtained from the study were subjected to appropriate statistical analyses. One-way analysis of variance (ANOVA) was performed to compare the hematological and biochemical parameters among the study groups. Pearson’s correlation analysis and multiple linear regression analysis were performed to evaluate the relationships between the bone marrow myeloid-to-erythroid (M:E) ratio and peripheral blood neutrophil, monocyte and erythrocyte counts. All statistical analyses were performed using SPSS Statistics version 22 (IBM Corporation, New York, NY, USA).

    RESULTS AND DISCUSSION

    During the study period, 66 dogs were diagnosed with pancytopenia. The identified etiologies included hemoprotozoan infections in 62% (41 dogs), immune-mediated diseases in 24% (16 dogs) and canine distemper in 1% (1 dog). Together, these accounted for 89% of all pancytopenia cases. There was a significant reduction in cell counts in the hemoprotozoan and immune-mediated groups, with RBC counts of 2.75±0.21 and 2.16±0.18, WBC counts of 3000.00±412.13 and 2723.08±509.29 and platelet counts of 22,347.06±3379.65 and 27,000.00± 3891.14, respectively, compared to the control (Table 1) group. In the study, hemoprotozoan diseases associated with pancytopenia were diagnosed in descending order: Ehrlichiosis 44% (n=18), Babesiosis (B.gibsoni) 24% (n=10), Anaplasmosis 7% (n=3) and concurrent infections of Ehrlichiosis, Babesiosis and Anaplasmosis 24% (n=10), as determined through PCR analysis. Among the dogs with immune-mediated etiologies, 8 dogs had immune-mediated thrombocytopenia, 4 dogs were diagnosed with evans syndrome and immune-mediated hemolytic anemia individually.

    Table 1: Mean±S.E values of hematological parameters in pancytopenic animals and healthy control.


           
    Out of 44 cases from this study, the cytological findings (Table 2) of marrow were hypoplastic in 19 (44.18%) dogs, hyperplastic in 15 (34.09%) dogs, normocellular in 4 (9%) dogs and mixed cell type in 6 dogs (13.6%). The mixed cells include erythroid hypoplasia with plasma cell infiltration in 2 dogs, myeloid hypoplasia with plasma cell infiltration in 2 dogs and 2 dogs had marrow necrosis. Two more animals had neutrophilic infiltration, one with myeloid hyperplasia and another with erythroid hypoplasia. None of the animals in the study were diagnosed with myelofibrosis, including through biopsy. Of the hypoplastic bone marrow the erythroid hypoplasia was observed in nine dogs (47%), myeloid hypoplasia was observed in four dogs (21%) and megakaryocytic hypoplasia was observed in four dogs (21%). Of the hyperplastic bone marrow, erythroid hyperplasia in 5 dogs (33.3%), myeloid hyperplasia in five dogs (33.3%) and megakaryocytic hyperplasia in two dogs (13.3%). 

    Table 2: Details of cytology examination with relation to etiology.


           
    The cytological findings in E. canis affected dogs were erythroid hyperplasia (Fig 1) in five cases and myeloid hypoplasia (Fig 2) in four cases. Erythroid hypoplasia (Fig 3) was observed in nine cases of B. gibsoni. and five dogs with co-infection of E.canis, B.giboni, A.platys, had myeloid hyperplasia. One co-infection animal had marrow necrosis (Fig 4) and another two dogs had myeloid hypoplasia with plasma cell infiltration.

    Fig 1: Erythroid hyperplasia.



    Fig 2: Myeloid hypoplasia.



    Fig 3: Erythroid hypoplasia-Adipose tissue infiltration-Hypoplastic bone marrow.



    Fig 4: Necrosis of marrow.


           
    The bone marrow changes in dogs with immune-mediated disease (n = 11) included erythrophagocytosis (Fig 5) of erythroid cell lines in six dogs, erythroid hypoplasia in two dogs and erythroid hyperplasia in three dogs. Megakaryocytic hyperplasia with concurrent erythroid hyperplasia was observed in two dogs (18.1%), while megakaryocytic hypoplasia was noted in four dogs (36.3%). Hemophagocytic syndrome was identified in four dogs (9%) in the overall cytological examination (Fig 6). Of these four, one dog was infected with Babesia gibsoni and the remaining three had immune-mediated diseases.

    Fig 5: Erythrophagocytosis.



    Fig 6: Hemophagocytosis by macrophage (Black arrow-RBC, Blue arrow-Platelet, Green and red arrow-WBC).


           
    The multilinear regression analysis revealed a significant correlation (p = 0.003; Table 3) between the myeloid-to-erythroid (M:E) ratio and the peripheral monocyte count at the 99% confidence level (p≤0.01). Additionally, pearson’s correlation (two-tailed model) also showed a significant association (p = 0.001; Table 4). This suggests a meaningful relationship between the peripheral monocyte count and the M:E ratio in bone marrow.

    Table 3: Multi linear regression coefficientsa.



    Table 4: Pearsons’s correlation of myeloid: Erythroid ratio value.


           
    Canine hemoprotozoan diseases, viz. ehrlichiosis, anaplasmosis and babesiosis, are commonly associated with severe anemia and thrombocytopenia, often accompanied by pancytopenic changes that can lead to multi-organ failure (Yadav et al., 2025; Sharma et al., 2026). The multiplex PCR assay could simultaneously detect natural co-infections of hemoprotozoan parasites in dogs, emphasizing the need for the assay in epidemiological studies (Senthil and Chakravarthi, 2023; Pati et al., 2025). Notably, the observation of a normal myeloid: erythroid ratio with no medullary changes in 9% of the dogs with pancytopenia suggests that the cytopenia’s origin may be attributed to peripheral destruction, sequestration, or ineffective hematopoiesis, as mentioned earlier (Stokol, 2010).
           
    The study identified that dogs affected by E. canis were in the initial stage of the disease, showing erythroid hyperplasia (n = 5), followed by myeloid hypoplasia due to chronic infection (n = 4) as notable findings. Dogs with erythroid hyperplasia were commonly associated with diagnoses such as blood-loss anemia and hemolytic anemia (Stacy and Harvey, 2017; Weiss, 2006). Although transient pancytopenia can accompany acute E. canis infection, it typically associates with bone marrow hypercellularity (Mylonakis et al., 2003). The observed erythroid hyperplasia in E. canis infection may be attributed to an increased demand for peripheral erythrocytes, as seen in cases of hemolysis (Girardi et al., 2017). Myeloid hyperplasia was noted in five dogs with concurrent infections of E. canis, B. gibsoni and A. platys, suggesting the presence of chronic infection, known to increase medullary compartments and bone marrow cellularity (Ikeda-Garcia et al., 2007). Increases in granulopoietic cells (myeloid hyperplasia) are often related to an inflammatory response (Travlos, 2006).
           
    The study observed erythroid hypoplasia in nine B. gibsoni cases, myeloid hypoplasia in four E. canis cases and megakaryocytic hypoplasia in four immune-mediated cases. The destruction of stem cells and progenitor cells is a well-established cause of marrow hypoplasia or aplasia and many toxins and infectious agents exert marrow-suppressive effects (Kearns and Ewing, 2006). Various factors, including infections such as ehrlichiosis and parvoviral infection, have been associated with myeloid or erythroid hypoplasia of the bone marrow. Chronic Ehrlichiosis can lead to a marked reduction of hematopoietic tissue, occupying less than 25% of the marrow flecks, usually consisting of adipocytes, endothelial and stromal cells (Mylonakis et al., 2019). Granulocytic hypoplasia is commonly associated with chemotherapy and septicemia (Weiss, 2006). Earlier study by Girardi et al., (2017) had similar results in their report, noting that two cases of E. canis showed myeloid hypoplasia. The observed erythroid hypoplasia in nine dogs with B. gibsoni suggests that babesiosis can lead to the development of septic shock and an unfavorable outcome (Matijatko et al., 2012).
           
    The observed erythroid hypoplasia and erythrophagocytosis in dogs with immune mediation suggest the presence of precursor-targeting immune-mediated anemia. Bone marrow hypoplasia, along with lymphocytosis or plasma-cell hyperplasia, is characteristic of immune-mediated anemia and immune-mediated thrombocytopenia (Weiss et al., 1999). Megakaryocytic hyperplasia indicates increased platelet consumption, possibly due to immune mediation secondary to infectious etiologies such as E. canis, aligning with previous study (Harvey, 2001). Thrombocytopenia with megakaryocytic hyperplasia can be seen in immune-mediated platelet destruction, increased peripheral utilization and hypersplenism (Stacy and Harvey, 2017). The observed megakaryocytic hypoplasia and hyperplasia, along with erythroid hypoplasia, are consistent with earlier reports.
           
    In the study, plasma cell proliferation in the marrow, particularly in cases of ehrlichiosis, was observed, suggesting a potential chronic infectious etiology. Chronic infectious diseases, especially ehrlichiosis, can lead to marked plasma cell proliferation in the marrow. The presence of myelonecrosis in certain cases could be attributed to various factors such as trauma, inflammation and thromboembolism (Raskin and Messick, 2012). Myelonecrosis and neutrophilic infiltration observed in the study might be associated with septicemia, reflecting the impact of infectious processes on the bone marrow.
           
    Hemophagocytic syndrome was diagnosed in four cases (9%), indicating a relatively high incidence that might be associated with secondary immune-mediated disease. Hemophagocytic syndromes can develop secondary to infection (Weiss, 2007). It was reported in humans that HPS occur more often in the summer and follow seasonal pattern (Chen et al., 1991) more in south east Asian tropical counties probably because of endemic malarial species (Sung et al., 2011) and Dengue infections (Mizutani et al., 2023). Although babesiosis, parvovirus, Epstein-Barr virus, malaria, COVID-19 and other infections have been reported as causes of secondary HPS in humans, no comparable studies have been conducted in veterinary medicine. Hemophagocytosis is achieved mostly by monocytes and macrophages and in nonviral pathogens by host lymphocytes and monocytes. Excessive activation of monocytes in HPS may be due to stimulation by high levels of activating cytokines (Fisman, 2000). The significant correlation between the myeloid-to-erythroid ratio and monocyte count suggests that a majority of pancytopenic cases in the study were likely of infectious origin. Erythroid suppression, along with lymphocytic, monocytic and macrophage hyperplasia in the bone marrow, was observed in dogs affected by vector-borne pathogens (De Tommasi et al., 2014). Monocytes play a crucial role in the innate immune system and elevated levels may be indicative of various diseases, especially those involving phagocytosis (Pierini et al., 2020). Although bone marrow cytology provided valuable insights into the underlying medullary quantitative changes in pancytopenic dogs, multicentric studies involving larger populations are warranted to further elucidate the pathogenesis and spectrum of bone marrow abnormalities associated with pancytopenia. Such studies may also contribute to the development of evidence-based therapeutic strategies, particularly in determining the appropriate use of immunosuppressive therapy in dogs with hemophagocytic syndrome.

    CONCLUSION

    Infectious diseases (89%) contribute significantly to pancytopenia in dogs. Erythroid hypoplasia as the most common finding, followed by erythroid hyperplasia. A significant correlation was observed between the myeloid-to-erythroid ratio and the peripheral monocyte count at a 99% confidence level (p≤0.01), suggesting that activated monocytes, likely induced by infection, play a major role in pancytopenic cases.

    ACKNOWLEDGEMENT

    The authors thank the administration of Tamilnadu Veterinary and Animal Sciences University for their support in conducting this research.
     
    Disclaimers
     
    The views and conclusions expressed in this article are solely those of the authors and do not necessarily represent the views of their affiliated institutions. The authors are responsible for the accuracy and completeness of the information provided, but do not accept any liability for any direct or indirect losses resulting from the use of this content.
     
    Animal ethics
     
    All the study animals were natural clinical cases and did not require ethical approval. However, owner’s written consent was obtained before bone marrow aspiration or biopsy.

    CONFLICT OF INTEREST

    The authors declare that they have no conflict of interest.

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