History

A 6.5-year-old spayed female Terrier mix was presented to the Orthopedic Medicine and Mobility (OMM) service at Colorado State University for evaluation of chronic, progressive left pelvic limb lameness. Ten months prior to evaluation with OMM, the patient was presented to the primary care veterinarian for evaluation of inappetence and lethargy after a camping trip. Exam findings revealed a temperature of 39.9 °C but was otherwise unremarkable. Baseline blood work showed a mild regenerative anemia and hyperglobulinemia, and 4Dx testing for heartworm and tick-borne disease was negative. The patient was discharged with carprofen and capromorelin. The patient next presented a month later for vaccines, and the owner reported a resolution of the previous clinical signs. Eight months later, the owner again noted an intermittent non–weight-bearing left hind limb lameness. Bilateral stifle effusion with resistance to range of motion was noted. Radiographs of the pelvis were unremarkable, while radiographs of both stifles and tarsi revealed effusion and raised concern for immune-mediated polyarthritis (IMPA). The patient was discharged with instructions to stop carprofen in the instance of immune-mediated disease and recommendations for strict exercise restriction for 2 weeks, and was started on gabapentin and methocarbamol. Five weeks later, the patient presented to the Colorado State University Neurology service and was again febrile at 40.2 °C, had no improvement in mobility, and was noted to have lost 1.8 kg over the course of 7 months. Pain was again localized to both stifles with a persistent non–weight-bearing lameness of the left hind limb. Neurologic examination was normal and orthopedic disease was suspected, so the dog was referred to the OMM service where examination revealed a body condition score of 3/9, muscle condition score of 2/3 over the forelimbs and right hind limb and 1/3 over the left hind limb, and a peripheral lymphadenopathy. The dog displayed a non–weight-bearing left hind limb lameness with multiple effusive and painful joints, most marked in the left stifle. No stifle laxity was identified. Given the history, signalment, clinical signs, and orthopedic examination findings, the primary differential at the time was IMPA.

Diagnostic Findings and Interpretation

The dog’s CBC revealed a strongly regenerative anemia with an Hct of 31% (reference range [RR], 40% to 55%) and a reticulocyte count of 402 X 10³/µL, an elevated plasma protein of 9.0 g/dL (RR, 6.0 to 7.5 g/dL), a severe thrombocytopenia of 18 X 10³/µL (RR, 200 X 10³ to 500 X 10³/µL) with rare clumps and an elevated mean platelet volume at 22.0 fL (RR, 7.5 to 14.6 fL), and otherwise normal WBC counts. There was 4+ saline agglutination, consistent with immune-mediated hemolytic anemia (IMHA). The chemistry panel revealed a low creatinine of 0.32 mg/dL (RR, 0.6 to 1.6 mg/dL), elevated globulins at 5.1 g/dL (RR, 3.0 to 4.3 g/dL), and a slight hyperbilirubinemia at 0.3 mg/dL (RR, 0.0 to 0.2 mg/dL). Urinalysis was unremarkable.

The dog was sedated, and the right carpal joint, right tarsal joint, and left stifle joint were aspirated. On aspiration, the synovial fluid grossly had negligible viscosity and was homogenously dark red and opaque. Three milliliters of fluid was drawn from the left stifle. Fluid cytology of the left stifle and right tarsus revealed individual and aggregated hematopoietic precursors with myeloid, erythroid, and megakaryocytic lineages seen. All stages of all hematopoietic cell lines were found, and some of the aggregates were associated with plump spindled mesenchymal cells and scant extracellular matrix (Figure 1). This cytology is consistent with extramedullary hematopoiesis (EMH), an expected response to the significant anemia and thrombocytopenia but in a previously unreported location in canines. Cytology of the right carpus was minimally cellular and nondiagnostic. Aerobic and anaerobic culture of the pooled joint fluid showed no growth.

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Cytology of fluid obtained from the left stifle (A and B) and right tarsus (C and D); 100X objective. Both locations contained individualized and aggregated hematopoietic precursors with myeloid, erythroid, and megakaryocytic lineages seen. Some aggregates were associated with plump spindled mesenchymal cells among scant, light-pink extracellular matrix. (Figure courtesy of Dr. Russell Moore.)

Citation: Journal of the American Veterinary Medical Association 262, 4; 10.2460/javma.23.11.0617

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Additional diagnostics included a basal cortisol of 12 µg/dL; a negative 4Dx test for heartworm, Anaplasma, Ehrlichia, and Borrelia; and a positive Coombs (warm) test (1:64). Flow cytometry showed that 67.7% of platelets were associated with immunoglobulin, consistent with an immune process, but a positive result does not differentiate associative versus nonassociative thrombocytopenia (ITP).

Abdominal ultrasound revealed mild medial iliac lymphadenopathy and mild splenomegaly, both thought to be reactive hyperplasia and EMH, respectively. The patient’s thrombocytopenia informed the decision not to attempt fine-needle aspiration of either structure. Thoracic radiographs were normal.

Radiographs of the left stifle revealed moderate to marked osteopenia of the femur and tibia, marked diffuse muscular atrophy of that limb, and increased soft tissue opacity within the stifle joint. Joint survey radiographs revealed mild diffuse osteopenia of all osseous structures and moderate soft tissue swelling in both carpi, marked diffuse osteopenia off all osseous structures, soft tissue swelling of both tarsi, and marked diffuse muscular atrophy.

Treatment and Outcome

The patient was started on pregabalin (2 mg/kg, q 12 h) and prednisolone (2 mg/kg, q 24 h). Physical therapy was also recommended but was not pursued by the owner.

Ten days after starting treatment, the dog was no longer febrile and the owners reported that the dog was “doing well” at home, although showing signs of fatigue during evening walks. The dog was still significantly underconditioned with diffuse muscle wasting, and mild effusion was appreciated in the stifle joints. The patient’s Hct had risen from 31% to 37% and was still strongly regenerative. Platelet count had increased from 18 X 10³ to 449 X 10³/µL with clumps. There was no saline agglutination noted on the 10-day recheck CBC. The prednisolone dose was decreased to 1.5 mg/kg every 24 hours, and cyclosporine (5 mg/kg, q 12 h) and clopidogrel (1.5 mg/kg, q 24 h) were added to the treatment regimen.

Two weeks later, the dog’s Hct was within normal limits at 43% and all other parameters were stable, although the WBCs then showed a typical steroid-induced stress leukogram. The owner reported that the dog was ambulatory on all 4 limbs, and mobility was overall much improved. Only mild left stifle discomfort was noted at this time. The treatment plan was to continue to taper the prednisolone as dictated by the continued clinical response.

Comments

Extramedullary hematopoiesis is demonstrated most frequently in the spleen or liver, usually in response to a reduction in intramedullary hematopoiesis.¹ If present in an unusual location, EMH may cause clinical signs that are a diagnostic challenge. For example, case reports include refractory ascites in a dog with peritoneal EMH and a T3-L3 myelopathy secondary to extradural spinal masses of EMH tissue.^2,3 This is the first known report of synovial EMH in a dog. This case differs from the previously reported cases of synovial EMH in humans in that a biopsy of the synovial tissue was not performed, only aspiration of joint fluid, and evidence of EMH was found in multiple joints.⁴

It would appear that this dog had untreated ITP and IMHA for some period of time before seeking veterinary care for lameness. The degree of anemia was not severe and was being supported by a highly regenerative response, and although the thrombocytopenia was marked, there was no obvious clinical evidence of ITP. It is impossible to determine what degree of the reported lethargy was due to painful joints, muscle wasting, or anemia. It is unclear why the dog was stimulated to utilize joint space for EMH as a way to help maintain the Hct in the face of a chronic immune-mediated challenge. There is a case report⁵ of a dog with peritoneal EMH and IMHA. It seems likely but remains an unanswered question as to whether this dog actually suffered from immune-mediated polyarthritis. None of the joints produced fluid with cytology consistent with joint fluid, much less IMPA. One theory would be that the dog’s joints were in fact the site of an immune-mediated process around the same time as the ITP and IMHA and, under the stress of those 2 conditions, the joints in some way became available as EMH depots. The rapidity and degree of response to prednisolone therapy at multiple levels—Hct, platelet count, and clinical comfort—strongly supports a single underlying immune-mediated etiology. An alternative interpretation could be that successful treatment of the anemia and thrombocytopenia removed the stimulus for EMH in the joint, which then returned to a normal, pain-free structure and function.

One limitation of this report was the absence of repeat joint taps after the other parameters normalized and the dog became comfortable. The diagnostic work-up failed to identify a definitive trigger, and hence the patient’s immune-mediated conditions would be considered primary or nonassociative. It would be interesting to determine whether the EMH receded from the joints with successful treatment of the presumed stimulus, but this follow-up information is not available.

This case represents the first published report of EMH in the joint of a dog. The dog presented for joint pain, with a prior history of seemingly untreated IMHA and ITP. It would appear that those preexisting comorbidities impacted the dog’s joints, but the actual timing, pathologic process, and causality remains unclear. As in similar but rare reports in humans, this case highlights the importance of being open-minded and diligent when presented with multiple problems that initially appear unrelated.

Disclosures

The authors have nothing to disclose. No AI-assisted technologies were used in the generation of this manuscript.

Funding

The authors have nothing to disclose.