Case Report: Primary Immune-Mediated Thrombocytopenia in a Japanese Terrier

 Clinical Course of Primary Immune-Mediated Thrombocytopenia in a Japanese Terrier Receiving Adjunctive Huaier-Derived TPG-1 

Dose multiples indicate multiples of the recommended daily amount for the canine/feline Huaier product.

A 10-year-old spayed female Japanese Terrier was presented with swelling of the cheek after falling on a staircase. During the examination, unexpected evidence of a marked bleeding tendency was identified, including purpura and blood adhering to the oral cavity and teeth.

Initial hematologic examination revealed severe thrombocytopenia, with a platelet count of 0/μL (reference interval, 14.8–48.4 × 10⁴/μL). The red blood cell count was 7.55 × 10⁶/μL, packed cell volume was 49.9%, hemoglobin concentration was 17.8 g/dL, and white blood cell count was 10.73 × 10³/μL. The leukocyte differential included neutrophils at 6.74 × 10³/μL, lymphocytes at 2.79 × 10³/μL, monocytes at 0.88 × 10³/μL, eosinophils at 0.31 × 10³/μL, and basophils at 0.01 × 10³/μL.

A Wright–Giemsa-stained peripheral blood smear was also examined as part of the hematologic evaluation (Figure 1).

Figure 1. Representative peripheral blood smear at initial presentation.
A Wright–Giemsa-stained peripheral blood smear was examined as part of the hematologic evaluation in a dog presenting with severe thrombocytopenia.

Serum biochemical analysis showed glucose at 138 mg/dL, creatinine at 0.53 mg/dL, blood urea nitrogen at 15.2 mg/dL, phosphorus at 4.3 mg/dL, calcium at 10.6 mg/dL, total protein at 6.9 g/dL, albumin at 3.1 g/dL, globulin at 3.8 g/dL, ALT at 59 U/L, AST at 34 U/L, ALP at 83 U/L, total bilirubin at 0.2 mg/dL, and total cholesterol at 138 mg/dL. Serum sodium, potassium, and chloride concentrations were 151, 4.0, and 112 mmol/L, respectively. C-reactive protein was increased to 11 mg/dL.

Additional coagulation testing showed a prothrombin time of 6.8 seconds (reference interval, 7.4–8.8 seconds), activated partial thromboplastin time of 17.6 seconds (reference interval, 12–28 seconds), and fibrinogen >650 mg/dL.

Serum iron was 62 μg/dL, total iron-binding capacity was 311 μg/dL, unsaturated iron-binding capacity was 249 μg/dL, transferrin saturation was 19.9%, and serum ferritin was 100 ng/mL. Antinuclear antibody testing was negative.

A broad real-time PCR panel for vector-borne infectious diseases, including Anaplasma, Babesia, Bartonella, Ehrlichia, Hepatozoon, Leishmania, Neorickettsia, Rickettsia, and hemotropic Mycoplasma species, was negative.

A diagnostic evaluation including review of relevant drug exposure, laboratory testing, infectious disease screening, and diagnostic imaging did not identify an underlying condition or other apparent secondary cause of thrombocytopenia. Based on the diagnostic evaluation performed, the dog was diagnosed with primary immune-mediated thrombocytopenia (pITP).

Initial immunosuppressive treatment with prednisolone and cyclosporine was initiated, resulting in a rapid increase in platelet count and successful induction of clinical remission.

The clinical course was broadly divided into three phases: initial remission induction, introduction of adjunctive TPG-1 during immunosuppressant tapering and withdrawal, and subsequent adjustment of TPG-1 administration during declining platelet counts and later recurrence of marked thrombocytopenia.

Phase 1: Acute Treatment and Initial Remission Induction

On Day 1, severe thrombocytopenia was confirmed, with a platelet count of 0/μL. Following the diagnosis of pITP, immunosuppressive therapy was initiated with prednisolone at 2.03 mg/kg once daily and cyclosporine at 8.5 mg/kg once daily.

By Day 7, the platelet count had rapidly increased to 37.7 × 10⁴/μL, indicating a favorable initial response to immunosuppressive treatment.

Platelet counts subsequently remained relatively stable during gradual tapering of prednisolone.

Phase 2: Introduction of Adjunctive TPG-1 During Immunosuppressant Tapering

On Day 92, the platelet count remained stable at 31.9 × 10⁴/μL. From Day 93, adjunctive Huaier-derived TPG-1 was initiated at the 1× recommended daily amount while immunosuppressive therapy was being gradually tapered.

Prednisolone was progressively reduced and was discontinued from Day 175. Cyclosporine was also subsequently tapered and discontinued during follow-up.

Platelet counts remained within or near the reference interval after withdrawal of prednisolone, including 34.5 × 10⁴/μL on Day 239 and 26.6 × 10⁴/μL on Day 323.

The temporal changes in platelet count, immunosuppressive treatment, and initiation of adjunctive TPG-1 are summarized in Figure 2.

Figure 2. Clinical course of platelet counts during initial immunosuppressive treatment, tapering, and adjunctive administration of Huaier-derived TPG-1.

The platelet count increased from 0/μL on Day 1 to 37.7 × 10⁴/μL on Day 7 following initiation of prednisolone and cyclosporine. Thereafter, platelet counts remained relatively stable during gradual tapering of immunosuppressive therapy. Adjunctive Huaier-derived TPG-1 was initiated at the 1× recommended daily amount on Day 93. Prednisolone was discontinued from Day 175, and cyclosporine was discontinued on Day 295. Platelet counts remained within or near the reference interval during subsequent follow-up while TPG-1 administration was continued.

The figure illustrates the temporal relationship between treatment changes and platelet counts and does not establish a causal effect of TPG-1.

 Phase 3: TPG-1 Adjustment During Platelet Decline and Management of Suspected Relapse

Following complete withdrawal of immunosuppressive therapy, the platelet count gradually decreased from 18.2 × 10⁴/μL on Day 498 to 14.0 × 10⁴/μL on Day 589.

At that time, immunosuppressive medication was not restarted. Instead, TPG-1 was increased from the 1× to the 2× recommended daily amount.

At the subsequent examination on Day 617, the platelet count had increased to 27.2 × 10⁴/μL, returning to within the reference interval.

This represents a temporal association between TPG-1 dose escalation and the subsequent increase in platelet count. However, because this was a single uncontrolled case, a causal relationship cannot be established.

On Day 709, the platelet count had again decreased to 19.8 × 10⁴/μL, and TPG-1 was increased from the 2× to the 3× recommended daily amount.

On Day 786, recurrent marked thrombocytopenia consistent with relapse of pITP was identified, with a platelet count of 5.1 × 10⁴/μL. Prednisolone was therefore restarted at 1.72 mg/kg once daily, and TPG-1 was increased from the 3× to the 4× recommended daily amount and continued thereafter.

By Day 793, the platelet count had increased to 17.7 × 10⁴/μL.

On Day 828, the platelet count had further increased to 35.2 × 10⁴/μL. At that time, prednisolone had been reduced to every-other-day administration, cyclosporine was being administered at 25 mg/head twice daily, and TPG-1 was being continued at the 4× recommended daily amount.

Because conventional immunosuppressive therapy was reintroduced during this later response period, the relative contribution of TPG-1 to the increase in platelet count following relapse cannot be determined independently.

The later clinical course and TPG-1 adjustments are summarized in Figure 3.

Figure 3. Changes in platelet count during TPG-1 dose escalation and subsequent recurrence of marked thrombocytopenia.

After withdrawal of immunosuppressive therapy, the platelet count gradually decreased from 27.5 × 10⁴/μL on Day 414 to 14.0 × 10⁴/μL on Day 589. At that time, Huaier-derived TPG-1 was increased from the 1× to the 2× recommended daily amount without reintroduction of immunosuppressive medication.

At the next examination on Day 617, the platelet count had increased to 27.2 × 10⁴/μL. TPG-1 was subsequently increased to the 3× recommended daily amount on Day 709 because of a renewed decline in platelet count.

On Day 786, recurrent marked thrombocytopenia consistent with pITP relapse was identified, with a platelet count of 5.1 × 10⁴/μL. Prednisolone was restarted at 1.72 mg/kg once daily, and TPG-1 was increased to the 4× recommended daily amount and continued thereafter.

By Day 793, the platelet count had increased to 17.7 × 10⁴/μL.

The increase in platelet count after TPG-1 dose escalation represents a temporal association and should not be interpreted as evidence of causality in this single uncontrolled case.

This case describes the long-term clinical course of a dog with primary immune-mediated thrombocytopenia receiving conventional immunosuppressive therapy together with adjunctive Huaier-derived TPG-1.

Of particular interest, following complete withdrawal of immunosuppressive therapy, the platelet count gradually decreased to 14.0 × 10⁴/μL by Day 589. TPG-1 was then increased from the 1× to the 2× recommended daily amount without reintroduction of prednisolone or cyclosporine. At the subsequent examination on Day 617, the platelet count had increased to 27.2 × 10⁴/μL.

The temporal association between TPG-1 dose escalation and the subsequent increase in platelet count is noteworthy. However, this observation alone does not establish that TPG-1 caused the increase in platelet count. Spontaneous fluctuation in platelet counts, the natural course of pITP, delayed effects of previous treatment, and other unmeasured factors cannot be excluded in a single uncontrolled case.

A subsequent marked decrease in platelet count, considered clinically consistent with relapse of pITP, occurred on Day 786 while TPG-1 was being administered at the 3× recommended daily amount. The platelet count at that time was 5.1 × 10⁴/μL. Although the recurrence was identified without a reported episode of severe overt bleeding, the present case does not provide sufficient evidence to determine whether TPG-1 influenced the severity of relapse, because no untreated comparator or directly comparable previous relapse was available.

Following relapse, prednisolone was restarted and TPG-1 was increased to the 4× recommended daily amount. The platelet count subsequently increased to 17.7 × 10⁴/μL on Day 793 and 35.2 × 10⁴/μL on Day 828. Cyclosporine was also being administered by Day 828. Therefore, the contributions of prednisolone, cyclosporine, TPG-1, and the natural course of the disease cannot be separated.

Experimental studies have suggested that Huaier-derived components may have immunomodulatory activity. However, the clinical efficacy of TPG-1 for canine pITP has not been established, and this single case cannot determine whether TPG-1 contributed to maintenance of remission, changes in platelet count, or response following relapse.

Prospective controlled studies would be required to determine whether adjunctive TPG-1 has any clinically meaningful effects in dogs with immune-mediated thrombocytopenia and, if so, to establish appropriate dosing, treatment duration, safety, and patient selection.

In this Japanese Terrier with primary immune-mediated thrombocytopenia, adjunctive TPG-1 administration was temporally associated with a long-term clinical course that included a period without immunosuppressive medication and an increase in platelet count following TPG-1 dose escalation without immediate reintroduction of immunosuppressive therapy.

However, because this represents a single uncontrolled case, the efficacy of TPG-1 for canine pITP cannot be established from these observations.

Further controlled studies would be required to determine whether adjunctive TPG-1 has any clinically meaningful effect on platelet response, relapse, immunosuppressive treatment requirements, safety, or long-term clinical outcomes in dogs with immune-mediated thrombocytopenia.