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Immune-Mediated Thrombocytopenia, Canine

Summary

  • Primary immune-mediated thrombocytopenia (IMT) is characterized by platelet destruction by the immune system due to the production of antibodies (typically IgG) directed against platelet antigens; it is often a diagnosis of exclusion
  • Secondary IMT may be associated with infection (including tick-borne illness), drug therapy, neoplasia, vaccination, transfusion therapy, or other immune-mediated disease (e.g., immune-mediated hemolytic anemia, systemic lupus erythematosus) that triggers production of antibodies against platelet antigens
  • Diagnosis is based on clinical signs, documentation of thrombocytopenia (< 100,000/µL), exclusion of underlying diseases, and response to immunosuppressive therapy; thrombocytopenia should be confirmed by blood smear examination
  • Treatment is aimed at suppression of the immune response, controlling ongoing hemorrhage, and management of concurrent illness, if identified
  • Dogs with IMT are at risk for spontaneous bleeding and bleeding complications secondary to invasive procedures; cystocentesis, aspiration, jugular venipuncture, and surgical interventions should be avoided until platelet numbers have improved
  • Prognosis is dependent on response to therapy; the severity of thrombocytopenia does not appear to be associated with prognosis
  • Referral to a veterinary internal medicine specialist or critical care specialist should be considered for patients with severe or refractory disease

Causes and Risk Factors

Causes

  • The underlying cause for development of anti-platelet antibodies in cases of primary immune-mediated thrombocytopenia (IMT) is unknown
  • Immune complexes and development of antibodies to nonself antigens bound to platelet surfaces have been implicated in the development of secondary IMT; these may occur secondary to a variety of infectious causes (e.g., tick-borne diseases: babesiosis, anaplasmosis, Lyme disease, ehrlichiosis), drug therapy, neoplasia, vaccination, transfusion therapy, or other immune-mediated disease

Signalment

  • Most often seen in middle-aged dogs
  • Females are affected more commonly than males
  • Can occur in any breed; Cocker Spaniels, Poodles, Old English Sheepdogs, and German Shepherds are overrepresented

Risk Factors

  • Tick exposure
  • Breed predisposition
  • Recent vaccinations
  • Recent cephalosporin or sulfonamide drug exposure

Differential Diagnosis

  • Other causes of thrombocytopenia:

Diagnosis and Screening

General Points

  • Clinical signs of thrombocytopenia rarely occur unless platelet count is < 50,000/µL
  • Clinical signs may be seen with higher platelet numbers if there is concurrent platelet dysfunction or vasculitis
  • Current testing methods cannot reliably distinguish primary vs secondary immune-mediated thrombocytopenia
  • Diagnosis is based on clinical signs, documentation of severe thrombocytopenia (< 100,000/µL), exclusion of underlying diseases, and response to immunosuppressive therapy
  • Blood smears should always be evaluated to confirm automated platelet counts
  • Cavalier King Charles Spaniels may have idiopathic asymptomatic thrombocytopenia (often with macrothrombocytosis); these dogs maintain normal coagulation function

Signs and History

  • History of:
    • Recent vaccination
    • Recent drug exposure
    • Tick exposure

  • Dogs may be asymptomatic; thrombocytopenia may be identified during routine blood testing
  • Mucosal hemorrhage (e.g., epistaxis, hematuria, gingival bleeding, melena)
  • Hematemesis
  • Bruising
  • Prolonged bleeding after trauma
  • Prolonged estrus
  • Intraocular hemorrhage or blindness
  • Lethargy
  • Hyporexia
  • Other signs may depend on underlying cause of thrombocytopenia

Physical Exam

  • Petechiation and/or ecchymotic hemorrhages
  • Pale mucous membranes (if anemia has developed)
  • Splenomegaly (occasional)
  • Physical findings as listed in Signs and History section

Laboratory Tests

  • Routine laboratory tests
    • Complete blood count with differential
      • Thrombocytopenia; automated counts should always be confirmed with a manual platelet estimate via evaluation of a blood smear
      • Variable anemia
      • Elevated mean platelet volume (MPV) may indicate megakaryopoietic activity
      • In patients with anemia, agglutination, and spherocytosis, consider concurrent immune-mediated hemolytic anemia
      • Concurrent non-regenerative anemia and leukopenia may be indicative of disease within the bone marrow

    • Biochemistry panel
      • May be unremarkable
      • Useful in identifying concurrent illness and secondary causes of thrombocytopenia

    • Platelet estimate
      • Platelet clumping or large platelets may lead to spurious low platelet counts on automated instruments; a manual, in-house platelet estimate must be done to confirm thrombocytopenia
      • Use a drop of anti-coagulated blood to create a blood smear and stain with Romanowsky stain (e.g., Diff-Quik)
      • Count the number of platelets in 10 oil immersion fields within the monolayer of the blood film; divide by 10 to find the average and multiply that number by 15,000 to 20,000 to arrive at platelet estimate
      • In a Level 2 study, dogs with primary immune-mediated thrombocytopenia had lower platelet counts than dogs with secondary disease
      • Large clumps of platelets at feathered edge may preclude an accurate platelet estimate

  • Coagulation testing
  • Infectious disease screening
    • Tick-borne disease screening
      • Consider based on geography, season, and risk of exposure; institute empiric therapy (doxycycline 5 mg/kg PO every 12 hours) while awaiting confirmatory results
      • A combination of serology and polymerase chain reaction (PCR) testing is recommended

    • Other infectious disease testing (e.g., distemper, leishmaniasis) will depend on history, clinical signs, and physical examination findings

Imaging

  • Thoracic radiography
    • Useful to identifying underlying disease (e.g., neoplasia, infection)

  • Abdominal radiography
    • Organomegaly or masses may be identified

  • Abdominal ultrasonography
    • Useful in identifying an underlying cause (e.g., neoplasia)
    • If organomegaly, masses, effusions, or enlarged lymph nodes are identified, aspirates and cytological evaluation should be considered, if possible

Other Diagnostic Tests

  • Platelet-bound canine IgG
    • Very sensitive but not very specific
    • Does not differentiate between primary and secondary immune-mediated thrombocytopenia
    • Contact reference laboratory regarding sample handling prior to collection
    • Treatment should not be withheld while results are pending

  • Bone marrow aspirate and biopsy
    • Should be considered for patients with neutropenia and/or non-regenerative anemia
    • Thrombocytopenia is not considered a contraindication to bone marrow aspiration

Prevention

  • Appropriate tick prevention can reduce risk of tick-borne disease transmission

Treatment

General Points

  • Treatment is aimed at suppression of the immune response, controlling ongoing hemorrhage, and management of concurrent illness if identified
  • Prednisone is the first-line drug of choice for immunosuppressive therapy; there is no evidence-based data to support the use of one agent over another when deciding on additional immunosuppressive agents
  • Blood transfusion may be required for patients with concurrent anemia
  • Whole blood transfusion solely for the purpose of correcting thrombocytopenia is rarely beneficial
  • Transfusion with platelet-rich plasma or platelet concentrate should only be considered for patients with signs of central nervous system hemorrhage, pulmonary hemorrhage, or for those with persistent or uncontrolled bleeding; see canine transfusion protocols monograph for dosing information
  • Cage rest is indicated to prevent bleeding complications in patients who are severely thrombocytopenic
  • Patients with primary immune-mediated thrombocytopenia (IMT) typically demonstrate an increased platelet count within 2 to 5 days of initiating therapy; a platelet count ≥ 100,000/µL is the goal of therapy
  • There is no consensus on duration of immunosuppressive therapy or standardized protocol for tapering of medications
  • Once platelet counts have stabilized, tapering of immunosuppressive therapy may be attempted
  • Tapering of other immunosuppressive agents should begin after glucocorticoid reduction
  • Patients with primary IMT typically require immunosuppressive therapy for ≥ 6 months; some may require life-long therapy
  • Referral to a veterinary internal medicine specialist or critical care specialist should be considered for patients with severe or refractory disease

Medications

  • Immunosuppressive therapy
    • Options include:

    • Prednisone 2 to 4 mg/kg PO every 24 hours or divided and given every 12 hours, for at least 3 to 4 weeks; daily dosage should not exceed 60 to 80 mg per dog
      • The dose of prednisone may be decreased by 25% every 3 to 4 weeks once platelet numbers are > 200,000/µL ; platelet counts should be evaluated before each dose reduction

    • Cyclosporine 5 to 8 mg/kg PO every 12 to 24 hours
      • Used in conjunction with glucocorticoids in patients that have severe disease, are not responding to therapy with glucocorticoids alone, or who are intolerant of high-dose glucocorticoid therapy
      • Gastrointestinal side effects and gingival hypertrophy have been reported
      • Immunosuppression-related infections have been reported

    • Mycophenolate 8 to 10 mg/kg PO every 12 hours
      • Very potent immunosuppressive agent
      • May cause severe vomiting and diarrhea; anemia and neutropenia may also occur
      • A Level 3 study suggested that the combination of mycophenolate mofetil and corticosteroids appears to be as effective as cyclosporine and corticosteroids for treating presumed primary immune-mediated thrombocytopenia in dogs

    • Azathioprine 2 mg/kg PO every 24 hours, for 1 to 4 weeks; then 0.5 to mg/kg PO every other day
      • Used in conjunction with glucocorticoids in patients that have severe disease, are not responding to therapy with glucocorticoids alone, or who are intolerant of high-dose glucocorticoid therapy
      • Has been associated with hepatotoxicity, bone marrow toxicity, and gastrointestinal signs

    • Leflunomide 2 to 4 mg/kg PO every 24 hours
      • Used in conjunction with glucocorticoids
      • Has been associated with diarrhea, decreased appetite, vomiting, increased liver enzymes, and cough

    • Human intravenous immunoglobulin (IVIG) 0.5 to 1.5 gm/kg IV over 4 to 12 hours; or 0.28 to 1.3 gm/kg IV over 4 to 12 hours
      • When used along with immunosuppressive therapy, has been shown to improve platelet recovery and shorten hospitalization time
      • Allergic reactions have been reported; premedication with diphenhydramine should be considered

  • Platelet-stimulating therapy
    • Vincristine 0.02 mg/kg IV once
      • Should be considered for dogs with clinically relevant bleeding
      • Should be used with caution in dogs breeds with a high incidence of the ABCB1 (MDR1) gene mutation; this would include Shetland sheepdogs, smooth/rough collies, long-haired whippets, and Australian shepherds
      • May be used for patients with severe or refractory thrombocytopenia
      • Perivascular injection of vincristine may cause necrosis and tissue sloughing
      • Dogs should be monitored for neutropenia; a Level 2 study reported an increased likelihood of neutropenia for dogs that had received cyclosporine
      • Should not be used as monotherapy

Surgical Interventions

  • Splenectomy
    • Should only be considered as a last resort in refractory cases
    • Thorough screening for infectious diseases, specifically hemoparasite infections, is imperative prior to the procedure

Other Therapies

  • Appropriate nursing care:
    • Apply pressure after IV placement or IV injections, to support hemostasis
    • Avoid intramuscular or subcutaneous injections, if possible
    • Avoid jugular venipuncture and cystocentesis
    • Gastrointestinal protectants may reduce GI irritation associated with oral medications (e.g., high-dose glucocorticoids, azathioprine, mycophenolate)

Follow-up

Diagnostic Follow-up

  • Recheck platelet count daily until level is >50,000/microliter; then recheck every few days until level stabilizes
  • Check platelet count every 7 to 14 days while tapering medication
    • Chemistry panel/CBC recheck every 14 to 30 days; urinalysis every 4 to 6 weeks
  • One study (Level 3) suggested that patients with more severe disease at diagnosis or that already experienced a relapse should be monitored more closely
  • For dogs receiving cyclosporine, therapeutic drug monitoring can help assess response and avoid toxicity however, optimal therapeutic ranges are unclear; blood sample should be obtained 2 hours after dosing

Therapeutic Follow-up

  • The dose of prednisone may be decreased by 25% every 3 to 4 weeks; platelet counts should be evaluated before each dose reduction

Prognosis

  • Prognosis is dependent on response to therapy; the severity of thrombocytopenia does not appear to be associated with prognosis
  • Patients with primary immune-mediated thrombocytopenia (IMT) typically require immunosuppressive therapy for ≥ 6 months; some may require life-long therapy
  • Melena and an elevated blood urea nitrogen level were associated with a worse prognosis in one study (Level 3)
  • In a Level 2 study, dogs with primary IMT that had decreased hematocrit and elevated blood urea nitrogen had a poorer prognosis
  • Recurrence rates between 9% and 58% have been reported; a Level 3 study reported a 23% relapse rate within 2 years

Evidence

Guidelines and Consensus Statements

  • LeVine DN, Kidd L, Garden OA, et al. ACVIM consensus statement on the diagnosis of immune thrombocytopenia in dogs and cats. J Vet Intern Med. 2024 Jul-Aug;38(4):1958-81. Level B Article
  • LeVine DN, Goggs R, Kohn B, et al. ACVIM consensus statement on the treatment of immune thrombocytopenia in dogs and cats. J Vet Intern Med. 2024 Jul-Aug;38(4):1982-2007. Level B Article

Systematic Reviews/Meta-analyses

  • None available

Randomized, Controlled Trials (RCTs)

  • Bianco D, Armstrong PJ, Washabau RJ. A prospective, randomized, double-blinded, placebo-controlled study of human intravenous immunoglobulin for the acute management of presumptive primary immune-mediated thrombocytopenia in dogs. J Vet Intern Med. 2009 Sep-Oct;23(5):1071-8. Level 2 Abstract

Other Studies or Reviews

  • Brooks MB, Goggs R, Frye AH, et al. A prospective cohort study to identify clinical diagnostic and prognostic markers of primary immune thrombocytopenia in dogs. J Vet Intern Med. 2024 Jan 11. doi: 10.1111/jvim.16985. Level 2 Article
  • LaQuaglia KA, Robertson JB, Lunn KF. Neutropenia in dogs receiving vincristine for treatment of presumptive immune-mediated thrombocytopenia. J Vet Intern Med. 2021 Jan;35(1):226-33. Level 2 Article
  • Huang AA, Moore GE, Scott-Moncrieff JC. Idiopathic immune-mediated thrombocytopenia and recent vaccination in dogs. J Vet Intern Med. 2012 Jan-Feb;26(1):142-8. Level 2 Article

  • Plumb’s Veterinary Drugs (online database), Tulsa, OK: Brief Media; 2024. Accessed March 22, 2024. Level 3
  • Callan MB, Catalfamo JL. Immune-mediated thrombocytopenia, von Willebrand disease, and other platelet disorders. In: Cote E, Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat. 9th ed. St. Louis: Elsevier; 2024:883-903. Level 3
  • Sparrow R, Swann JW, Glanemann B. Comparison of timing of relapse in dogs with nonassociative immune-mediated hemolytic anemia, thrombocytopenia, or polyarthritis. J Vet Intern Med. 2024 Feb 2. doi: 10.1111/jvim.17004. Level 3
  • Stikeman E, Bianco D. Use of human intravenous immunoglobulin for the treatment of 12 dogs with newly diagnosed malignant disease and presumed secondary immune-mediated thrombocytopenia. J Small Anim Pract. 2024 Jan 19. doi: 10.1111/jsap.13700. Level 3
  • Christodoulou V, Meletis E, Kostoulas P, et al. Clinical and clinicopathologic discriminators between canine acute monocytic Ehrlichiosis and primary immune thrombocytopenia. Top Companion Anim Med. 2023 Jan-Feb;52:100750. Level 3
  • Kane BK, Greer RM. Human intravenous immunoglobulin use for hematological immune-mediated disease in dogs. J Am Vet Med Assoc. 2023 Apr 18;261(7):1004-10. Level 3
  • Sykes JE. Tick-Borne Diseases. Vet Clin North Am Small Anim Pract. 2023 Jan;53(1):141-54. Level 3
  • Bestwick JP, Skelly BJ, Swann JW, et al. Splenectomy in the management of primary immune-mediated hemolytic anemia and primary immune-mediated thrombocytopenia in dogs. J Vet Intern Med. 2022 Jul;36(4):1267-80. Level 3
  • Viviano KR. Glucocorticoids, cyclosporine, azathioprine, chlorambucil, and mycophenolate in dogs and cats: clinical uses, pharmacology, and side effects. Vet Clin North Am Small Anim Pract. 2022 May;52(3):797-817. Level 3
  • Fukushima K, Lappin M, Legare M, et al. A retrospective study of adverse effects of mycophenolate mofetil administration to dogs with immune-mediated disease. J Vet Intern Med. 2021 Sep;35(5):2215-21. Level 3
  • Papich MG. Papich Handbook of Veterinary Drugs, 5th Edition. St Louis, MO: Elsevier; 2021. Level 3
  • Spurlock N, Prittie J. Use of human intravenous immunoglobulin in veterinary clinical practice. Vet Clin North Am Small Anim Pract. 2020 Nov;50(6):1371-83. Level 3
  • Simpson K, Chapman P, Klag A. Long-term outcome of primary immune-mediated thrombocytopenia in dogs. J Small Anim Pract. 2018 Nov;59(11):674-80. Epub 2018 Aug 13. Level 3
  • Cummings FO, Rizzo SA. Treatment of presumptive primary immune-mediated thrombocytopenia with mycophenolate mofetil versus cyclosporine in dogs. J Small Anim Pract. 2017 Feb;58(2):96-102. Level 3
  • Kohn B. Thrombocytopenia, primary immune-mediated. In: Tilley LP, Smith FWK, ed.’s. Blackwell’s Five-Minute Veterinary Consult: Canine and Feline. 6th ed. West Sussex: Wiley-Blackwell; 2016:1304-5. Level 3
  • Neel JA, Birkenheuer AJ, Grindem CB. Thrombocytopenia. In: Bonagura JD, Twedt D, ed's. Kirk's Current Veterinary Therapy XV. Philadelphia: Elsevier Saunders;2014:280-6. Level 3
  • Yau VK, Bianco D. Treatment of five hemodynamically stable dogs with immune-mediated thrombocytopenia using mycophenolate mofetil as single agent. J Small Anim Pract. 2014 Jun;55(6):330-3. Level 3
  • Balog K, Huang AA, Sum SO, et al. A prospective randomized clinical trial of vincristine versus human intravenous immunoglobulin for acute adjunctive management of presumptive primary immune-mediated thrombocytopenia in dogs. J Vet Intern Med. 2013 May-Jun;27(3):536-41. Level 3
  • O'Marra SK, Delaforcade AM, Shaw SP. Treatment and predictors of outcome in dogs with immune-mediated thrombocytopenia. J Am Vet Med Assoc. 2011 Feb 1;238(3):346-52. Level 3
  • Spurlock NK, Prittie JE. A review of current indications, adverse effects, and administration recommendations for intravenous immunoglobulin. J Vet Emerg Crit Care (San Antonio). 2011 Oct;21(5):471-83. Level 3
  • Brooks MB, Catalfamo JL. Immune-mediated thrombocytopenia, von Willebrand disease, and platelet disorders. In: Ettinger SJ, Feldman EC, ed.'s. Textbook of Veterinary Internal Medicine. 7th ed. St. Louis: Saunders Elsevier;2010:772-83. Level 3
  • Dircks BH, Schuberth HJ, Mischke R. Underlying diseases and clinicopathologic variables of thrombocytopenic dogs with and without platelet-bound antibodies detected by use of a flow cytometric assay: 83 cases (2004-2006). J Am Vet Med Assoc. 2009 Oct 15;235(8):960-6. Level 3
  • Putsche JC, Kohn B. Primary immune-mediated thrombocytopenia in 30 dogs (1997-2003). J Am Anim Hosp Assoc. 2008 Sep-Oct;44(5):250-7. Level 3
  • Rozanski EA, Callan MB, Hughes D, et al. Comparison of platelet count recovery with use of vincristine and prednisone or prednisone alone for treatment for severe immune-mediated thrombocytopenia in dogs. J Am Vet Med Assoc. 2002 Feb 15;220(4):477-81. Level 3

Additional Reading

  • Liu PY, Xia D, McGonigle K, et al. Immune-mediated hematological disease in dogs is associated with alterations of the fecal microbiota: a pilot study. Anim Microbiome. 2023 Sep 29;5(1):46.
  • Francey T, Etter M, Schweighauser A. Evaluation of membrane-based therapeutic plasma exchange as adjunctive treatment for immune-mediated hematologic disorders in dogs. J Vet Intern Med. 2021 Mar;35(2):925-35.
  • Kopecny L, Palm CA, Naylor S, et al. Application of therapeutic plasma exchange in dogs with immune-mediated thrombocytopenia. J Vet Intern Med. 2020 Jul;34(4):1576-81.
  • Kohn B, Bal G, Chirek A, et al. Treatment of 5 dogs with immune-mediated thrombocytopenia using Romiplostim. BMC Vet Res. 2016 Jun 10;12:96.