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Management of canine primary immune-mediated thrombocytopenia (ITP)

Dr Kit Sturgess MA VetMB PhD CertVR DSAM CertVC MRCVSRCVS Recognised Specialist in Small Animal MedicineAdvanced Practitioner in Veterinary Cardiology

Dr Kit Sturgess graduated from Cam-bridge University in 1986 and then spent 6 years in general veterinary practice. He has further professional qualifications in imaging, cardiology and internal medicine as well as a PhD awarded for looking at the effects of FIV on mucosal immune function. Kit is recognised by the Royal College of Veterinary Surgeons as a specialist in small animal medicine. Kit has been see-ing referral small animal medicine cases for the past 20 years both at university-based and private specialist practices. Kit’s love of teaching and learning has led him to develop a new, more flexible role, centred on lecturing, writing and 60% clinic time. The majority of his clini-cal time is spent providing an internal medicine referral service at Optivet Referrals in Havant. Kit is a member of the Royal College of Veterinary Sur-geons Council and is chairman of the Small Animal Medicine Society.

Vet Freedom Ltd., PO Box 343, Brockenhurst, Hampshire, SO41 1BWTel: 01590 623033E-mail: kit@vetfreedom.com

Optivet Referrals Ltd., 3 Downley Road, Havant, Hampshire, PO9 2NJTel: 01243 888091 E-mail: medicine@Optivet.com

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Immune-mediated thrombocytopenia can be a life threatening disease requiring patients to be aggressively managed and supported. Like all haematologic values, the measured platelet count is a balance between production and loss. Loss can be consumptive (i.e. used as part of the coagulation cascade) or destructive, mediated by the immune system. Platelets are produced from megakaryocytes in the bone marrow. Their normal circulating life span is a little over one week. Senescent (aged) platelets are removed from the circulation and phagocytosed, particularly within the spleen.

Key words: dog, platelet, immune-mediated disease, thrombocytopenia

Review of coagulationCoagulation is a complex system of interconnected events involving platelet aggregation (primary clot) and thrombin production. Figure 1 illustrates a cell-based model reflecting our current understanding that coagulation occurs in distinct overlapping phases requiring cell-bearing tissue factor and platelets resulting in the rapid conversion of prothrombin to thrombin necessary for fibrin production and stabilisation of aggregated platelets to form the secondary clot. In this model coagulation factors exist on both tissue factor bearing cells and platelets with simultaneous activation of multiple factors by proteases rather than the traditional amplifying cascade. (Figure 1).

ThrombocytopeniaThrombocytopenia can be classified as mild, moderate or severe (Table 1), with patients in the severe category at risk of spontaneous bleeding. Whether a thrombocytopenic patient bleeds or

not is not just a matter of the absolute numbers of platelets but also their function as well as the clotting environment. Platelet counts above 40x109/L are highly unlikely to be the cause of spontaneous haemorrhage, indeed many patients with counts of 10-20x109/L and even with a zero platelet count will not bleed.

Laboratory error and breed idiosyn-crasies giving low platelet countsThe most common causes of a mild to moderate thrombocytopenia are platelet clumping and machine error (particularly when using some “in-house” haemocytometers). This makes evaluation of a fresh blood smear a vital part of the diagnosis of thrombocytopenia.

Multiplying the average platelet count per high power field (HPF) (x1000 magnification) by 20,000 gives the approximate platelet count/µL. So if you see less than one platelet per HPF, this equates to a marked thrombocytopenia and a count of <20,000/µL.

Figure 1: Cartoon of cell-based model of coagulation

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Table 1: Categorisation of platelet numbers

Category ThrombocytosisReference interval

Mild thrombocytopenia

Moderate thrombocytopenia

Marked thrombocytopenia

Platelet Count (x 109/L) >600 160-600 120 60 <20

Platelet Count (/ µL) 600,000 160,000-

600,000 120,000 60,000 <20,000

Some breeds of dogs, notably the Cavalier King Charles Spaniel (CKCS), have lower numbers of large platelets (macrothrombocytes) and will consistently give low platelet counts, partly due to the lower numbers, but also due to the larger platelets being counted in with the red cells. In machines that calculate mean platelet volume (MPV) the result will usually be above the expected reference interval of 9-15fL (femtolitres =10−15L). Other breeds such as Greyhounds frequently have relatively low platelet counts in the 100-200x109/L range.

Other causes of thrombocytopeniaThe majority of cases of thrombocyto-penia (Table 2) occur due to platelet loss out-stripping production. Consumptive thrombocytopenia associated with bleeding are usually mild to moderate unless there is disseminated intravascular coagulation (DIC).

Immune-mediated thrombocytopeniaCan be primary, or secondary to another disease process (Table 2).

• Neoplasia is the most common secondary disease process resulting in thrombocytopenia usually as a paraneoplastic syndrome, but sometimes directly e.g. haemangiosarcoma (microangiopathic tumours).

• Drug-associated immune-mediated thrombocytopenia appear quite rare and there have been only sporadic case reports apart from gold compounds (Bloom et al 1985). Thrombocytopenia can also be associated with bone marrow suppression e.g. oestrogen toxicity.

• A mild reduction in platelet count in puppies following vaccination has been reported (Stokol and Parry 1997). Sporadic case reports of ITP occurring following vaccination are reported however no clear association between vaccination and thrombocytopenia has been established (Huang et al 2012).

Table 2: Causes of (apparent) thrombocytopenia in dogs

• Laboratory error• Breed idiosyncrasy • Macrothrombocytes e.g. CKCS • Low reference interval

e.g. Greyhounds• Sequestration • Hypersplenism• Decreased production • Infectious disease

– e.g. Ehrlichia (outside UK) • Drugs – chemotherapeutic

agents, phenylbutazone, oestrogen, chemicals, toxins

• Myelophthisis (replacement of bone marrow by malignant cells or fibrous tissue)

• Marrow aplasia/pancytopenia • Anti-megakaryocyte antibodies

• Increased destruction • Immune-mediated • Primary • Paraneoplastic • Drug-associated • Vaccine-induced? • Microangiopathic neoplasia

• Increased consumption • Haemorrhage • Disseminated intravascular

coagulation • Neoplasia

Primary immune-mediated thrombocytopenia (ITP)Primary ITP occurs due to the produc-tion of anti-platelet antibodies resulting in rapid destruction of circulating platelets such that this exceeds the bone marrow’s capacity to replace them (Figure 2). The majority of immune-mediated throm-bocytopenia cases are primary but each case should be evaluated carefully before making this diagnosis, particularly if there is bleeding in the face of only a mild to moderate reduction in platelet count.

Primary ITP most commonly affects middle-aged female dogs, with an average age of onset of six years with the most common presenting sign being petechial (pin-point) (Figure 3) haemorrhage in an often otherwise bright and well patient.

Figure 3 (left): Three year old neutered female Rhodesian Ridgeback with thrombocytopenia

Figure 2 (above): Pathophysiology of primary immune-mediated thrombocytopenia (ITP). B cells migrate from the bone marrow and are activated by T cells. The activated B cells mature into plasma cells which produce the autoreactive antibodies

Common causes are highlighted in bold

An#-­‐platelet  an#bodies  

Coated  platelets  removed  by  re#culoendothelial  system  especially  the  spleen  

B  cells  

T  cells  

Ac#va#on  

Plasma  cells  

Matura#on  

An#body  produc#on