Elsie the Vampire

20/Jan/2014

Use of Human IV Immunoglobulin to treat Primary Immune Mediated Thrombocytopenia in Dogs

Elsie is a 7 year old, female de-sexed Rottweiler. She presented to her regular vet for lameness which was treated with Meloxicam and Carprofen. She then re-presented four days later with lethargy, inappetence and bleeding from her gums. She had imaging and full bloods and a presumptive diagnosis of primary immune mediated thrombocytopenia (pIMT) was made. She was transferred to AEC due to a dropping PCV and given an initial blood transfusion. After the first blood transfusion the bleeding from the gums resolved. She did develop some cutaneous ecchymosis but it was suspected that the majority of the blood loss occurred from her GI tract.

Elsie was initially treated with prednisolone and gut protectants and on her second day at AEC she was given 0.02mg/kg of Vincristine to try to stimulate platelet production. Elsie was hospitalised for seven days and during that time she required five blood transfusions using eight units of blood.

Elsie was referred to our internal medicine specialist, Dr David Davies due to her failure to respond to immunosuppressant and Vincristine therapy. He suggested using human IV immunoglobulin (HIVIG). Elsie’s owner is a human emergency doctor and managed to use her own sources to obtain the HIVIG, which was delivered to AEC by special courier. The HIVIG was given that night. Elsie finally managed to maintain her PCV/TP and her platelets rebounded a day later.

Human IV immunoglobulin is a sterile immunoglobulin preparation that is pooled from the plasma of 10,000 to 60,000 healthy donors. It contains mostly IgG but also contains traces of IgA, IgM, CD4, CD8, human leucocyte antigen molecules and certain enzymes. The mechanism of action off HIVIG is not fully understood. But its effect in pIMT is thought to be due to immunoglobulin binding to the Fc receptors of phagocytic cells, preventing binding to and destruction of platelets.

Other mechanisms by which HIVIG is thought to produce its immunomodulatory effects include:

  • Anti-idiotypic antibodies that neutralise auto-antibodies  
  • Negative feedback and down regulation of antibody production
  • Binding to CD5 receptors, interleukin (IL)-1a, IL-16, tumour necrosis factor-alpha and T cell receptors supressing pathogenic cytokines and phagocytes
  • Modulation of complement and cytokine production
  • Increased catabolism of IgG •
  • Possible role in apoptosis

There have been a number of studies in veterinary medicine into the use of HIVIG as an adjunctive therapy to treat primary immune mediated thrombocytopenia. In the majority of cases of pIMT, platelet recovery occurs after seven days when treated with glucocorticoids alone or five days when Vincristine is used as well. But in the meantime, serious complications due to blood loss may occur, necessitating multiple transfusions, as in Elsie’s case. This can be very expensive and multiple transfusion requirements are a common cause of euthanasia in these cases. The aim of using HIVIG would be to cause platelet recovery earlier in the course of the disease, to try to reduce the requirement for multiple blood transfusions.

In a study of five dogs (1) with pIMT treated with glucocorticoids and HIVIG, four of the dogs had significant increases in platelet counts within 24 hours of HIVIG administration and did not require any additional blood product administration after receiving the HIVIG.

Another study (2) compared the use of HIVIG and Vincristine as adjuncts to glucocorticoid therapy in the management of pIMT. In this study of twenty dogs, no significant differences in time to platelet recovery, hospitalisation length or requirement for blood product administration was found between the HIVIG and Vincristine groups. The only significant difference was in cost with HIVIG being a lot more expensive than Vincristine.

A third study (3) of eighteen dogs with pIMT, showed reduced time to platelet recovery, shorter duration of hospitalisation and decreased blood product requirements for the HIVIG group versus the placebo group. Both groups were receiving glucocorticoids. In this study, no significant increase in cost was found for the HIVIG group.

In each of the studies, no adverse effects were encountered from the use of HIVIG. Recommended dose rates are between 0.5 to 1.5g/kg, although lower doses were used in some cases due to financial constraints. Possible adverse effects that have been noted in humans include headaches, fever, flushing, sudden onset of hypotension, volume overload, acute renal failure, thromboembolism and aseptic meningitis.

In animals, reported adverse effect include hypersensitivity, anaphylaxis, hypercoagulability, hyperviscosity and thromboembolism, renal failure (due to use of sucrose as the stabilising agent), hypotension, psudohyponatraemia (due to an increase in plasma proteins and decreases in plasma water volume. This is not actually an adverse effect, but clinicians should be aware of it so as not to initiate unnecessary or potentially harmful treatment), aseptic meningitis and volume overload especially in small patients.

In human medicine HIVIG is FDA approved for six conditions: - Kawasaki disease, bone marrow transplantation, idiopathic thrombocytopenic purpura, chronic B cell lymphocytic leukaemia (CLL), paediatric HIV and primary IgG deficiency. But it is used for many other conditions, including: - sepsis, autoimmune haemolytic anaemia, myasthenia gravis, necrotising fasciitis, toxic epidermal necrosis, graft versus host disease and Guillian-Barr Syndrome.

HIVIG has also been used in the treatment of other immune mediated diseases in veterinary medicine, notably IMHA. But, due to the potential for causing hypercoagulability, hyperviscosity and thromboembolism and the underlying thromboembolic nature of the disease, it is not recommended for treatment of this condition.

So far, HIVIG has reportedly been used in veterinary medicine to treat pIMT, Evan’s syndrome, cutaneous drug reactions, pemphigus foliaceus, sudden acquired retinal degeneration (SARDS) and myasthenia gravis.

In conclusion, early research does seem to show that HIVIG is efficacious in producing a rapid, reliable increase in platelet counts in dogs with severe pIMT. No short term side effects were noted in any of the above studies, but long term follow up was not reported. The major drawback to using HIVIG is cost and availability. These are especially important as HIVIG has not been shown to cause platelet recovery faster than Vincristine which is widely available to veterinary clinicians and much cheaper. But HIVIG may be useful in dogs with pIMT that are not responding to traditional therapy and are requiring prohibitive numbers of blood transfusions.

In Elsie’s case, it is difficult to assume whether or not the HIVIG made any difference to her platelet count or whether she would have rebounded at that stage in her treatment anyway. This was a great case to be involved in allowing us the opportunity to learn about and then actually use HIVIG. Elsie is so far doing well and her owners are extremely happy to have her home.

I would like to thank the Greyhound Adoption Program. Throughout the week when Elsie was sick, multiple foster carers selflessly gave up their time at short notice to bring dogs to the clinic to donate blood. I was amazed by their generosity and know that without them we would not have had a good outcome in this case.

References:

  1. Treatment of Severe Immune-Mediated Thrombocytopenia with Human IV Immunoglobulin in 5 Dogs - Domenico Bianco, P. Jane Armstrong and Robert J. Washabau.
  2. A Prospective Randomized Clinical Trial of Vincristine versus Human Intravenous Immunoglobulin for Acute Adjunctive Management of Presumptive Primary Immune-Mediated Thrombocytopenia in Dogs - K. Balog, A.A. Huang, S.O. Sum, G.E. Moore, C. Thompson, and J.C. Scott-Moncrieff.
  3. A Prospective, Randomized, Double Blinded, Placebo-Controlled Study of Human Intravenous Immunoglobulin for the Acute Management of Presumptive Primary Immune-Mediated Thrombocytopenia in Dogs - D. Bianco, P.J. Armstrong and R.J. Washabau.  
  4. A Review of Current Indications, Adverse Effects, and Administration Recommendations for Intravenous Immunoglobulin - Nicole K. Spurlock, DVM and Jennifer E. Prettie, DVM, DACVIM, DACVECC
  5. Intravenous Immunoglobulins in the Therapy of Immune-Mediated Hematological Disorders - Cornell University Veterinary Specialists - Susan G. Hackner, BVSc.MRCVS.DACVIM.DACVESS.
  6. Immunomodulatory Drugs and their Application to the Management of Canine Immune-Mediated Disease - N.T. Whitley and M.J. Day
  7. Human Intravenous Immunoglobulin: Current Indications in Small Animal Medicine - ACVIM 2012 - Domenico Bianco, DVM, PhD, DACVIM. (from V.I.N.)
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