Non-regenerative anemia

[Gracesnow]

Hi everyone,

I own a 6 year old female Maltese named Snow. Snow was first diagnosed with IMHA in January of 2018 by a vet from a small animal clinic. Although the vet didn't have the tools to check for reticulocyte, she assumed that my dog has IMHA based on observation. (She saw red blood cell aggregates) My dog's RBC count was around 14% but since the vet suspected that her RBC count seemed to drop little by little, we decided to start immunotherapy and see how she responds. The vet started her on 1 mg of steroids and 1 mg of azathioprine per day (she was around 3.8kg back then). A week later, her RBC counted increased by 1% then the vet increased the dose of steroids  to 2mg. It worked wonderfully and her RBC count was increased to 25%. But a week later, her RBC count fell to 22% for some reason and the vet raised Azathioprine to 2 mg.

But then, Snow suddenly refused to eat and started vomiting. I rushed her to a larger vet facility and she was hospitalized. There, my dog was diagnosed with acute pancreatitis and induced cushing's syndrome, which resulted in electrolyte imbalance and diabetes like symptoms. The vet also did comprehensive blood work and told me that her reticulocyte level was below the normal range and she is not suffering from IMHA but non-regenerative anemia. Snow recovered from pancreatitis, electrolyte imbalance and high glucose level. But her RBC level fell to 14% and she had to go through packed blood cell transfusion. (Her platelet level and white blood cell counts were always steady and within the normal range. So the vet decided to just do packed blood cell instead of whole blood cell transfusion) Blood transfusion was successful and her RBC count increased to 45%. Since Snow was suffering from induced Cushing's syndrome, the vet had to decrease the steroids to 0.5mg/day and started her on 50mg/day of CyclosporinA. Snow's RBC level was maintained around 40% and reticulocyte level was within the normal range for the following week. Since she developed induced Cushing's syndrome, the vet tapered the steroids to 0.3 mg/day with the same dose of cyclosporinA.

Unfortunately, a week later, her RBC level dropped to 32% with few reticulocytes confirmed by blood test results and blood cell smear. The vet thinks the meds aren't working. The vet kept the steroids to 0.3mg/day and switched to Tacrolimus.l (The vet also sent her blood work to the lab to test to see if cyclosporinA level is within a working range) But he is not sure if this will work as well. He suggested that we perform the bone marrow smear to diagnose the exact cause for the anemia. He suspects that it is either Non-regenerative IMHA or PRCA since it is only the red blood cells that are affected. (all other organs are healthy) If we can confirm that it is NRIMHA, then he suggests that we perform splenectomy. If it is PRCA, there might not be any other solution.

I really love Snow and she is my best buddy. I have been fighting against this disease for almost three months and I kept my spirit up hoping that one day this effort and money I spent on treating Snow will be worth it. But now I feel very devastated and hopeless. Not sure if performing bone marrow smear will do good for such sick dog. The vet told me Snow is healthy enough to endure the procedure but I am not sure if this is the right approach.

Do you have any advices? Thank you so much!!

Best regards,

Grace

[Jo CIMDA]

Hi Grace

I am sorry Snow has non-regenerative AIHA.

There is no doubt that prednisolone, in immunosuppressive doses, is the first line treatment for inflammatory AI diseases and as you have seen with Snow, the dogs usually respond well. 

As soon as you start a dog on high doses of steroids there will be a degree of  drug induced Cushing's.  As long as the Cushing's stays at a level that the dog can cope with then usually the preds are lowered before serious side effects occur (usually within 28 days).  In addition to Cushing's symptoms, it is well documented that some dogs on immunosuppressive doses of prednisolone may be prone to pancreatitis.  It is a shame Snow developed pancreatitis and I can understand why the vet wanted to reduce the preds asap but it seems that the prednisolone was still very effective and it is likely the drop in pred dose was perhaps too early, but there is no way of knowing this.  It is also known that Azathioprine can cause pancreatitis especially if it is used in combination with prednisolone.  So I wonder if it might be the Aza that tipped Snow into developing pancreatitis?   Pancreatitis can be very nasty so your vet has done well to get Snow over this complication.

Whether Snow has PRCA or non-regenerative AIHA the treatment is the same, and both are generally termed as the same thing.

Explanation, see below:
Primary non-regenerative AIHA (an autoimmune destruction of the immature red blood cells, or the precursor cells, within the bone marrow) where there is no detectible underlying disease.

Primary non-regenerative immune mediated haemolytic anaemia (NRIMHA) may also be termed as acquired Pure Red Cell Aplasia (PRCA).  It is thought that NRIMHA progresses to acquired PRCA and therefore the term PRCA is interchangeable.



You know by the low number of reticulocytes that Snow's bone marrow is under producing at this time, and you know that the most likely reason for this is an autoimmune destruction of the immature red blood cells or the precursor red blood cells within the bone marrow.  You also know that her bone marrow is capable of producing immature red blood cells because Snow's red blood cell count increased after the transfusion and when she was on a significant immunosuppressive drug regimen, especially the preds.  The vet's regimen sounds very reasonable.

Given that her red blood cell count dropped following a reduction in preds (likely as a result of reducing the reducing the level of immunosuppression) and also at the same time her reticulocyte count dropped,  it has to be assumed that the cause of the anaemia is due to the lack of red blood cell production and not a destruction of the red blood cells by the spleen.  With this in mind, how will the removal of the spleen help the bone marrow to produce normally again?

If the spleen is destroying the red blood cells, and therefore responsible for the anaemia, then removal of the spleen would be an option, but the anaemia is being caused by an immune destruction of the precursor cells or the immature red blood cells within the bone marrow and the way to stop this destruction is to significantly suppress the immune system with drugs  which will allow the bone marrow to produce the red blood cells again without them being destroyed.  So perhaps you could ask your vet what is to be gained by removal of Snow's spleen?   Below are some extracts and links about removal of the spleen.


http://vetfolio-vetstreet.s3.amazonaws.com/mmah/1c/533bd548c2472d83d8a1095cfa0658/filePV_31_01_33_0.pdf

Splenectomy

Splenectomy may be considered for patients with IMHA that fail to respond to, or have severe adverse effects from, immunosuppressive therapy or that require long-term, high-dose therapy to remain in remission. The spleen is a major site of autoantibody production and of sequestration and destruction of IgG-sensitized RBCs. A thorough search for an underlying infection is mandatory before proceeding with splenectomy. Preliminary results of a small, prospective, unpublished study showed that splenectomy as an adjunctive therapy is superior to medical therapy alone in reducing mortality and shortening the interval to normal PCVs in dogs with severe IMHA. In fact, splenectomy may be effective for both remission induction and maintenance therapy for severe IMHA. It may also be helpful in dogs with multiple acute relapses or in those that only partially respond to medical immunosuppression. However, as the site of clearance of IgM-sensitized RBCs appears to be the hepatic Kupffer cells, splenectomy is unlikely to be beneficial in dogs with positive Coombs' test results or IgM autoantibodies. No large-scale studies have evaluated the short- and long-term safety of splenectomy in dogs. Due to the cost of surgery and risk of complications, splenectomy is rarely recommended as a first-line therapy for severe IMHA. On the other hand, given the encouraging preliminary data, further studies to evaluate the safety and efficacy of splenectomy in the treatment of canine IMHA are warranted.

https://en.wikipedia.org/wiki/Hemolytic_anemia

Sometimes splenectomy can be helpful where extravascular hemolysis, or hereditary spherocytosis, is predominant (i.e., most of the red blood cells are being removed by the spleen.

http://www.secondchanceaihadogs.com/AIHA_Terms/spleen

The spleen is classed as a hematopoeitic organ, capable of producing blood cells (as it does in fetal stages & early life). Although in normal dogs most blood cells are produced by the bone marrow, certain cells are still produced by the spleen. Under certain circumstances such as bone marrow failure, the spleen can produce more blood cells if needed (see extramedullary hematopoeisis) to maintain an adequate supply in the body.

If Snow's PCV at the moment is 32%, although this is a drop it is nowhere near the level when to considering another blood transfusion.  If, and I hope it doesn't, it drops to 12% or just over then a another transfusion might be needed in which case your vet might consider doing an IVIG transfusion.  I have known these to be very successful and be the turning point for AIHA.

IVIG. Intravenous human immunoglobulin (IVIG) (0.5 to 2 g/kg intravenously daily, given over six to 12 hours) has been infrequently used to treat a variety of immune-mediated diseases in dogs, including IMHA. The mechanism of action of IVIG is thought to be a blockade of the Fc receptors on macrophages, thereby reducing phagocytosis of antibody-coated RBCs, interfering with complement, and suppressing antibody production. In addition, IVIG inhibits erythrocyte phagocytosis by binding to canine monocytes and lymphocytes and possibly by an anti-idiotypic down-regulation of antibody production.

IVIG can be given to patients with IMHA as a single infusion or on two or three consecutive days.  Although IVIG appears to impart short-term benefits (reflected by a rising packed cell volume and reticulocytosis) within days of infusion, long-term benefits were not seen. No complications have been seen with a single IVIG infusion in dogs. Unfortunately, IVIG is also costly and difficult to obtain.

I have only known Tacrolimus to be used in ointment form for skin or eye problems in dogs and not for the treatment of AIHA. I believe it is used in human medicine as an immunosuppressive.

There are other immunosuppressive drugs that can be used, such as mycophenolate

https://www.mspca.org/angell_services/mycophenoloate-mofetil-the-latest-in-immunosuppressive-therapies-in-veterinary-medicine/

Leflunomide and other therapies.

http://vetfolio-vetstreet.s3.amazonaws.com/mmah/1c/533bd548c2472d83d8a1095cfa0658/filePV_31_01_33_0.pdf

Little dogs can usually cope very well with high doses of steroids but I can understand why your vet is very reluctant to put Snow back on to an immunosuppressive doses of prednisolone, but I wonder if the pros and cons of using a significant pred dose again would be considered. It's just a thought.  It is probably the best treatment option but a risk pancreatitis has to be taken into consideration.  Snow should be on a low fat diet and also feed her smaller meals and more often.

When a dog is on high doses of steroids  it is prudent to also include a gastroprotectant such as omeprazole or ranitidine in the drug regimen. If Snow isn't having a gastroprotectant then perhaps you can have a chat with your vet.

At this stage a bone marrow biopsy might not prove anything conclusive because the immune cells have been significantly suppressed and often these drugs will mask test results and the result could likely be inconclusive, and then you are back to square one after putting her through a general anaesthetic and procedure.

I hope Snow starts to improve very soon and that this can be resolved without a splenectomy.

Jo

[Gracesnow]

Thank you so much for your help. I truly appreciate it