Immune mediated platelet destruction

[tildesaz]

My 3 1/2 year old Springer ezzy has just been diagnosed with this. She started her steroids yesterday. It's all so new and terrifying. We lost my father in law last week the same day as moving house so lots all going on at once. Can anyone offer any advice/ experiences. Our vet picked it up straight away and has been great so far.

[Bbell]

Hello
How stressful for you! My girl, Bluebell, is having trouble with her platelets at the moment.  We are only a couple of posts down but there is a wealth of knowledge here.
Having a vet who is on top of it helps massively. What are her platelet numbers currently and what meds is Ezzy on?

[Jo CIMDA]

Hi and welcome

I am sorry Ezzy has IMTP.  Below is some information about this autoimmune disease.  If you have any queries, please let us know.
I hope you see an improvement very soon.

Jo


Information about Thrombocytopenia
As the blood platelets are essential for blood clotting, a dog with very low platelets can bleed to death in a relatively short period of time. The life of a blood platelet in a normal dog is approximately 5 days.  In a dog with thrombocytopenia, the life of a platelet is no more than one day and may be only a few hours or even less.
"Immune Mediated Thrombocytopenia (IMTP) is the most common cause of markedly decreased platelet count in the dog.  A strong presumptive diagnosis can be based solely on the detection of severe thrombocytopenia if history, physical examination and laboratory testing reveal no evidence of other causes. Treatment should therefore not be withheld in dogs with suspected IMTP pending results of specific anti-platelet antibody testing, particularly as such tests tend to be unreliable.  A presumptive diagnosis can usually be confirmed within 1-2 weeks by an appropriate response to immunosuppressive therapy".  Andrew  Mackin, Chapter 36, Bleeding Disorders, Canine Medicine and Therapeutics by Neil Gorman
There is a very good reason for including the above reference as I have known several young dogs that have appeared well but showing signs of bruising, bleeding, and a low platelet count that have not been treated appropriately and have died. This is usually because the vet cannot identify the reason for the dog's low platelet count and bruising etc., and is unsure of what to do or what treatment to give, but by not treating with immunosuppressive doses of steroids the dog's life is at risk. To the best of my knowledge, Beardies are not one of the breeds that suffer from genetic bleeding disorders such as Von Willebrand's disease or haemophilia A; therefore, if a Beardie shows classic, clinical signs of thrombocytopenia and a low platelet count, and no other reasons for the low platelets can be identified, AITP should be hastily considered and correct, immunosuppressive treatment started without delay.  The treatment is designed to significantly suppress the immune system, in order to halt the destruction of the platelets, and allow platelet numbers in the circulation to increase. Lower doses of steroids will not have the desired effect.
Clinical signs

The similarities between these two cases are the extensive bruising, and the fact that both dogs were not showing any obvious signs of serious illness (which would be more likely if there is an underlying condition causing IMTP). The dog's apparent wellness belies this serious condition and owner or vet should not be lulled into a false sense of security because the dog is bright and eating well. Misty had a nose bleed because her platelets were so low she was spontaneously bleeding (bleeding for no apparent reason). Any minor trauma can cause a bleed if the platelets are very low, even lifting or touching the dog can cause bruising.

You might see the first signs of bruising on the belly, under the arms, chest or legs.  Small pin-point bruising is very characteristic of AITP but areas of larger bruises and purple patches can also appear.  Your dog may vomit dark digested blood, which looks like 'coffee grounds',  and evidence of blood in the urine and/or black tarry faeces (melaena) indicates internal bleeding. A haematoma may be visible or felt (a swelling containing clotted blood). Blood shot eyes and spontaneous bleeding from the nostrils, gums (in fact any orifice), can occur when the platelet count is low.  Bleeds within the central nervous system may cause neurological signs and a haemorrhage within the eye can cause sudden blindness. Regenerative anaemia may be present due to bleeding. If non-regenerative anaemia is present with AITP then the dog may have Evan's Syndrome.

Some clinical signs that may aid a diagnosis and help to differentiate between primary autoimmune thrombocytopenia and secondary immune mediated thrombocytopenia

1. Autoimmune thrombocytopenia is more common in young to middle age dogs.

2. Small pin point bruises (known as petechiae or ecchymoses) and purple patches (purpura) are common in primary autoimmune thrombocytopenia (AITP) but are rare in secondary thrombocytopenia (IMTP) 

3. Secondary IMTP caused by, for example, rat poisoning would more likely show as larger areas of haemorrhage, such as body cavity haemorrhage,  haematomas (swelling containing blood), and bleeding into joints and muscles (which may show as limping). 

4. A dog with AITP is likely to appear well. Fever, enlarged spleen, enlarged liver and lymph node involvement are more common in secondary IMTP and uncommon in primary AITP.

Note: Sophie had a haematoma which is quite rare in cases of primary autoimmune thrombocytopenia (AITP) but common in dogs with secondary thrombocytopenia (IMTP). The above points are to be used as guidelines only.

Diagnosis:

Diagnosis of AITP is often presumptive and based on the absence of an underlying cause, blood test and smear results, which not only evaluate platelet numbers, platelet clumping and size,(indicating the magnitude of thrombocytopenia) but can also exclude underlying causes, such as leptospirosis, heartworm and other parasites (especially important for dogs that have travelled abroad), recent drug use, cancer, and rat poisoning, which is usually on top of the vet's list of differential diagnoses. The dog's medical and travel history, and the appearance of clinical signs, age and breed of the dog should also be taken into consideration.

Unless the evaluation of blood results suggests otherwise, a bone marrow biopsy is not routinely performed.

Twice as many females develop thrombocytopenia than males. The influence of hormones is considered to be a major trigger factor for AITP.

A blood test to check for anti-platelet antibodies, capable of binding to the blood platelets, can confirm thrombocytopenia; however, a positive result does not differentiate between primary and secondary causes of the disease.

AITP may occur alongside other autoimmune diseases, such as autoimmune haemolytic anaemia (AIHA), known as Evan's syndrome, with rheumatoid arthritis, or with a multisystemic autoimmune disease, Systemic Lupus Erythematosus (SLE).
Note: Platelet counts by an automated machine analyser should always be verified by examination of a blood smear.


Treatment
Keeping your dog as quiet and relaxed as possible, even cage rest, is very important to minimise trauma whilst there is a risk of haemorrhage.
Steroids are the main stay of treatment for most autoimmune diseases.  It is essential that they are given in immunosuppressive doses and for the correct duration of time.
'Immunosuppressive dose of prednisolone: 1-2mg/kg/12hours, starting at the lowest dose, for a period of 10-28 days then the dose is reduced by 25% every 10-28 days until an every other day dose is achieved or the drugs stopped altogether'. (Clinical Immunology of the Dog and Cat by Michael J Day).
EXAMPLE:
Immunosuppressive Protocols for Oral Prednisolone in the Dog.
Ref: Clinical Immunology of the Dog & Cat by Michael J Day  – Professor of Veterinary Pathology, University of Bristol, UK and WSAVA - Chairman of Scientific Advisory Committee.

This example is based on a dog receiving an induction dose of 1.0mg/kg/q12hrs

Dose                Duration (based on clinical effect)

1.0mg/kg/q12h             10-28 days
0.75mg/kg/q12h            10-28 days
0.5mg/kg/q12h             10-28 days
0.25mg/kg/q12h          10-28 days
0.25mg/kg/q24h          10-28 days
0.25-0.5mg/kg/ Every other day      at least 21 days
0.25-0.5 mg/kg/ Every third day       at least 21 days

With kind permission of Prof.  M J Day.

The treatment regime is absolutely crucial to the outcome.  The main objective is to 'knock out' the immune system and virtually stop it from working (or near enough) so the destruction will cease and give the body a chance to recover.  All dogs are different and some can tolerate the side effects of the drugs better than others. Small dogs seem more able to tolerate higher doses of steroids than larger dogs.
'Prednisolone: Doses above 2.2mg/kg/day do not give more immunosuppression but do cause more side effects. Many internists believe that prednisolone doses should not exceed 80mg per day, regardless of the dog's weight.'  Plumb's Veterinary Drug Handbook Eight Edition.
The vet may decide to use a combination therapy, using two drugs, for example prednisolone (a steroid) and Azathioprine.  A combination therapy minimises the side effects of the drugs and allows the steroids to be reduced whilst maintaining a good level of immunosuppression. Other, less commonly used drugs prescribed with prednisolone include: Cyclophosphamide, Cyclosporin and Danazole. Recent studies suggest the addition of Melatonin to immunosuppressive treatment increases platelet count and is safe and effective in the treatment of refractory IMTP with little or no noticeable side effects.
Recent studies suggest the addition of Melatonin to immunosuppressive treatment increases platelet count and is safe and effective in the treatment of refractory IMTP with little or no noticeable side effects.

A gastroprotectant should be given whilst a dog is on high doses of steroids to counteract the excess stomach acid produced by the steroids. Also, as a precaution, some vets will prescribe antibiotics when the immune system is significantly suppressed.
In addition to immunosuppressive doses of steroids, with or without the addition of a combination drug, a single dose of the drug Vincristine can produce a dramatic rise in platelets and may be used in life threatening cases of IMTP.
Note:  Vincristine is on the list of drugs that is likely to cause an adverse reaction if the dog has MDR1 gene mutation. MDR1 is the multi-drug resistance gene that produces a protein called P-glycoprotein which prevents toxins from crossing the blood-brain-barrier. If this protein isn't present, because of a gene mutation, the body is unable to excrete the drug and toxins will build up within the brain resulting in neurological symptoms. A simple cheek swab or blood test will determine the dog's status for the MDR1 gene, and it might be prudent to consider this before using Vincristine. Collie breeds more likely to have a MDR1 deficiency but for a list of breeds known to have the MDR1 mutation please refer to:  http://www.ashgi.org/home-page/genetics-info/faq/mdr1-faqs
If the platelet count is dangerously low, it may be necessary to give a whole blood transfusion or a platelet rich transfusion to 'buy time' for the treatment to work.
The aim is to achieve remission. Some dogs are able to be weaned off of steroids altogether whilst others have to remain on a low every other day dose of steroids to control the disease.  When the dog is in remission it will be able to lead a normal, happy life. Some dogs can relapse but I have known many who have only had one episode of the disease. The best chance for survival is early diagnosis and the correct treatment regime.
Jo Tucker

[tildesaz]

Thank you both so much. She is on 20mg pred twice a day at the mo and a daily antiobotic as her temp was increased on Monday. Have next blood test next Monday. Hope she keeps getting better. I'm watching her for any bleeding at all. She's super sad cos it's the first time it's ever snowed here in her life time and she wants to play in it!!

[Jo CIMDA]

Hi

It seems like your vet is treating her correctly.  Fingers crossed.  The snow will have to wait!!!

Jo

[FudgeKelly]

I cant offer any expert advice but our 2 year old Sprocker (fudge) developed what seems to be an autoimmune disease a couple of months ago.  It paralysed her tongue meaning she couldn't eat or drink.  We were terrified probably like you are.  We put our faith in the vets and in common sense and now, despite some periods of real despair, our horrible, funny, cheeky, adorable, bouncy little girl is starting to look like she's recovering.  I posted on it 'Fudge Kelly Paralysed Tongue' and although that will probably have no technical use to you it might at least show that you are far from alone with lots of unknown people rooting for you and your hound and that there is always hope.  Good luck and my best wishes are with you all. 

[tildesaz]

Thank you all so much!! It's been a terrifying few weeks. Her bloods this Monday showed a rebound and platelets are high now. Staying on same dose of steroids for second week then it has stabilised will decrease. Her thirst is insane though and she is weeing a lot in the house despite going out every half hour/ hour by day. Vets say she could have a UTI so sample going in on Monday. She did have one at the start of all this and is on a urinary food to dissolve crystals in her wee but we've decided just to give her that once a day for now as I think it's just increasing her thirst. Fingers crossed things start to settle!

[Jo CIMDA]

Hi

It is good that Ezzy's platelets have greatly  increased.  The steroids are doing their job, and this is also reflected in her wanting to drink and wee excessively.  These are side effects of the steroids and are unavoidable.  The good news is, as you lower the preds the side effects will lessen and by the time you have weaned Ezzy down to a low dose they will hardly be noticeable, so although this is a nuisance it will not last forever.  Because this is the most common side effect of taking high doses of steroids it may be that she doesn't have a urine infection.  Having said that, Izzy's immune system is very suppressed and this means that UTI's are very common, because her body can't fight off bacteria, and antibiotics may be necessary but this is nothing to be worried about and a special renal food isn't really necessary. 

It all seems to be going in the right direction.

Below is some information about what to expect when treatment has started.
Jo



WHAT TO EXPECT ONCE TREATMENT HAS STARTED
If a dog has a serious autoimmune disease, then the sooner treatment commences the better chance the dog has of survival.  The main delay to starting treatment is obtaining a diagnosis or at least your vet being sure that he hasn't missed anything that could be made worse by giving high doses of steroids.  Achieving a diagnosis can be a fight against time. 
If your vet has decided that in all probabilities your dog has an autoimmune disease, then to a certain extent, which autoimmune disease your dog has, as far as treatment is concerned, is irrelevant because with the exception of a few diseases, they are all treated the same, that is, with immunosuppressive drugs.  The main objective is to 'knock out' the immune system and virtually stop it from working (or near enough) so the destruction will cease and give the body a chance to recover.  As previously stated, this treatment regime works in most cases, that is, if it has been given early enough and the dosage is correct.  All dogs are different and some can tolerate the drugs better than others. In proportion to their size, small dogs seem more able to tolerate higher doses of steroids than large ones. Some diseases are more serious than others and carry a poorer prognosis. So the initial crisis is a crucial time, however anecdotal evidence shows that many more dogs survive than die if correct treatment is administered in good time.
It is hoped that a positive response can be seen within 4-6 hours of starting treatment (depending on the disease), but in a serious, life threatening situation, the first 2-7-14 days can be a very worrying time.  Assuming the dog has stabilised he will quickly feel much better, and if he is in hospital may be allowed home within a week.
When he comes home he will probably have a 'goody bag' full of drugs.  He will be on a high dose of steroid, usually prednisolone, and he may also be on another immunosuppressive drug, such as Azathioprine.  Your dog will be weaned off in a controlled manner according to his wellness and clinical observations. 
Note: High doses of steroids must not be stopped abruptly.  Your dog could go into an adrenal crisis if the medication is withdrawn too quickly. 
In addition to immunosuppressive drugs he should have something to protect his stomach from excess acid.  The last thing your dog needs when he is feeling poorly is a bleeding stomach ulcer caused by the drugs.  Sometimes, Antepsin is given to coat and protect the stomach (but this must not be given within two hours of other medication otherwise it will stop the drugs from being absorbed).  Zantac (Ranitidine) may also be prescribed to take away the excess acid. Another gastroprotectant used is Omeprazole. To minimise irritation to the stomach it is usual for the daily dose of steroid to be split into two doses and given with food, one dose in the morning with breakfast and the other dose with his evening meal. I have known several dogs, who did not receive a gastroprotectant as a part of their treatment regime, and went on to develop anaemia. This is not autoimmune haemolytic anaemia but iron deficiency anaemia caused by bleeding stomach ulcers. Using a gastroprotectant is a good preventative measure. When the steroids have been significantly reduced to a low dose, a gastroprotectant may not be necessary.
Excess acid, produced because of the drugs, may make a dog prone to developing pancreatitis. A dog with pancreatitis will appear in pain and his back may be arched as if he can't straighten up.  He may be lethargic, seem bloated and have a tender abdomen. Dogs usually go off food and water, may vomit and look depressed.  If you suspect that your dog has pancreatitis, don't try to feed him because it will make the condition worse. Take him to the vet as soon as possible as he may require treatment or need to go on an intravenous drip to stop him dehydrating.  Again, the risk of pancreatitis should be minimal once the dog is on a lower dose of steroids.   A low fat diet is best when your dog is on high dose steroids or prone to pancreatitis. 
As your dog's immune system is being significantly suppressed, he will be more likely to pick up infections, and will not have the ability to fight against them.  As a precaution a broad spectrum antibiotic is often prescribed. Also it is sensible not to exercise him in areas where he is more likely to encounter infections, for example, a park or a popular dog walking area. 
Whilst your dog is on high dose steroids he will want to eat and drink excessively. However, this also means that he will want to urinate more and this can sometimes cause temporary incontinence.  You may have to get up to let him out during the night and if you leave the garden door open during the day, it may save some mopping up!  He cannot help it and won't like it either, so don't be too hard on him, it's only temporary. You will notice as he is weaned off the drugs the unwanted side effects will subside and he should return to normal habits and behaviour.  Urinary tract infections and/or bacterial skin pustules are not uncommon when a dog's immune system is suppressed, and this is often the reason for a dog to be off colour during this time.  Note: Always consider a urine infection if your dog seems under par.  A course of antibiotics will usually sort this out quickly.
Depending on what autoimmune disease your dog has, he will probably need to have regular blood tests.  Biochemical blood tests will also keep an eye on other body functions, such as those of the liver and kidneys, which is important at this stage.
Assuming good progress is being made, the clinical signs of his illness are diminishing and positive signs of improvement are apparent, your vet will want to start weaning him down from the high doses of steroid.  This process can take 3-6 months or more, and usually begins any time after 10 - 28 days from the start of treatment, depending on the results of his blood tests and his clinical signs.
Relapses are not uncommon, especially in diseases that are difficult to control, for example SLE.  A relapse may mean that initially, your dog needed to be on a higher dose of immunosuppressive drugs for a longer period of time, or your dog may have been weaned off a little too quickly and then the dose withdrawn too soon.
If a relapse occurs he will probably show similar clinical signs to his initial crisis.  He will have to go back on an immunosuppressive dose of prednisolone, but it may not have to be quite as high as before. A combination drug may need to be added at this stage. The weaning process will then have to start all over again. Returning to an immunosuppressive dose will mean that he has to go back on a gastroprotectant.

Side Effects of the Drugs – Iatrogenic Cushing's Syndrome
Iatrogenic Cushing's syndrome is a side effect of high dose steroids and is caused by too much corticosteroid in the body. To a lesser extent, the immhttp://cimda.co.uk/smf/Smileys/default/wink.gifediate side effects observed when the dog initially goes on steroids eg., drinking, eating and urinating excessively is a mild example of Cushing's syndrome.  Personally I like to see dogs responding to high doses of prednisolone in this way, as it means that they are responding to the drugs as they should.
Usually, Cushing's syndrome only becomes a real problem when exceptionally high doses, or prolonged high doses of steroids are administered, maybe due to a relapse, or in some cases where the vet is inexperienced in reducing steroid doses and keeps the dog on a high dose for longer than necessary; or when the dog is not responding to treatment and higher doses are necessary to control the disease.  This is where the cytotoxic drug Azathioprine is very useful. 
All drugs carry side effects and Azathioprine is no exception, but it does not carry the same side effects as prednisolone, therefore by using this drug in combination with prednisolone it reduces the risk of iatrogenic Cushing's syndrome.  As Azathioprine takes at least 10 days to take effect, starting the 'combination' therapy at the beginning of treatment may enable the prednisolone to be lowered within the 10-28 day band and still maintain a good level of immunosuppression. If your dog is not responding to treatment then your vet may consider changing his treatment to other immunosuppressive drugs.
How Can I Tell if My Dog Develops Iatrogenic Cushing's Syndrome?
Iatrogenic means 'drug induced'.  Clinical signs of Iatrogenic Cushing's syndrome are the same as primary Cushing's syndrome but can present with acute clinical signs. It reflects the level of corticosteroid in the body.
The most notable side effects are, heavy panting, some hair loss, and an increase in drinking and urinating, excessive pigmentation.  This is something everyone seems to be aware of and accepts as normal when a dog is on high dose steroids. Very often the dog will be weaned down to a low dose before any major problems arise. 
Acute Cushing's syndrome due to overdosing of corticoid steroids can be very serious.  Blood results will reflect this, especially the liver enzymes which may be extremely high. Red blood cells and blood platelets may also be high and blood clotting may be a risk.
So when should you alert your vet to suspected, unacceptable level of corticosteroid?  The owner should take note when other clinical signs occur, such as: Depression, anorexia, muscle wasting and extreme weakness, continuous panting, lethargy - unwillingness to exercise, skin lesions and thinning of the skin, excessive hair loss, pot-bellied appearance and sagging back, behavioural changes (aggression).
If your dog is showing these signs it will probably mean that the dose of steroids needs to be lowered. It is important that it is not confused with a relapse of the dog's condition or an infection. The dilemma is that steroids must not be withdrawn too quickly otherwise the dog may go into an adrenal insufficiency crisis.  If the clinical signs of iatrogenic Cushing's syndrome is intolerable, it is hoped that the high dose of steroids that he has been on will have already done their job and that his autoimmune disease will be stable. As long as the steroids are lowered in a controlled manner and in time, all the symptoms of Cushing's will subside and your dog will return to normal, but extreme signs must not be ignored.

Reducing the Tablets
When significant improvement in the dog's condition is seen, usually between 10-28 days, the initial steroid dose is usually reduced by up to half. The dose is generally given for another 10 - 28 days and depending on the dog's progress and clinical signs the dose is significantly reduced once more for a further 10-28 days; and again in another 10-28 days. Anecdotal evidence has shown that if at this stage the dose is lowered more slowly, or reduced to an every other day dose over a period of months rather than weeks, relapse are less likely to occur.  It is always tempting to get your dog off steroids as soon as possible, but when treating autoimmune disease, as long as the dog is on a low, every other day dose then taking the last stage slowly seems to work best, depending, of course, on the severity of the disease and allowing for the difference in individual response - no two dogs reactions are exactly the same.  With some autoimmune diseases such as SLE, the dog is likely to be on steroids for the rest of his life. Usually an every other day dose can be achieved, but you risk a relapse if you take the dose too low. Below is the best example of a reducing immunosuppressive protocol I have come across. It is an excellent guide and can be adjusted to the individual.

[tildesaz]

Just wanted to update you. Ezzy dropped to 3 tablets twice a day a week after my last post and then 3 weeks later we returned to the vet this week. Her platelets are now in normal range as are her RBC and overall WBC. She's down to 2 tablets twice a day and allowed to build up her exercise again. Hoping she keeps going in the right direction. Thanks so much for your last post Jo. She did have a UTI but 5 days of abx sorted her out!!

[Jo CIMDA]

Hi

This is brilliant news and thank you so much for the update.

UTI's are so common and such a nuisance, but easily sorted.

Great stuff!

Jo