WHAT IS A PLATELET?
A platelet is a cloud-shaped blood cell, neither related to
the red blood cell line nor the white blood cell line. Platelets
act in the clotting of blood in that they home to damaged
areas of blood vessels, and “aggregate” there, meaning that
they pile onto each other and bind, forming a small plug to
seal the hole in the leaking blood vessel. Of course, large
tears are too big for platelets to seal and there are other
blood clotting mechanisms besides platelet aggregation but
when it comes to small bleeds and normal blood vessel wear
and tear, platelets are the star of the show.
There is a saying that “platelets are vascular integrity and
vascular integrity is platelets.”
A small bleed unstaunched by a platelet aggregation quickly
becomes a large bruise. Spontaneous bruising (in other words
visible bruising from the normal wear and tear of one’s body)
is a sign of reduced platelet numbers or poor platelet function.
THE LIFE AND TIMES OF JOE
We would like to present a more detailed explanation of a
platelets life from beginning to end. Platelets come from
the bone marrow where a large (actually gigantic relative
to the red and white blood cell precursors) cell called a
“megakaryocyte” spits off little active pieces of itself.
These pieces are platelets, ready to enter the circulation
where they will live for an average of 8-12 days (in the dog)
or 6-8 days (in a human) before a bleeding capillary calls
them to their destiny. At any given time some 200,000-500,000
platelets are on patrol in the circulation, though only about
50,000 are considered the bare minimum to prevent spontaneous
bruising and bleeding. About 1/3 of the circulating platelets
are actually stored in the spleen like boats in a harbor,
ready to mobilize if necessary. When platelets become too
old to be useful, the spleen has special cells called “phagocytes”
which essentially eat old cells and recycle their inner materials.
IMMUNE-MEDIATED PLATELET DESTRUCTION
For reasons unknown, platelets can be mistaken by the immune
system as invaders. When this happens, antibodies coat the
platelets and the spleen’s phagocytes remove them in numbers
up to 10 times greater than the normal platelet removal rate.
The megakaryocytes in the bone marrow respond by getting larger
and growing in numbers so that they may increase their production
of platelets. The platelets produced under these circumstances
tend to be larger and more effective than normal platelets
and are called “stress platelets.” The bone marrow attempts
to overcome the accelerated platelet destruction rate; unfortunately,
with immune-mediated destruction occurring, a human platelet
can expect to survive only one day in the circulation instead
of its normal 6-8 days. If antibody levels are very high,
a platelet may survive only minutes or hours after its release
from the bone marrow and, making matters worse, antibody coated
platelets still circulating do not function normally. This
is balanced by the especially effective stress platelets entering
the scene so that overall it is hard to predict how the balance
will work out in a given patient.
WHAT WOULD CAUSE THE IMMUNE
SYSTEM TO GET SO CONFUSED?
In many cases, a cause is never found; however, in cases a
primary reaction in the immune system precedes the platelet
destruction. For example, immune destruction of some other
stimulus could be occurring. A blood parasite, tumor, drug,
or other cell type (as in lupus or immune-mediated red cell
destruction) might all generate an antibody response. As antibodies
are produced in response to the surface shapes of the “enemy”
cell, some of the surface shapes may unfortunately resemble
“self” shapes such as shapes on the surface of platelets.
WHAT HAPPENS TO THE PATIENT?
The usual patient is a middle-aged dog. Poodles appear to
be predisposed though Cocker Spaniels and Old English Sheepdogs
also seem to have a higher than average incidence of this
Spontaneous bruising is the major clinical sign. The gums
and oral surfaces or on the whites of the eyes are a obvious
areas to check as is the hairless area of the belly. Small
spots of bruising in large conglomerations called “petecchiae”
(“pet-TEEK-ee-a”) are the hallmark sign. A large, purple expansive
bruise might also be seen. This is called “ecchymosis.” Large
internal bleeds are not typical of platelet dysfunction, though
bleeding small amounts in urine, from the nose, or rectally
may also indicate a platelet problem.
When these sorts of signs are seen, a platelet count is drawn,
along with usually an array of clotting parameters, red blood
cell counts to assess blood loss, and other general metabolic
blood tests. Since testing to detect actual anti-platelet
antibodies is not available, the veterinarian must determine
if any other possible causes of low platelet count make sense.
OTHER CAUSES OF PLATELET DYSFUNCTION
Dramatic reduction in platelet numbers is almost always caused
by immune-mediated destruction, though certain tick-borne
blood parasites could also be responsible:
Very low platelet counts can also occur in response to the suppression of megakaryocytes within the bone marrow. This might be caused by:
Disseminated Intravascular Coagulation is a life-threatening disastrous uncoupling of normal blood clotting and clot dissolving functions in the body and one of its hallmark signs is a drop in platelet count (along with a constellation of other signs).
If platelet numbers are normal but it is obvious that platelet function is not, some other causes to look into might include:
THERAPY FOR IMMUNE MEDIATED PLATELET DESTRUCTION
Once a tentative diagnosis of immune-mediated platelet destruction has been made, the goal in therapy is to stop the phagocytes of the spleen from removing the antibody-coated platelets and cutting off antibody production. This, of course, means suppression of the immune system using whatever combination of medication seems to work best for the individual patient.
These steroid hormones are the first line of defence and, often, all that is necessary in bringing platelet counts back up. Unfortunately, long term use should be expected and this means steroid side effects are eventually inevitable: excessive thirst, possible urinary tract infection, panting, poor hair coat etc. The good news is that these effects should resolve once medication is discontinued; further, if side effects are especially problematic, other medications can be brought in to reduce the dose of steroid needed.
This injectable medication is mildly immune suppressive but also seems to stimulate a sudden burst of platelet release from the marrow megakaryocytes. The platelets released in response to vincristine contain a phagocyte toxin so that when they are ultimately eaten by spleen phagocytes, the phagocytes will die. While repeated injections of vincristine ultimately do not yield the same effect, at least a one time dose may be extremely helpful. One should note that vincristine is extremely irritating if delivered outside of the vein. It must be given IV cleanly or the overlying tissue will slough.
Male hormones may have some masculinizing side effects but they do seem to cut production of anti-platelet antibodies. It also seems to
synergise with the corticosteroid hormones like prednisone and dexamethasone. Danazol has been the androgen typically recommended in the treatment of immune-mediated platelet destruction with weight gain being the most common side effect.
These are stronger immune suppressive agents typically used in cancer chemotherapy. If steroid side effects are unacceptable or if the patient does not respond to steroids alone, one of these medications may be indicated. Cyclosporine, a newer medication made popular in organ transplantation, also may be used but expense has been problematic.
One might think that a transfusion of blood or at least “platelet rich plasma” might be helpful in the treatment of a platelet dysfunction. The problem is that platelets do not survive well after removal from a blood donor. One has about 12 hours to deliver the freshly withdrawn blood to the recipient before the platelets become inactive. After the platelets are delivered they are likely to live only hours. In general, most efforts are spent on establishing immune suppression.
GAMMA GLOBULIN TRANSFUSION
Gamma globulins are blood proteins including antibodies. Human gamma globulin appears to occupy the phagocyte antibody binding site so that coated platelets cannot be grabbed out of the circulation. This has been a promising therapy for both humans and dogs but is generally prohibitively expensive.
If medication simply does not work or the condition keeps recurring once medications are discontinued, the solution may be to simply remove the spleen.
After all, this is where the phagocytes removing the platelets are primarily located. In humans, immune-mediated platelet destruction is generally treated with splenectomy first.
Response in dogs has not been as predictably good thus in veterinary medicine it is generally one of the last therapies invoked.
IMMUNE MEDIATED THROMBOCYTOPENIA
What is thrombocytopenia?
The term thrombocytopenia refers to a condition where a patient has lower than normal levels of circulating platelets. This may be due to increased loss (i.e. hemorrhage), increased destruction (i.e. immune disease), increased consumption (i.e. clotting abnormalities) or decreased production (i.e. disease within the bone marrow). Immune mediated destruction of platelets is one of the more common problems we see here.
Why are platelets important?
Platelets are cells within the blood that play a critical role in normal blood clotting functions. They are produced in the bone marrow (like the red and white blood cells) and are then released into the circulation.
What are the causes of IMTP?
Immune mediated plated destruction can be due to a variety of underlying problems that trigger an abnormal immune response. Things such as infections (bacterial, viral), drugs, certain cancers, etc have all been implicated as potential causes of IMTP. It is also possible that no underlying problem is found in which case it is called idiopathic IMTP. This is the most common cause of life threatening thrombocytopenia in dogs. In order to diagnose the idiopathic form of the disease however, the other potential causes need to be ruled out.
What are the signs of IMTP?
Because thrombocytopenia leads to problems with normal clotting, the most common signs you may notice at home are bruising, blood in the stool or the urine or nose bleeds. In some instances thrombocytopenia can lead to bleeding into the abdomen, chest, brain or spinal cord. In these cases clinical symptoms may include labored breathing, abdominal distension or neurologic signs.
How is IMTP diagnosed?
Routine blood tests will show low platelet levels however the key is in looking for a cause for the low platelets. Your veterinarian may perform blood tests to look for specific infectious diseases such as Ehrlichia or heartworms. Since cancer is also a potential trigger of this disease your veterinarian may perform chest x-rays or an abdominal ultrasound.
If no underlying cause is found then a diagnosis of primary IMTP is made and immunosuppressive therapy is begun.
How is IMTP treated?
The mainstay of therapy, aside from treating the underlying cause, is immunosuppressive therapy. Prednisone is one of the main medications used but there are other drugs that may be required as well (i.e. Azathioprine, Cyclophosphamide). Regardless of the type of therapy that your veterinarian chooses, frequent rechecks will be an extremely important part of the plan.
If the thrombocytopenia is severe, your veterinarian may recommend hospitalizing your pet for observation and more aggressive treatment. Unfortunately, a blood transfusion will not supply enough platelets to reverse thrombocytopenia. If the low platelets however have led to blood loss and subsequent anemia, then a transfusion may be indicated.
The prognosis with IMTP can be quite variable and depends on the underlying cause, response to therapy or drug complications. Overall, if there is no severe underlying disease and your pet responds well to therapy, the prognosis is generally good although lifelong medication may be required.
Gold Coast Veterinary Specialists
THROMBOCYTOPENIA, PRIMARY IMMUNE MEDIATED
Immune-mediated destruction of platelets
Autoimmune process in which antibodies develop against platelet antigens. Antibodies bind to the antigen on the platelet surface, and then the antibody-coated platelets are prematurely removed from the circulation by the macrophage phagocytic system.
If the platelet count is low enough (< 40,000/ µl) hemorrhage can occur into any organ
system. Systems commonly recognized as
affected clinically include integumentary,
gastrointestinal, respiratory, and urinary.
Incidence and Prevalence
In a recent study at North Carolina State Veterinary Teaching Hospital, 5.2% of dogs admitted to the hospital had thrombocytopenia. In patients with thrombocytopenia, 2.8% were thought to have primary immune-mediated thrombocytopenia. In similar studies in cats, 1.2% had thrombocytopenia, and 2% of these were thought to have immune-mediated thrombocytopenia.
- Cocker Spaniel, Poodle, Old English Sheepdog, and, possibly, German Shepherd
- No known breed predilection in cats
Mean Age and Range
- Mean age in dogs, 6-7 years
- Age range in dogs, 7 months to 14 years
More common in female dogs
- Hemorrhages in the skin and mucous membranes
- Excessive hemorrhage associated with a mild traumatic event
- Spontaneous epistaxis
- Vomiting blood
- Blood in the stool
- Lethargy, weakness, and collapse
- Bleeding less commonly seen in cats
Physical Examination Findings
- Petechial and ecchymotic hemorrhages in the skin and mucous membranes
- Melena, hematochezia, or hematemesis
- Pale mucous membranes
- Lethargy, weakness, and collapse
- Scleral and retinal hemorrhages and hyphema
- Heart murmur
- Neurologic signs
- Disseminated intravascular coagulation. To rule out, perform coagulation profile
- Blood loss as a result of trauma or secondary to vitamin K antagonist (thrombocytopenia is mild)
- Low platelet production (thrombocytopenia is usually moderate to severe)
- Evaluate animal for other cytopenias such as nonregenerative anemia and leukopenia, and perform examination of bone marrow aspirate and core biopsy to identify the type of primary bone marrow disease.
- Myeloproliferative disorders and FeLV infection commonly cause thrombocytopenia in cats. FIV sometimes causes thrombocytopenia. Perform FeLV
and FIV tests to rule out these diseases.
- Hepatomegaly and splenomegaly (mild thrombocytopenia)
- Secondary immune-mediated thrombocytopenia. Clinical and laboratory findings are identical to those of primary immune-mediated thrombocytopenia. Causes of the former include drugs, neoplasms, infectious diseases (e.g., ehrlichiosis, FeLV infection, and, probably, Rocky Mountain spotted fever), and immune-mediated diseases such as systemic lupus erythrematosis and immune-mediated hemolytic anemia. Perform serum titers to rule out ehrlichiosis and Rocky Mountain spotted fever. Perform ANA test for systemic lupus erythematosis. Evaluate blood film for spherocytes and agglutination to help determine if patient has immune-mediated hemolytic anemia.
- Thrombocytopenia develops secondarily to many infectious diseases.
- In most patients, severe thrombocytopenia (platelet count < 20,000/µl); not uncommon to see platelet counts in the 1000-5000/µl range
- Mild to moderate anemia often with hypoproteinemia. If there has been enough time for the bone marrow to respond, the anemia is regenerative.
- Neutrophilia in some patients
- Antiplatelet antibody test--if positive and other causes of thrombocytopenia are ruled out, it strongly supports the diagnosis. False-negatives do occur.
- Antimegakaryocyte antibody test--if positive and other causes of thrombocytopenia are ruled out, it strongly supports the diagnosis. False-negatives do occur. This test may be less sensitive than the antiplatelet antibody test.
- Mean platelet volume. Microthrombocytosis (mean platelet volume, < 5.4 fl) has been documented in some patients and usually is seen early in the disease process. As the disease progresses, the platelets increase in size resulting in macrothrombocytosis.
Used to rule out other causes of thrombocytopenia
Bone marrow aspiration with or without core biopsy. Cytological evaluation of the bone marrow is helpful to make sure that thrombocytopenia is not caused by low production. If megakaryocytes are readily observed, then low production of platelets is unlikely. Selective immune-mediated destruction of megakaryocytes is rare. Erythroid and megakaryocytic hyperplasia is seen in some patients.
- Petechial and ecchymotic hemorrhages in the mucous membranes, skin, and serosal surfaces
- Hemorrhage into any organ, especially the gastrointestinal, respiratory, and urinary systems
- Possibly, erythroid and megakaryocytic hyperplasia in the bone marrow
If the patient has severe hemorrhage, stabilize and then treat as an outpatient.
- Animals with severe hemorrhage should be brought to the hospital for monitoring and treatment.
- Fatal hemorrhage is more likely if exercise is not restricted.
Splenectomy may be done in cases that are refractory to medical treatment.
Drugs and Fluids
- Prednisone or prednisolone (1-2mg/kg PO q12h for at least 2 weeks or until marked
improvement in the platelet count is seen). Once the platelet count is within the normal reference range, the dosage should be gradually tapered over weeks to months.
- Dexamethasone can be used initially (0.1-0.2 mg/kg IV q12h).
- If the patient is unresponsive to corticosteroid, vincristine can be added (0.02-0.03 mg/kg or 0.5-0.75 mg/m2 IV once a week).
- In addition to the vincristine or alternatively to the vincristine, cyclophosphamide can be added (2.2 mg/kg or 50 mg/m2 PO q24h 3-4 days per week).
- Blood transfusions if the anemia is severe and causing clinical signs
- Platelet-rich plasma may be given if available.
- If glucocorticoid-associated, gastric ulceration develops, drugs such as sucralfate can be used
- Long-term treatment with corticosteroids can cause iatrogenic hyperadrenocorticism.
Cyclophosphamide can cause bone marrow suppression and sterile hemorrhagic cystitis.
- Vincristine is irritating if injected perivascularly. It can also cause constipation, peripheral neuropathy, and bone marrow suppression.
- Dogs -- danazole (5 mg/kg PO q12h) can be used concurrently with glucocorticoids. Do not use danazole in cats.
- Dogs -- azathioprine (2 mg/kg or 50 mg/m2 PO q24h-q48h) can be used to maintain remission.
Platelet count daily until the count is >50,000/µl and then weekly until the count returns to the normal range (in some patients the count will not return to the normal range). If the owner notices severe bleeding, the patient should be brought in for evaluation.
Minimize stress that may initiate recurrence.
Severe hemorrhage and death
Course and Prognosis
If the thrombocytopenia is severe and cannot be quickly improved by immunosuppressive therapy, animals may succumb as a result of fatal hemorrhage. Approximately 25% of patients referred to a veterinary teaching hospital died or were euthanatized. Of the patients that survived, approximately 50% had acute disease requiring only one course of immunosuppressive drugs, and 50% had chronic disease that recurred months to years later. In patients with acute disease that respond to corticosteroids, the platelet count increases in several days.
Immune-mediated hemolytic anemia
Age Related Factors
Use of immunosuppressive drugs may cause damage to the fetus.
- Idiopathic thrombocytopenia purpura
- Idiopathic immune-mediated thrombocytopenia
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