Download Immune-Mediated-Disasters

Immune Mediated Disasters
Megan Brashear, BS, CVT, VTS (ECC)
VCA Northwest Veterinary Specialists, Clackamas OR
Immune Mediated Thrombocytopenia
In order to understand what happens when the body can no longer clot its blood, it is important to understand the
normal clotting process.
 Endothelial damage occurs
 A platelet plug is formed with the help of Von Willibrand factor. Tissue factor activates the coagulation
cascade
 Thrombin activates the platelets, and converts fibrinogen into fibrin which stabilizes the clot
 The activated endothelium then participates in the slow dissolution of the clot as the healing process
continues
Any break in the system can cause an animal to not clot appropriately and end up with inappropriate bleeding into
any number of body cavities. When an animal presents to the hospital with evidence of bleeding (petechia,
ecchymosis, melena, hematemesis, hematochezia, hyphema, etc.); lab work should be performed to determine the
cause of the bleeding.
 PCV/TS: a decrease in both PCV and TS points to whole blood loss, where a decrease in PCV only points
to RBC destruction
 Platelet Count: leads to a diagnosis of platelet consumption, destruction, and/or bone marrow suppression
of platelets
 Clotting Times: measures manufacturing (liver) of clotting factors, can also be prolonged due to
consumption
 BMBT: measures platelet function, often only measured if other parameters are WNL and a diagnosis has
not yet been made
Immune mediated thrombocytopenia is a disease where the animal’s immune system is attacking and destroying
platelets. It is a diagnosis of exclusion, when other disease processes have been ruled out. Radiographs and an
abdominal ultrasound can be performed to rule out a neoplastic process, and extensive laboratory work may need
to be performed to rule out congenital clotting factor diseases.
Patients presenting with ITP may be cardiovascular stable but bleeding inappropriately. Owners may notice
hematuria, epistaxis, or blood-tinged saliva. It is possible for an ITP patient to hemorrhage to the point of clinical
anemia, but most of these patients are relatively stable on presentation. While most animals need to have a platelet
count as low as 20k-50k/ul before spontaneous bleeding occurs, it is difficult to predict bleeding and is
recommended that these patients are hospitalized for treatment until their platelet count rises above 50k/ul
Treatment is aimed at supportive care and immunosuppression. Glucocorticoids (like prednisone) are the
mainstay in ITP treatment; prednisone will decrease the killing response of lymphocytes and is most commonly
used. In many cases, other chemotherapeutic drugs are combined with prednisone in treatment:
 Azathioprine: inhibits DNA synthesis of proliferating cells, like T and B lymphocytes. It can cause bone
marrow suppression thus patients should have a CBC monitored while they are on azathioprine. Can also
cause vomiting and diarrhea, pancreatitis, monitor patients for hepatotoxicity. WEAR GLOVES when
administering, do not inhale dust of broken/crushed tablets. This medication can take 7-10 days to reach
therapeutic levels so will not help in the acute phase.
 Vincristine: chemotherapeutic and will interfere with the immune system, but used in ITP as it may force
quicker production of platelets in the bone marrow. Wear gloves, gown, eye protection when
administering, avoid extravascular infusion. Can take 3-5 days to see effects.
 Human Intravenous Human Immunoglobulin (hIVIG): Pooled IgG from human donors. Thought to
interfere with receptors on macrophages to decrease extracellular destruction, interfere with B and T cell
activation, and decrease the animal’s own immunoglobulin production. It also may reduce cytokine
production decreasing inflammatory pathways. It’s use in animals is extra-label and can only be used
once due to potential severe reactions upon additional dosing.
While hospitalized, ITP patients should be treated with care. No jugular blood draws, no neck leads, and no IM or
SC medications administered. It can be helpful to mark their skin where petechia is present to monitor for
increase. Monitor perfusion parameters closely in these animals as they can bleed into body cavities and become
critical without dramatic outward signs. If the patient is clinical for anemia (based on tachycardia, tachypnea,
bounding pulses, elevated lactate), providing a fresh whole blood transfusion may supply some platelets. The
problem with administering platelets is that the body will destroy them as it is destroying its own platelets making
it difficult to keep up.
Immunosuppressant drugs can take three days to begin working, during that time the ITP patient should be closely
monitored in the hospital. Some patients are eating and feeling quite good, but it is important to keep them quiet
and monitor them closely for any changes in status. Blood is drawn at least once daily to monitor a hand platelet
estimate and blood smear morphology. In most cases once the platelet count rises about 50k the patient is
discharged for home monitoring and checked less frequently by the veterinary staff. When the platelet count is
normal for four weeks, the prednisone dose can begin to be tapered, and continue to slowly drop in the following
months as blood values remain normal.
Immune Mediated Hemolytic Anemia
Immune Mediated Hemolytic Anemia (IMHA) can result from the body attacking and destroying its own red
blood cells. Immunoglobulins mark the red blood cells for destruction which mostly occurs in the spleen. While
any dog is susceptible to developing IMHA, Cocker Spaniels, Poodles, Schnauzers, and Springer Spaniels are
over-represented in the patient population. IMHA in cats is rare but can be secondary to another disease process.
The clinical signs for IMHA include weakness, tachycardia, tachypnea, pigmenturia, and pale or icteric mucous
membranes. The diagnostic process begins as a way to rule out common causes of anemia before landing on a
diagnosis of immune mediated. IMHA becomes a diagnosis of exclusion, as hemolytic anemia can be caused by
parasites, rickettsia disease, neoplasia, drug reactions, and systemic inflammation. In cats, mycoplasma is the
most common culprit in hemolytic anemia. In dogs, Babesia spp. and tick borne disease should be ruled out
depending on the area of the country they live. A complete database consisting of CBC, chemistry panel, and
urinalysis should be performed on any anemic patient.
IMHA patients will commonly have increased hepatic values and hyperbilirubinemia (result of the red blood cell
destruction) in their chemistry panel. Profound anemia and often leukocytosis is present in the CBC, and the
anemia is often regenerative. On blood smear analysis spherocytes, polychromasia, and marked anisocytosis are
often present. Performing a blood smear is important in these patients, as sphereocytes can help to solidify the
diagnosis. Many (but not all) patients with IMHA will also be auto agglutinating, and a saline agglutination test
should be performed. A direct Coombs test can also aid in diagnosis, but is not 100% accurate for these patients.
Looking for evidence of hemolysis in both blood and urine is important in these patients and should be noted if
present.
Radiographs and an abdominal ultrasound may also be recommended in these patients to rule out any other cause
for hemolytic anemia like neoplasia or zinc toxicity. If coins are found in the GI tract, the patient should be
stabilized as much as possible and then surgical removal performed. Regardless of the cause, supportive treatment
for these patients is similar.
Treatment for IMHA is immunosuppression, to essentially ‘turn off’ the immune system that is attacking the red
blood cells. While there are various drugs that can achieve immunosuppression, glucocorticoids are the most
commonly used to the best effect. Prednisone (2-4mg/kg/day) has been shown to be the most successful drug used
in IMHA treatment and is started as soon as possible after diagnosis. If the patient is vomiting, IV dexamethasone
(or dexamethasone sodium phosphate) is administered. Prednisone will decrease the “killer response” of
lymphocytes. While in many cases other immunosuppressant drugs are used in conjunction with prednisone, there
is no research to support their use in every patient. However, the use of other immunosuppressant drugs may
result in quicker discharge from the hospital, avoidance of the side effects of high dose glucocorticoids, and faster
reduction of steroid doses. Other drugs used in IMHA include:
 Azathioprine
 hIVIG
 Cyclosporine: inhibits the activities of lymphocytes. Side effects include GI ulceration, vomiting and
diarrhea, renal and hepatic toxicity. Drug trough levels must be monitored, so client compliance on this
drug is important. WEAR GLOVES when administering.
 Mycophenolate mofetil: Immunosuppressant used in humans to help against organ transplant rejection,
still relatively new use in veterinary patients. May help reduce the length of time steroids (prednisone) is
needed. Can cause GI toxicity, especially at higher doses.
Prednisone can take three days before the effects on the immune system are noticed, azathioprine and
cyclosporine can take even longer. While the patient waits for the benefits of drug therapy, supportive care is
administered. Some of the mild cases are treated on an outpatient basis, steroid therapy is started and outpatient
blood work is performed every few days until a response is noted. Many patients are too weak for outpatient care
and must be hospitalized. IV crystalloid therapy is initiated, drug therapy started, and blood transfusions
administered as needed. In these patients it is important to treat the patient and not the number, transfusions are
decided upon based on the patient’s clinical state (tachycardia, bounding pulses, tachypnea, degree of weakness,
lactate measurement) rather than the PCV (less than 20% for example). In many patients the anemia has been
slowly progressing over many days and they can tolerate a PCV lower than we may expect. If at all possible,
blood type and cross match patients before administering blood to minimize immune system activity. These
patients will often lyse the new red blood cells as quickly as they lyse their own cells, and it is not uncommon to
see a temporary increase in PCV only to see it drop again in a few hours. These patients should have BID-TID
monitoring of their PCV/TS until they are holding steady and they are no longer clinical for their anemia. A bone
marrow aspirate may be performed if a patient is not responding to the treatment protocol. Some animals will
have no evidence of cancer on radiographs or ultrasound, but may have evidence of cancer in their bone marrow.
While anemia, hypovolemia, and drug side effects are enough to make any IMHA patient feel pretty miserable in
the hospital, the most common complication (often leading to death) in these patients is thromboembolism. In
IMHA, there is excessive platelet activation and activation of the clotting cascade. Sphereocytes will bind more
readily to the endothelium lining the blood vessels, this can occlude smaller vessels. In the past, heparin was
administered to IMHA patients to attempt to prevent thrombosis. But heparin is not a one dose fits all medication,
and these patients needed intense clotting time monitoring and adjusted dosing. Retrospective studies do not
support heparin therapy on IMHA patients. However, ultra-low dose aspirin (0.5mg/kg q24hr) administered to aid
in preventing platelets from sticking together has proven to improve both short and long term survival in IMHA
patients. While these ultra-low dose doses may need to be compounded for many patients, the effort seems to be
worth it.
Once IMHA patients are discharged from the hospital they remain on immunosuppressant drugs until their
laboratory values are normal for at least four weeks, then the doses are slowly tapered over months. Some patients
may need to remain on a low dose of prednisone for the rest of their lives.
Nursing care for IMHA patients involves careful and intense monitoring of perfusion parameters, blood
transfusion administration, blood smear evaluation, respiratory system monitoring, barrier nursing,
immunosuppressant drug therapy, and TLC. These patients can be quite critical and their owners will require
counseling and education of this disease. With a mortality rate reported as high as 70% in some cases, it can be a
frustrating disease to treat. Patients can relapse at any time, either during weaning of immunosuppressant drugs or
years after their first bout. Drug therapy should be reinstituted and further hospitalization is often necessary.
The nursing team must be cognizant of barrier nursing and keeping immune patients away from infectious
patients. Critical thinking is required to think ahead and notice changes that can mean a decline in the patient’s
status. While frustrating, immune mediated diseases are treatable and these patients can return home with
appropriate care and medication.
References:
Cohn, Leah A., DVM, PhD, DACVIM. "Acute Hemolytic Disorders." Small Animal Critical Care Medicine. By
Deborah C. Silverstein, DVM, DACVECC and Kate Hopper, BVSc, MVSc, DACVECC. St. Louis, MO:
Saunders/Elsevier, 2009
Day, Michael J., BSc, BVMS(Hons), DSc, DECVP, FASM, FRCPath, FRCVS. "Canine Immune Mediated
Hemolytic Anemia." Clinician's Brief (2012): 53-61
Kerl, Marie E., DVM, MPH, DACVECC, DACVIM. "Immunology." Technician Multidisciplinary Systems
Review. Proc. of International Veterinary Emergency and Critical Care Symposium, Tennessee, Nashville.
Nakamura, Reid K., Emily Tompkins, and Domenico Bianco. "Therapeutic Options for Immune-mediated
Thrombocytopenia." Journal of Veterinary Emergency and Critical Care 22.1 (2012): 59-71.
Spurlock, Nicole K., DVM, and Jennifer E. Prittie, DVM, DACVIM, DACVECC. "A Review of Current
Indications, Adverse Effects, and Administration Recommendations for Intravenous Immunoglobulins." Journal
of Veterinary Emergency and Critical Care 21.5 (2011): 471-83.
Viviano, Katrina R., PhD, DVM. "A Practical Approach to Immunosuppressive Therapies." A Practical Approach
to Immunosuppressive Therapies.
Whelan, Megan F., Therese E. O'Toole, Daniel L. Chan, Elizabeth A. Rozanski, Armelle M. Delaforcade, Sybil
L. Crawford, and Susan M. Cotter. "Use of Human Immunoglobulin in Addition to Glucocorticoids for the Initial
Treatment of Dogs with Immune-mediated Hemolytic Anemia." Journal of Veterinary Emergency and Critical
Care 19.2 (2009): 158-64.