CE Notes: CSU Veterinary Conference 2014
IMHA Review
Intravascular – complement mediated, uncommon with primary IMHA
Red cell intravascular lysis
This type of IMHA is generally more severe and difficult to treat
Free Hgb can damage kidneys
IMHA treatments are targeting macrophages in tissues, so animals with intravascular IMHA won’t respond as well to therapy
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Hemoglobinuria (port wine color), hemoglobinemia (pink serum)(won’t change color when spun down)
Extravascular – phagocytosis by macrophages in spleen and liver, much more common
Tend to be easier to treat
Have elevated bilirubin from Hgb breakdown, not free Hgb
Hemolysis can occur in spleen, liver, bone marrow or lung (one reason why splenectomy is not always effective – because hemolysis will still occur in other tissues)
Jaundice, hyperbilirubinemia, hyperbilirubinuria
Canine IMHA –
Dogs can have intra and extra vascular hemolysis simultaneously or convert from one form to another
Differentials for hemolysis in the dog: immune mediated, erythroparasites
(babesia), microangiopathic hemolysis, Heinz body anemia, zinc induced, inherited defects (Basenjis)
Feline IMHA –
Differentials for hemolysis in the cat: FeLV, Mycoplasma haemofelis, hypophosphatemia, Heinz body anemia, IMHA (usually secondary; primary is extremely rare)
Secondary IMHA – consider infection, medications (TMS, thyroid meds), neoplasia, vaccines
IMHA general points –
IMHA generally causes anemia without hypovolemia or hypoproteinemia
Can occur without jaundice, hemoglobinemia/uria
Mild to moderate to severe anemia without jaundice is common unless there is concurrent liver disease (liver can usually process the bilirubin)
PCV <20% tends to cause hemic murmur
Tissue hypoxia triggers sympathetic nervous system
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bounding pulses, tachycardia, tachypnea, mental dullness; if pulses are weak (consider blood loss over IMHA)
IMHA
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massive inflammatory disease
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splenomegaly, hepatomegaly, fever, anorexia, mild lymphadenopathy (20-25% of cases), leukocytosis
Next to leukemia, IMHA has the highest level of leukocytosis
IMHA complications –
80% that go to post mortem have PTE
development of dyspnea in IMHA patient is nearly always due to PTE

DIC is rare – low platelets are usually due to embolism or immune destruction; bloodwork parameters seen with embolism often mirror that seen with DIC
May suddenly develop ascites – generally due to vasculitis or PTE
IMHA diagnosis –
Regenerative anemia usually (unless early, regeneration takes 3-5 days)
Normal blood volume and serum protein
Sometimes spherocytes (negative for many IMHA cases), bilirubinemia
Spherocytes generally equal immune mediated disease; very rarely seen with snake bites and zinc toxicity
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IMHA can be non regenerative, either because it’s early or bone marrow is affected (affected bone marrow is more common with primary IMHA); up to 1 in
3 IMHA patients have a poor retic count
Pure red cell aplasia – may be only in the marrow with no evidence of peripheral hemolysis
Aplastic anemia – all cell lines affected
Saline agglutination test – this test should not be run with cold blood or cold saline (cold temperature can cause agglutaination or hemolysis)
Severe agglutinating IMHA (like intravascular IMHA) is harder to treat and carries a worse prognosis – fortunately both of these types are relatively uncommon
IMHA workup –
CBC with smear to evaluate for spherocytes (in dogs), parasites, Heinz bodies, schistocytes, retic count
Evaluate smear immediately for parasites (all cats should be treated with doxy; infectious is very rare in the dog, but chance increases depending on geographic region, if splenectomized, and if grey hound or pit bull)
Slide agglutination - 1 drop EDTA red blood cells + 1 drop room temperature saline in dogs (use 3-4 drops in cats)
If (-) for slide agglutination, cannot rule out IMHA
Coombs test – quality of the test varies greatly, only run if really unsure of diagnosis (if positive, most likely IMHA; if negative, you cannot r/o IMHA)
Bad cases of IMHA will usually have elevated ALT due to ischemic injury to the liver (rather than primary liver disease)
Further testing – imaging (screen for neoplasia, other), retrovirus (cats), rickettsia/protozoal (dogs), coagulation testing
Patients that are <1 year of age, >8 years of age, or feline should receive a more thorough workup
IMTP Review
General notes
In dogs, IMTP is the most common acquired bleeding disorder
Dogs – IMTP is usually primary; secondary causes are similar to list for IMHA, with Rickettsial disease being higher on the list
Cats – IMTP is usually secondary (infectious, lymphoma)
Antibodies bind to the platelet surface, so platelet function is affected in addition to platelet count; lifespan of a platelet in IMTP is 1-2 hours (vs 1 week for normal platelet lifespan)
Spectrum of disease: o Classic IMTP

o Megakaryocyte aplasia (don’t respond well to treatment; diagnosis via bone marrow) (usually other cell lines are affected as well; but rarely only the megakaryocytes are affected) o Compensated thrombocytolysis (eg platelet count is at 100,000, no bleeding; have immune disease but patient is compensating) o Platelet dysfunction (bleed with okay platelet numbers)
Clinical signs: petechia, ecchymosis, gingival bleeding, hematemesis, hematuria, epistaxis, melena, hematachezia
Patients can still clot – can see significant urinary tract clots
Most common cause of death: 1. hypovlemic shock due to GI hemorrhage, 2. intracranial hemorrhage
Causes of platelet destruction – immune mediated, infectious (RMSF, babesia,
Ehrlichiosis (but usually not severe thrombocytopenia)), DIC
Evaluation of thrombocytopenia
Always look at a smear – CBC can falsely decrease counts (giant platelets are counted as rbc or lymphs and clumped platelets aren’t counted), especially in cats
Very few things can falsely elevate the platelet count on CBC
Estimate off a smear – normal is 10-30 plt/hpf
Each platelet per hpf is equivalent to a circulating platelet count of 15-20 x 10
9
/L
Cavaliers have macrothrombocytes and can have pseudothrombocytopenia (with a falsely elevated lymph count); reported rarely in other breeds
Diagnostic approach
First tier: CBC, Chem, Coags, d dimmers, Rickettsial serology +/- babesia
Second tier: imaging, retroviral serology (cats), bone marrow
Confirmatory tests – only useful one is the platelet-bound antibody levels offered at Kansas State, but offered intermittently
Consider secondary causes if not responding to treatment, <1 yr, >8 yrs of age, or cat
Immune Mediated Polyarthritis
General info
Usually very pred responsive
In dogs, estimate that >80-90% of polyarthritis cases are immune mediated o Non erosive is much more common; estimate <1% are erosive o Estimate that <10-20% of cases are infectious (depends on geographic region) (E. canis, Lyme)
In cats, infectious causes are much more common and erosive lesions are more common
Presentation: the most common presenting complaint is fever; often these patients do not have lameness; however, you may detect joint effusion; Without swelling or lameness, the only clinical sign may be decreased range of motion;
Polyarthritis is a very commonly missed cause in FUO cases
Carpi and tarsi most affected
Diagnostics:
CBC
Chem with CK (can have syndrome with polyarthritis and polymyositis together)
UA with urine culture
SNAP test – heartworm, Lyme Rickettsial

Retroviral testing in cats (foamy virus in cats can cause polyarthritis and is often picked up on FeLV/FIV snap)
Predictable results:
Inflammatory or stress leukogram
Anemia of chronic disease
Mild hypoalbuminemia (negative acute phase protein)
Mild to marked hyperglobulinemia
Mature neutrophilia is common
R/O – Hepatozoon (muscle pain, some bone pain, polyarthritis)
Further diagnostics, recommend tapping:
2 small joints (carpi) – most commonly affected with immune mediated disease
And 2 large joints (stifles) – most commonly affected with infectious disease o If large joints are inflamed with normal small joints – immune mediated disease is very unlikely
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Plus any joint that’s swollen o If only one joint is inflamed – usually infectious
Cytology can look the same in non-erosive IMP, erosive IMP or infectious
(healthy neutrophils); vs degenerative joint disease (mononuclear cells)
Culture – generally low yield; highest yield if collected in blood culture tube rather than a swab
Etiologies
Type I – uncomplicated, no underlying disease, most common
Type II – Reactive, formed immune complexes elsewhere, ie Lupus, Lepto,
Lyme, heartworm, Rickettsial disease, Bartonella, endocarditis
Type III – Enteropathic, formed immune complexes elsewhere, ie IBD, parvo, pancreatitis, food allergy, leaky bowel (showering antigen)
Type IV – neoplasia
Can also see secondary to drugs, especially TMS
Additional notes:
Concurrent neck pain
1 in 3 patients with IMP has cervical pain
Consider a sterile meningitis concurrent with IMP – the meningitis will respond to steroid therapy
R/O discospondylitis, which can shower bacteria to the joints
Erosive polyarthritis
Most common in small, middle-aged dogs
Additional diagnostic tests:
Rheumatoid factor – rarely useful; recommended for cases with polyarthritis, erosive, and negative for infection
ANA – test for ANA only when SLE is possible diagnosis
Run when multiple systems are affected by immune mediated disease
Urine culture – in infectious polyarthritis, urine culture is the most likely culture that will be positive
Infectious vs Immune Mediated (Lappin notes)
Cats: if develop hemolytic anemia post bite wound, consider FIV and hemoplasmosis (Mycoplasma haemofelis)
Hemoplasmosis: transmission through direct contact (cat fights), sick within 17 days, treat with doxycycline (10 mg/kg q24h for 7-28 days), life threatening cases or rescue cases treat with Baytril; up to 50% falsely negative on cytology
(especially if not immediately reviewed)

Pradofloxacin is an option for cats with better ocular safety than Baytril (7.5 mg/kg q24h) up to 28 days
Immune Complex disease
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affects joints, eyes, kidneys (do an antigen search)
Uveitis and lameness in cats:
immune mediated disease, FIP, FeLV (uveitis is usually due to lymphoma), FIV,
Ehrilichia, T. gondii, C. neoformans, Bartonella henselae, FHV1
If they have uveitis without conjunctivitis – give pred
Best toxoplasmosis screening tool: IgG and IgM o PCR is NOT recommended – costs more money and healthy animals can be (+); save PCR for BAL and CSF testing o Serology is especially useful if negative to rule out disease
In general, when struggling whether disease is infectious vs immune mediated, treating with pred is advised UNLESS you’re suspicious of lepto, septic, bacterial endocarditis or protozoal infection (Neospora worsens dramatically with steroids) o RMSF, lepto and sepsis can have a similar presentation – treat with doxy, Baytril
+/- ampicillin o Most common causes of bacterial endocarditis: staphs, streps, E coli and
Bartonella
Immune Mediated Blood Disorders: Emergency Management
Mortality rates:
Usually low for IMTP
Around 50% for IMHA
Poorer if IMHA + IMTP
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½ pass during initial episode due to anemia, hypovolemia, PTE*
Treatment aims:
Remove underlying cause if secondary
Immunosuppressive therapy
Transfusion
Other (see below)
Immunosuppressive therapy:
Steroids
+/- azathioprine, cyclosporine
Chlorambucil – effective in cats
Leflunomide – IMP in dogs
Steroids
Prednisone: recommend 2 mg/kg per day orally
>2 mg/kg/day is NOT more immunosuppressive and not recommended
Can go up to 2 mg/kg BID in cats
Dexamethasone: recommend 0.1-0.6 mg/kg once daily
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No evidence that it’s better than prednisone
However, occasionally patients respond differently to different steroids, so may want to try dex if not responding well to pred
Also useful if vomiting and needing an IV drug
When to add a second agent:
Prednisone takes 7-10 days to take effect
Other agents take 1-2 weeks to take effect

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Recommend a second agent if there’s bad disease, eg severe anemia, severe thrombocytopenia, transfusion dependent, intravascular hemolysis, hypovolemia, strong agglutination
If mild disease, recommend using prednisone as sole therapy
Management:
Minimize trauma – don’t place catheter unless necessary (IMHA), don’t over monitor bloodwork, use small needles, etc
Transfusion – see below
Fluid therapy
Not recommended with IMHA; remove catheters after transfusion, usually these patients don’t need fluids
Exception is patients with intravascular hemolysis where Hgb is causing kidney injury or bad ischemic injury (elevated ALT)
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IMTP: recommend maintaining a catheter so you’re ready to bolus fluids if there’s a large bleed; hypovolemic shock is usually what leads to death
Oxygen therapy
Hgb is already saturated – usually need more Hgb, not oxygen
Exception is PTE – need oxygen support
Vincristine – useful for IMT
Platelet survival time increases from 1 hour to 1 day
Also have a transient surge in platelet release from the bone marrow
Tends to decrease hospitalization time (3 days with vincristine vs 5 days with pred alone)
Liposomal clodronate –
Knock out monocytes and macrophages, which ingest lipid
Used for histiocytic disease
Can be useful for IMHA if nonresponsive to typical therapy
Very expensive (eg $1600 for greyhound), very limited availability
IV immunoglobulin
Concern that pro-thromboembolic, avoid with IMHA
Have had individual positive results with IMTP; however, IV immunoglobulin tends to have similar result to vincristine (out of hospital in 3 days vs 5) but immunoglobulin is much more expensive
Splenectomy
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Patient often isn’t stable enough for surgery
Sometimes the MPS elsewhere in the body (liver) may take over for spleen
Transfusion guidelines – be conservative
Recommend waiting until PCV is 10-15% for acute disease or 8-12% for chronic disease, or extreme lethargy
IMHA – reach for pRBCs and avoid plasma
IMTP – fresh whole blood, need plasma and volume
In 2 nd week of therapy, only use universal donor blood
PTE prevention
Avoid risk factors (IVIG, jug caths)
Cyclosporine may increase risk of PTE – avoid with IMHA
Heparin therapy –
Difficult to dose; best to titrate based on antifactor Xa activity
LMWH (enoxaparin) is recommended at standard dose: 0.8 – 1.0 mg/kg
SC QID (often reduce to BID)
Recommend aspirin and plavix
Aspirin: 1 mg/kg once daily

And/or plavix: 1-3 mg/kg daily if solo, or 0.5-1 mg/kg daily if in combination with aspirin
Recommend plavix and aspirin for 1 month
Immunosuppresive Agents
Glucocorticoids
Starting dose: 2 mg/kg/day in dogs, 2 mg/kg BID in cats o Cats tolerate high doses of steroids much better than dogs, although possibly increases risk of diabetes (reversible if caught early)
Aim for a maintenance dose of 0.5 to 1 mg/kg every other day
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this dose is tolerated longterm; otherwise, add a second agent
Cyclophosphamide
Not Recommended – non specific (affects many cell types), not very potent in dogs
Side effects – myelosuppression (dose dependent and cumulative), GI disease, alopecia, refractory cystitis or bladder neoplasia** (breakdown product is very irritating to bladder; could use with Lasix, encourage drinking)
Recheck CBC two weeks after starting, then monthly
Very inexpensive
Chlorambucil
Indicated for IBD in combo with pred
Tablet size makes it convenient for cats
Only recently being used more in dogs
Same side effects as cyclophosphamide, except no cystitis; also, occasionally in cats it can cause neurologic signs
Very expensive
Azathioprine
Little cheaper and usually well tolerated; good choice in larger dogs
Works in about 1 week
Dosing in cats – need much lower dose in cats; has a low margin of safety and generally not recommended (we have much better and safer options)
Dog side effects: decreased rbc production (normal PCV 28-32), myelosuppresion, hepatotoxicity, pancreatitis; myelosuppression and hepatotoxicity can be severe and reversible, tend to be idiosyncratic reactions rather than dose dependent; severe side effects are rare and will usually occur within the first week of therapy
Check CBC and Chem at 2 weeks
Once in remission, begin to taper either the pred or azathioprine (whichever is causing more side effects) every two weeks; monitor response prior to each dose reduction; once at an acceptable maintenance dose, continue therapy for 6-12 months; prefer partial resolution of disease over side effects
Give all therapies two weeks before deciding that they’re not working
Cyclosporine
Recommended for nonregenerative IMHA
There is great variability from dog to dog in what dose is needed to achieve immunosuppression; it’s primary function is to inhibit T cell function; an assay at
Mississippi State has been developed to measure T cell IL2 so that you can target the dose
Use in combo with Ketoconazole – turns off P450 system, may use lower dose of
Atopica

Side effects: nausea* (freeze; better to give without food), gingival hyperplasia
(may improve with oral rinse or clindamycin, or may need to discontinue), hepatotoxicity/nephrotoxicity (idiosyncratic), not myelosuppressive
**predisposes to thromboembolism – not recommended in IMHA (unless occurring at level of the bone marrow) o Cyclosporine turns on platelets and enhances procoagulant activity; increases thromboxane in humans (marker of platelet activation)
Do not use compounded, however liquid formulation of Atopica is good; great agent for cats
Also a great drug for IBD
Leflunomide
Recommended for polyarthritis
Can affect marrow and cause hepatotoxicity
Mycophenylate
Never use in combination with azathioprine (same mechanism of action)
Used as an alternative to azathioprine if patient has developed hepatotoxicity
Not recommended over azathioprine for IMHA
Can cause severe GI side effects
Transfusion Medicine
Notes:
2,3 DPG depleted in stored blood; not as effective at unloading oxygen
Oxyglobin: causes vasoconstriction because of NO scavenging; can really decrease cardiac output; really useful if pathologic vasodilation, like with heat stroke or sepsis
Plasma transfusions: only if elevated PT/aPTT and bleeding
FLUTD
Etiology
Idiopathic cystitis 63%
Urolithiasis 10%
UTI 12% (older cat population; rarely the cause in younger cats)
Interstitial cystitis
Urine is usually highly concentrated, sometimes very acidic, often hemorrhagic, wide range in wbc count, pyuria identified in 3-77% of cases but not usually due to infection, crystalluria 25-48%
Etiology: infectious agents <2% of cases, leaky urothelium, mast cell activation, neurogenic inflammation, stress
1 st time offenders: recommend UA +/- culture, radiograph to rule out stones
Repeat offenders: UA, culture, ultrasound
Treatment
**rate of reobstruction is 2.5x greater with use of 5 Fr catheter vs 3.5 Fr; recommend 3.5 Fr and try to pull urinary catheter within 36 hrs max
Topical glucosaminoglycans: empty bladder, administer 2.5 mls A-CYST; perform 3 times over initial 24 hours; occlude the catheter for 1 hour following treatment
Alpha adrenergic antagonists (prazosin, phenoxybenzamine) – prazosin is 1 st choice
Steroids probably not helpful

NSAIDs – anectodal evidence that NSAIDs are helpful, but no documented evidence of improved outcome
Opioids recommended
Chronic treatment
Glycosaminoglycans
Amitriptyline, decreases detrusor activity, decreased His release, antispasmotic, anti-inflammatory activity, analgesia; no evidence that it improves outcome in the short term
Canned food
Parvo Outpatient therapy
Anti-emetic therapy
Cerenia, recommended if > 8 weeks old
Can be used up to 14 days safely; will go out for more than 5 days in parvo patients if needed
Zofran, for young patients or patients needing an additional antiemetic on top of
Cerenia
0.5 mg/kg IV TID
Cerenia IV dosing
Causes a transient decrease in blood pressure and nausea if given too quickly
Decreases the drug’s half life in half (may have break through vomiting toward the end of the 24 hour period)
Antibiotics
Recommend cefoxitin at 22 mg/kg TID if hospitalized
Cefovecin 8 mg/kg SQ if outpatient
Feeding
Hold food for 12 hours, then begin force feeding if outpatient or place feeding tube
Syringe feeding: 1 ml/kg PO QID a/d
Analgesia – buprenex IV or SQ
Tips for successful outpatient protocol:
Need to stabilize with shock IV fluids before transferring to outpatient (even if only hospitalized for 1-2 hours for bolus)
Aim for 120 ml/kg/day Norm R – 40 ml/kg TID unless not absorbing it
Replace dehydration over 24 hours + losses
Recommend measuring lytes and glucose daily
*have owners monitor temp at home and maintain patient >99 o
using heat support, or they will never absorb their sub q fluids
Treat hypoglycemia if <80; if outpatient, administer 1-5 ml Karo syrup bucally q
4-6 hours
Potassium support for outpatient protocol: 0.5 – 1 t/10 lbs Tumil K q 4-6 hrs
Arterial thromboembolism
Notes
About 50% of patients are in CHF on presentation with ATE
Difficult to distinguish tachypnea due to CHF vs pain
Often start Lasix, even if cant get radiographs

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Recommend echo (though not an emergency), to ensure there isn’t still a thrombus in the left atrium that will cause an additional event (in this case, want to use a thrombolytic agent)
Thrombolytic therapy
TPA – more effective on fresh thrombus; less effective by 12-24 hr
Does not improve overall survival rate
High incidence of reperfusion injury
Anticoagulant therapy
Preventing extension of a clot
Heparin, unfractionated
Not recommended, dose is too variable; need to monitor effect via aPTT
LMWH
Dosed by body weight
We do not know ideal frequency but generally done BID, one study recommended TID dosing
Warfarin
Oral anticoagulant in people
Need to monitor PT very closely and highly dependent on diet and other meds
Very challenging to use
Dabaqatrin and apixaban – oral form, don’t have the diet and med variability seen with warfarin; less monitoring required; on going study at CSU
Antiplatelet therapy
Prevent extension of thrombus
Aspirin
Plavix 18.75 mg/cat daily
Longer time to recurrence when treated with Plavix vs aspirin
Prognosis
Poor prognostic factors: both rear limbs affected, severe pain, hypothermic, no motor function, CHF
Treatment recommendations
Powerful opioid, methadone recommended; buprenex is not potent enough
Oxygen, lasix +/- radiographs
Plavix +/- aspirin +/- LMWH
Outcome
Survival to discharge 35-45%
65% of treated cats died/euthanized within 24 hours
12% survival beyond 7 days