Haemolysis Flashcards
Evidence for imaging screening in IMHA
ACVIM - low level of evidence for neoplasia as a trigger but dependent on individual case
AVJ 2020 - CXR had no findings of trigger, u/s 7.3% found trigger. This study followed assoc cases to confirm were weaned from meds within 6 weeks. Concluded low value in CXR but u/s can be useful.
JSAP 2022 - 50 IMHA dogs 20% had CXR abnormalities none relevant to anaemia; 50% had relevant u/s changes but unable to determine if truly causative or just incidental. Did not follow cases assigned as associative
JFMS 2016 - 35/10 cats were associative
ACVIM Criteria for IMHA Dx
Signs of immune mediated destruction: spherocytes, positive SAT or DAT or Flow
Signs of haemolysis: hyperbilirubinemia or bilirubinuria (and no liver/biliary dz); haemoglobinemia or haemoglobinuria; ghost cells
> 2 signs of IMD with haemolysis signs is consistent with IMHA
2 IMD signs without haemolysis or 1 of each is supportive of IMHA
1 IMD without other signs is suspicious
No IMD signs means it is not IMHA
Pathomechanisms for IMHA - known and hypothesised
Epitope unmasking
Molecular mimicry
Haptenisation
Superantigens
Occult/unrecognised: genetic/epigenetic factors; tolerance defects; microbiome influence; environment; transient infections
Accuracy of immunodiagnostics for IMHA
> 5 spherocytes/ 10hpf Sens 63%; Spec 95%
Not after transfusion
SAT - 40-100% Spec; 88% sensitivity at 1:4
Not after transfusion
DAT (Coombs) - Sens 61-82% dogs 82% cats; Spec 95-100% for both
Flow Cytometry Sens 87% sensitivity; 92% specificity. Quantitative results
Dont know effect of transfusion or immunosuppressives on DAT/SAT
CarboxyHgb - new test reported Sensitivity 96 and Specificity of 96% in pilot study. Used in humans.
Level of Evidence for haemolysis triggers
Neoplasia - low in dogs, low in cats though retrospective evidence suggests a relatively high prevalence of concurrent cancer in cats with IMHA.
Most studies do not assess if cancer was associated with IMHA or not nor look for a causal relationship
Vaccines - low, esp given wide practice of vaccinations and only retrospective series and conflicting results
Inflammatory disease - low in dogs, moderate in cats
(incl pancreatitis)
Infectious disease - moderate to high
Babesia gibsoni infections in dogs -high (Ab target host erythrocyte antigens exposed by infection). low to intermediate for other spp. (moderate in cats)
Anaplasma - low LoE but most studies not designed to investigate for this
Mycoplasma haemofelis in cats - high (low for others)
FeLV - low to moderate. Whether coinfection and host immune status play roles in development of IMHA in cats infected with different hemotropic Mycoplasma species requires further study.
FeLV - low LoE, difficult to evaluate because of other comorbidities.
Other tick borne infections - low
Other infections - low to moderate
Drugs - low LoE or underreported. mostly case reports
LoE for IMHA treatments
Prednisolone - moderate to high, about 80% of dogs respond to this single treatment
2nd line - low to moderate. no one drug better than others, JVIM 2022 retrospective series found no benefit of different combos between eachother or compared to pred alone but may have reduced risk of relapse.
Significant case selection bias in these studies with retrospective designs
IVIg - low evidence. recent JVIM paper found no benefit compared to pred alone (prospective but v low numbers). Carries risk of AEs as well. Prev studies were retrospective and thus had case selection bias. Recommended only if 2 Tx fail
Thromboprophylaxis - weak LoE overall but thrombosis is significant cause of mortality in IMHA so dual therapy is preferred over single and recent JVIM paper supported this (albeit barely) by reduced number of thrombotic events in dual Tx group compared to clopidogrel only.
See FATE study which showed synergistic effects of these medications.
ACVIM consensus on Tx timing, blood transfusions/ products
Start treatment once diagnostics complete unless this results in delay
Auto agglutination may interfere with test results for cross matching
pRBCs are recommended for IMHA as it is normovolaemic. Though no specific literature exists to suggest it is superior to WB. Avoid pRBC >7d old as these are associated with increased risk of haemolytic transfusion reactions
FFP is not recommended in IMHA treatment - based on human guidelines that use in non-haemorrhagic DIC patients has little if any benefit. There is also no evidence of benefit in the literature
ACVIM consensus on Immunosuppressive Tx in IMHA in dogs
- Start immunosuppressive doses of pred/dexamethasone at diagnosis
(Add 2nd line for GC sparing effect or signs suggestive of poor prognosis) - If after 7 days no response to Tx then re-evaluate for associative IMHA (if not done) and add 2nd immunosuppressive
- If still no response after 7 days check drug doses, compliance, GI absorption, diagnostic confidence
Then trial IVIg - After a further 7 days consider 3rd immunomodulatory drug or splenectomy
(evidence for 3rd drug is minimal as rarely will this improve response, and should avoid combination of aza and mycophenolate)
What is the LoE for different immunosuppressives in IMHA dogs
Pred - published lit reports 80% RR
Decrease to <2mg/kg/d within 2 weeks of starting
Mycophenolate
Cyclosporine
(Dose adjusted by therapeutic drug monitoring).
Azathioprine
Leflunomide
LoE for starting second drug being beneficial to survival is weak, there is significant case selection bias in retrospective studies available and prospective studies are lacking.
Likewise prospective studies comparing one 2nd line drug to another for outcome are also lacking, and available retrospective studies have not identified any correlation
When to start 2nd immunosuppressive in IMHA
- severe life threatening disease at presentation (increased T bili or Urea at presentation are negative Px indicators)
- PCV decreasing by >5% within 24h in the first 7 days (on GC)
- dependent on blood transfusions
- high risk of GC side effects
LoE for these recommendations is weak and based on clinical experience. 2 drugs from outset is recommended in severe cases due to possibility that some dogs will have insufficient response to single agent
Evidence for hIVIg in treatment of IMHA
As a salvage measure in dogs not responsive to 2 treatments.
While an attractive Tx option due to rapid onset of action, several studies have shown no benefit in comparison to current immunosuppressive regimens (various designs and risk of bias but all same conclusion). Efficacy and safety in dogs has not been established beyond 3 days of treatment
When should tapering of immunosuppressive drugs be started
When PCV has been >30% and stable for 2 weeks and with improvement of other measures of disease activity.
Can start with GC or the 2nd line treatment depending on case specifics and AEs occurring.
Typical treatment duration of 4-8 months for all immunosuppressives. Tapering every 3 weeks by 25% pred dose reduction - greater reduction or shorter intervals if good response or on 2nd line
Monitoring recommendations for immunosuppressive drugs
Aza - CBC and Bio fortnightly fdor 2 months then every 2 months on Tx
Cyclo - biochem every 2-3 months, clinical signs of GI disease or gingival hyperplasia
Monitoring with serum levels is not beneficial, but activity of the drug is with IL2 suppression assays is best
Myco - GI upset, CBC fortnightly for month then every 2 months
If myelosuppression occurs the causative drugs should be discontinued
ACVIM recommended relapse approach
- Confirm using IMHA criteria
Be aware some test results may be affected by use of immunosuppressive drugs - Reassess for any potential new trigger/emergence of undiagnosed old trigger especially emerging infection if patient is still on immunosuppression
- evaluate compliance, dose, TDM, whether drug being given with food/GI absorption
- increase back to previously effective dose if mild, if fulminant disease then back to immunosuppressive doses.
- Consider addition of 2nd line or use of hIVIg if not responding to dose increase of pred
- Once in remission again taper more slowly (doubling time)
- If recurrent relapses then life-long immunosuppression may be required (weak LoE, ensure vector borne disease is ruled out).
Splenectomy may be considered if infectious causes are excluded (retrospective case series report possible benefit, more recent JVIM retrospective series reported no benefit in IMHA)
True prevalence of IMHA relapse is not reported but based on previous publications is 10-15%.
Guidelines based on clinical reasoning.
Evidence for Thromboprophylaxis requirement in IMHA
Strong - unless Evan’s syndrome (or DIC related thrombocytopaenia)
Substantial evidence of association of IMHA with venous thrombosis which causes morbidity and mortality.
Combination of intravascular tissue factor, endothelial activation, platelet activation, inflammatory stimulation of procoagulant state.
GC and hIVIg may also increase risk of thrombosis
Continued until patient is in clinical remission and no longer receiving GC (latter part weak evidence as risk period seems to be first 2 weeks)
