VCS80610_IMHA_2023.pptx
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Canine ImmuneMediated Hemolytic Anemia VCS 80610 Fall 2023 Andrew Woolcock, DVM, DACVIM Purdue University College of Veterinary Medicine Murphy Presenting Complaint: Profound lethargy and a collapse episode 4 yo MN Miniatu re Poodle www.dogcare.com Physical Exam • • • • • • • • All the hits: C...
Canine ImmuneMediated Hemolytic Anemia VCS 80610 Fall 2023 Andrew Woolcock, DVM, DACVIM Purdue University College of Veterinary Medicine Murphy Presenting Complaint: Profound lethargy and a collapse episode 4 yo MN Miniatu re Poodle www.dogcare.com Physical Exam • • • • • • • • All the hits: Collapse Lethargy Pale/Slightly Icteric Mucous Membranes Icteric sclera Tachycardia (HR 180 bpm) Tachypnea (RR 60 breaths/min) Grade II/VI left systolic murmur www.dogcare.com Initial triage diagnostics PCV/TS = 11%/6.8 g/dL IMHA Demographics DOGS > CATS Cocker Spaniels Female Middle-Aged (Median 6Y) Majority of cases are Primary/Idiopathic Secondary Refers to an external trigger IMHA Demographics FELINE IMHA DOGS > CATS Cocker Spaniels Female Middle-Aged (Median 6y) Main Secondary Causes FeLV Mycoplasma haemofelis Lymphoma Observed less frequently than dogs Median age 2 years Slight male predisposition 50% non-regenerative Spherocytes difficult to identify Secondary cause more often identified than in dogs (Idiopathic is a diagnosis of EXCLUSION) Confirming Diagnosis DIOPATHIC MMUNE-MEDIATED HEMOLYTIC ANEMIA WORK BACK WARDS Confirming the Diagnosis ANEMIA HEMOLYTIC MMUNE-MEDIATED DIOPATHIC Confirming the Diagnosis ANEMIA HEMOLYTIC MMUNE-MEDIATED DIOPATHIC PCV/TS = 11%/6.8 g/dL Confirming the Diagnosis nemia HEMOLYTIC uto-antibodies econdary causes Confirming the Diagnosis Extravascular nemia HEMOLYTIC Intravascular Innate uto-antibodies Complement econdary causes Adaptive Antibody Confirming the Diagnosis nemia HEMOLYTIC Clinically: Pigment changes uto-antibodies and/or cell morphology econdary causes Morphologic Changes - Spherocytes Y Y Y Y Y Y Y Y Y Y U Y Y Y Y Y Y Y Morphologic Changes – Ghost Cells https://vetclinpathimages.files.wordpress.com/2018/03/ghost-cells-1-equine-1-imha-arrows.png? Morphologic Changes - Schistocytes MICROANGIOPATHIC **Not technically immunemediated Heartworm disease Vasculitis (RMSF, e.g.) Certain tumors (hemangiosarcoma) Confirming the Diagnosis • Confirming diagnosis - CRITERIA nemia HEMOLYTIC SITE OF HEMOLYSIS EXTRAVASCUL INTRAVASCU AR LAR uto-antibodies PIGMENTEMIA/ BILIRUBIN HEMOGLOBIN MORPHOLOGIC SPHEROCYTE econdary causes GHOST CELL URIA CHANGE Confirming Diagnosis ANEMIA HEMOLYTIC MMUNE-MEDIATED DIOPATHIC Confirming the Diagnosis MMUNE-MEDIATED Y Y YY Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Auto-antibodies Y Autoagglutination Present in ~1/3 of cases Positive Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Autoagglutination Y Negative Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Auto-antibodies Y Coombs’ Test Indicated if NOT auto-agglutinating Auto-antibodies Y YY .Y . . Y. Y Coombs’ Test Addition of antiserum (Anti-IgG, Anti-IgM, AntiC3) Auto-antibodies Y Y Y Y Y Coombs’ Test Addition of antiserum (Anti-IgG, Anti-IgM, AntiC3) Auto-antibodies Y Y Y Y Y Coombs’ Test Addition of antiserum (Anti-IgG, Anti-IgM, AntiC3) False Negatives Insufficient antibodies False Positives Recent transfusion Other inflammatory disease Confirming the Diagnosis ANEMIA HEMOLYTIC MMUNE-MEDIATED DIOPATHIC Proving IDIOPATHIC IDIOPATHI To rule out all Cpossible DIAGNOSTIC PLAN causes…do I test for all possible causes? How to prioritize? CBC with Reticulocytes Chemistry Profile Urinalysis Thoracic and Abdominal Imaging Infectious Disease Testing etc etc… Approach to Secondary Causes LEVEL OF CLINICAL SUSPICION (LOCS) Infection Neoplasia Toxicity Vaccine Drug Rxn Approach to Secondary Causes Infection Neoplasia Toxicity Vaccine Drug Rxn LEVEL OF CLINICAL SUSPICION (LOCS) Important premises: • Not every vector-borne disease has been associated with IMHA • The SNAP 4DX does not test for all infections which have been associated with IMHA Infection • Infectious Disease Causing IMHA www.idexx.com Infection • Infectious Disease Causing IMHA Cytauxzoon felis Mycoplasma haemofelis Babesia gibsonii www.eclinpath.com Approach to Secondary Causes Infection Neoplasia Toxicity Vaccine Drug Rxn LEVEL OF CLINICAL SUSPICION (LOCS) RISK FACTORS: • Tick exposure 0 • Lack of No risk preventives • Environmental factor exposure s • PE concern (e.g. LN) • Regional or breed risk 1 1 risk factor 2 >2 risk factor s Approach to Secondary Causes Neoplasia Infection Toxicity Vaccine Drug Rxn LOCS Diagnostics Approach 0 1 2 No infectious disease testing, or minimal (e.g. blood smear and SNAP 4DX) Blood smear and SNAP 4DX, or disease-specific testing (e.g. Babesia) Comprehens ive infectious disease testing Approach to Secondary Causes Infection Neoplasia Toxicity Vaccine Drug Rxn LOCS Treatment Approach • If infection is suspected but finances won’t allow any testing OR if infection is suspected and tests are pending: • DOXYCYCLINE 10 mg/kg/day • Treat for 28 days OR until you receive negative test results Approach to Secondary Causes Infection Neoplasia Toxicity Vaccine Drug Rxn LEVEL OF CLINICAL SUSPICION (LOCS) • LYMPHOMA and LEUKEMIA could incite an inappropriate immune response and this disease may look like traditional IMHA • If in the bone marrow, anemia more likely to be nonregenerative • HISTIOCYTIC SARCOMA can cause HEMOPHAGOCYTIC SYNDROME, a process in the spleen leading to EXTRAVASCULAR hemolysis. • HEMANGIOSARCOMA are tumors originating from vascular endothelium and can lead to abnormal, Approach to Secondary Causes Infection Neoplasia Toxicity Vaccine Drug Rxn LEVEL OF CLINICAL SUSPICION (LOCS) RISK FACTORS: • Age > 8 years • PE concern (LN, organomegaly) • CBC concern (blasts, schistocytes) • Chem concern (hypercalcemia, hypoalbuminemia, hypocholesterolemia) 0 No risk factor s 1 1 risk factor 2 >2 risk factor s Approach to Secondary Causes Infection Neoplasia Toxicity Vaccine Drug Rxn LOCS Diagnostics Approach 0 1 None, or just thoracic/abdom inal radiographs LN aspirate (if applicable); thx/abd rads +/- FNA 2 Advanced imaging with FNA of lymphoid structures +/bone marrow Approach to Secondary Causes Infection Neoplasia Toxicity Vaccine Drug Rxn • ONIONS OR GARLIC • Toxic dose unknown but can be cumulative • Remind owners that ONION or GARLIC powder are dangerous as well • Causes OXIDATIVE DAMAGE HEINZ BODIES • HEAVY METALS • Zinc most common, but copper and iron have been reported Approach to Secondary Causes Infection Neoplasia Toxicity Vaccine Drug Rxn LEVEL OF CLINICAL SUSPICION (LOCS) RISK FACTORS: • Witnessed ingestion • History of dietary indiscretion • Intravascular hemolysis • Heinz bodies on blood smear 0 No risk factor s 1 >1 risk factor Approach to Secondary Causes Infection Neoplasia Toxicity Vaccine Drug Rxn LOCS Diagnostics Approach 0 1 None Blood smear if not performed already; Thoracic and abdominal radiographs Approach to Secondary Causes Infection Neoplasia Toxicity Drug Rxn Vaccine LOCS Treatment Approach • Onion/garlic – supportive care, pRBC if needed, antioxidants (e.g. Denamarin/Denosyl, Nacetylcysteine) • Heavy metal – remove FB if present; consider chelation if hemolysis is severe Approach to Secondary Causes Infection Neoplasia Toxicity Vaccine Drug Rxn LEVEL OF CLINICAL SUSPICION (LOCS) RISK FACTORS: • History of vaccine reaction • Vaccination in the last 30 days 0 No risk factor s 1 >1 risk factor Approach to Secondary Causes Infection Neoplasia Toxicity Vaccine Drug Rxn LEVEL OF CLINICAL LOCS Approach SUSPICION (LOCS) RISK FACTORS: 0 1 • History of vaccine reaction 0 1 Contact vaccine • Vaccination in the last 30 No >1 manufacturer and days risk None risk report possible adverse factor reaction;sTreat like afactor typical IMHA Approach to Secondary Causes Infection Neoplasia Toxicity Vaccine Drug Rxn LEVEL LOCS OF CLINICAL Future Vaccination? SUSPICION (LOCS) RISK FACTORS: 1 • History of vaccine reaction Depending on client’s risk aversion: 0 • Vaccination • Could avoid in thefuture last 30vaccinesNo days • Perform titers (Distemper, risk Parvo) to factor determine need s stagger • Pre-treat (anti-histamine) and vaccines (2 weeks) 1 >1 risk factor Approach to Secondary Causes Infection Neoplasia Toxicity Vaccine Drug Rxn • Only the antibiotics are medications that the CLIENTS are likely to have at their home which could have been ingested in appropriately. The others are likely to be medications that YOU or another veterinarian have prescribed, so a HISTORY and review of the MEDICAL RECORD is key to investigate this association. Antibioti Methimaz Penicill cs: TMS ole in Toxicity RARE Famotidin Cephalospori Toxicity other e ns when given thanFelinePARENTERAL Propof TMS only LY toxins ol Chemo Approach to Secondary Causes Infection Neoplasia Toxicity • For Murphy: • No environmental exposure, but owners aren’t sure if they’ve remembered his monthly preventives consistently. Elect to pursue a SNAP 4DX (negative) • Up to date on all vaccinations, none within 30 days • Does chew on things he should not, so thoracic and abdominal radiographs pursued (negative) • No recent prescriptions and none in the home • No LN or organomegaly noted • Presumptive for IDIOPATHIC disease Vaccine Drug Rxn Confirming the Diagnosis ANEMIA HEMOLYTIC MMUNE-MEDIATED DIOPATHIC Therapeutic Goals • Improve red blood cell mass and oxygen carrying capacity • Minimize impact of pigment on target organs • Mitigate risk of thromboembolic disease • Suppress immune system – Factors to determine balanced approach – Therapeutic vs adverse effects Therapeutic Goals Treat Seconda ry Cause (?) Blood Product Other Support Thromboprophylaxis ImmuneSuppressio n • Discussed previously based on level of clinical suspicion Therapeutic Goals Treat Seconda ry Cause (?) Blood Product Other Support Thromboprophylaxis ImmuneSuppressio n • Blood transfusions not given based on the RBC or Hct, but rather on the identification of clinical compensation OR decompensation due to anemia c and decreased DO2 • E.g. tachycardia, tachypnea, collapse, arrhythmia Therapeutic Goals Treat Seconda ry Cause (?) Blood Product Other Support Thromboprophylaxis ImmuneSuppressio n • Product PACKED RBC or FRESH WHOLE BLOOD • First transfusion? No need to cross-match, but beyond this cross-match is necessary to determine viable donor • Cross-match Incompatible result determined by agglutination, so if patient is auto-agglutinating, cross-match may not be possible. Therapeutic Goals Treat Seconda ry Cause (?) Blood Product Other Support Thromboprophylaxis • Pigment accumulation can increase risk for organ damage including: • Pigment nephropathy • Hemoglobin • Kernicterus • Bilirubin encephalopathy ImmuneSuppressio n Therapeutic Goals Treat Seconda ry Cause (?) Blood Product Other Support Thromboprophylaxis • IV fluid support • Therapeutic plasma exchange • Francey et al JVIM 2021 • Culler et al JVECC 2022 • Safe and effective • Refractory cases • Similar outcomes as medical mgt ImmuneSuppressio n Therapeutic Goals Treat Seconda ry Cause (?) Blood Product Other Support Thromboprophylaxis ImmuneSuppressio n • IMHA associated with a HYPERCOAGULABLE state. • High risk for pulmonary thromboembolism (among others) • Leading cause of (natural) death in canine IMHA Therapeutic Goals Treat Seconda ry Cause (?) Blood Product Other Support Thromboprophylaxis ImmuneSuppressio n • Venous thromboemboli form in low-shear systems, and are attribute more to abnormalities in the coagulation cascade • ANTICOAGULANTS (Heparin, Rivaroxaban) • Arterial thromboemboli form in high-shear systems, and are attributed more to platelet hyper-reactivity • PLATELET INHIBITORS (Aspirin, Clopidogrel) Therapeutic Goals Treat Seconda ry Cause (?) Blood Product A number of different protocols have been utilized: Thromboprophylaxis Other Support ImmuneSuppressio n Rivaroxaban Aspirin and heparin Ultra-low dose aspirin Individually adjusted unfractionated heparin dosing Fixed-rate unfractionated heparin dosing Clopidrogrel and heparin Clopidrogrel and aspirin Clopidogrel Low-molecular weight heparin Therapeutic Goals Treat Seconda ry Cause (?) Blood Product Other Support Thromboprophylaxis ImmuneSuppressio n Consider • Practical approach • IMHA with NO evidence of a TE Rivaroxaban, though still cost • Start a platelet inhibitor prohibitive • Clopidogrel > Aspirin • IMHA WITH evidence of a TE • Start both a platelet inhibitor and anticoagulant • LMWH + Clopidogrel/Aspirin Therapeutic Goals Treat Seconda ry Cause (?) Blood Product Other Support Thromboprophylaxis ImmuneSuppressio n • CORTICOSTEROIDS are still the mainstay of immune-suppressive therapy • Broad immune-suppressive properties • Onset of action within 3-7 days • Multiple formulations • Evidence-based https://www.chemspider.com/ImagesHandler.ashx?id=5551&w=250&h= Therapeutic Goals Treat Seconda ry Cause (?) Blood Product Other Support Thromboprophylaxis ImmuneSuppressio n • Adjunctive immune-suppressive agents Azathioprine Cyclosporine Mycophenolat e Therapeutic Goals Treat Seconda ry Cause (?) Blood Product Other Support Thromboprophylaxis • Adjunctive immune-suppressive agent – • How to choose? • Balance • Therapeutic indication • Medication risks • Cost ImmuneSuppressio n Therapeutic Goals Treat Seconda ry Cause (?) Blood Product Other Support Thromboprophylaxis ImmuneSuppressio n • Indications for an adjunctive immune-suppressive agent: • 1. Severe steroid side effects • QoL (pet or owner) • Extreme (diabetes, calcinosis • Sri-Jayantha cutis, recurrent et al, CVJ infections) 2022 • Risk of muscle atrophy • Maxbreed • Large Dose dog 60 and polyphagia increase • Pred-dose mg/dog “ceiling” • 50 mg/m2 per day by 30% per 5kg of additional body weight Therapeutic Goals Treat Seconda ry Cause (?) Blood Product Other Support Thromboprophylaxis ImmuneSuppressio n • Indications for an adjunctive immune-suppressive agent: • 2. Multiple transfusions needed within the first 48 hours of therapy • Relative measure of severity Therapeutic Goals Treat Seconda ry Cause (?) Blood Product Other Support Thromboprophylaxis ImmuneSuppressio n • Indications for an adjunctive immune-suppressive agent: • 3. No response to steroid therapy within 5-7 days • E.g. Remains non-regenerative*, persistent agglutination, continued hemolysis Envisioning the Long-Term Plan PREDNISONE CYCLOSPORINE CLOPIDOGREL • AFTER DISCHARGE Recheck visit at 1 WEEK then 3 WEEKS • At 3 WEEKS POST-DISCHARGE, check CBC. Initiate a steroid taper IF: • Improved/normal RBC and hematocrit • Appropriate regeneration in relation to the RBC/Hct • No ongoing hemolysis (plasma is clear, no spherocytes/ghost cells, no agglutination) Envisioning the Long-Term Plan PREDNISONE CYCLOSPORINE CLOPIDOGREL • Prednisone taper Important to do so CAUTIOUSLY and INTENTIONALLY to reduce risk of relapse and to allow the adrenal gland to slowly resume their own cortisol production. NEVER abruptly stop this medication. • Taper REDUCE PREDNISONE DOSE BY 20-25% EVERY 2-3 WEEKS. ALWAYS CHECK A CBC OR PCV/TS PRIOR TO EACH TAPER TO ENSURE THAT NO RELAPSE HAS OCCURRED. • During taper of Prednisone, adjunctive medications (cyclosporine and clopidogrel) are continued at UNCHANGED DOSES. Envisioning the Long-Term Plan PREDNISONE CYCLOSPORINE CLOPIDOGREL • If at any time during TAPER a relapse of hemolysis is noted, EITHER: • Increase PREDNISONE back to the most recent effective dose • Do this if relapse is MILD (e.g. RBC/Hct is roughly the same but CBC shows spherocytes, agglutination, or is suddenly profoundly regenerative despite a normal hematocrit) • Increase PREDNISONE back to the starting dose • Do this if relapse if SEVERE (e.g. RBC/Hct has dropped considerably and/or if there is concern again for a need for blood product) Envisioning the Long-Term Plan PREDNISONE CYCLOSPORINE CLOPIDOGREL • Swann et al 2019: • Clopidogrel (OR ANY THROMBOPROHYLAXIS) should be continued at unchanged dose during the entirety of prednisone therapy. • Clopidogrel can be discontinued when Prednisone is discontinued. Envisioning the Long-Term Plan PREDNISONE CYCLOSPORINE CLOPIDOGREL • Once the Prednisone is DISCONTINUED, recheck a CBC or PCV/TS at the time of discontinuation and then again ONE MONTH later. • If patient remains stable after ONE MONTH without steroid, can consider a taper of the ADJUNCTIVE immune-suppressive. • This taper should have similar goals of reducing risk of relapse, but there is no concern for adrenal atrophy, so can consider a 25-50% reduction every 2-3 weeks. Envisioning the Long-Term Plan • Relapse rate is 20-25% • If relapse were to occur, it would likely occur with a relapse of the same sings, but has a tendency to be more difficult to control once relapse occurs • Occasionally dogs will relapse with ANOTHER immune-mediated disease Envisioning the Long-Term Plan • Recheck 1 MONTH after discontinuing all meds • Then, for FIRST YEAR of remission, recheck every 3 months • For SECOND YEAR of remission, recheck every 4 months • For THIRD YEAR and BEYOND of remission, recheck wellness exam every 6 months
