Domenico Bianco, DVM, PhD, DACVIM August, 26 th 2013

Transcription

1 Domenico Bianco, DVM, PhD, DACVIM August, 26 th 2013

2 Most common hemolytic disorder in dogs Primary (idiopathic) or secondary 60-75% of cases are idiopathic Mortality as high as 70%

3 Pathophysiology Presentation Diagnosis Treatment Recent literature

4 Anti-erythrocyte antibody production Type II hypersensitivity reaction Extravascular hemolysis Immunoglobulin G mediated Macrophages in liver, spleen or both Intravascular hemolysis Immunoglobulin M mediated Intravascular complement activation Hemoglobinemia and hemoglobinuria

5 Middle aged Cocker spaniels overrepresented Females overrepresented Recent vaccination

6 Weakness Lethargy Anorexia Pale or Jaundice Difficulty breathing Collapse Discolored urine

7 Febrile Pale Icterus Weakness Tachycardia Tachypnea Splenomegaly Hepatomegaly Lymphadenopathy Pigmenturia

8 Diet history Possible zinc-containing foreign body ingestion Recent vaccinations or drugs Travel history Past transfusions or dog fights Tick exposure or bee stings Heartworm status

9 Bacterial infections Ehrlicia canis Anaplasma phagocytophilia Mycoplasma Leptospira Parasitic causes Babesia Heartworm Leishmania Neoplasia Drugs Sulfonamides Cephalosporins Amiodarone Toxins Onion or garlic Zinc Copper Naphthalene Bee sting envenomation

10 Check PCV/TS Anemia with normal proteins Hemolyzed or icteric serum Blood smear Slide agglutination test Mix one drop blood with saline Submit minimum database CBC with reticulocyte count Chemistry profile Urinalysis

11 Regenerative anemia Polychromasia Anisocytosis Nucleated RBCs Spherocytosis Autoagglutination Macroscopic Microscopic

12

13

14

15 Dr. Robin Coombs Coombs Test Detects antibodies or complement on RBC surface Not sensitive or specific Positive in 35-60% of IMHA False negatives up to 42% Does not differentiate between primary or secondary IMHA Unnecessary if autoagglutination

16 Leukocytosis Thrombocytopenia Hyperbilirubinemia Elevated liver enzymes Alkaline phosphatase Alanine tranaminase Aspartate transaminase

17 Rule out causes of secondary IMHA Thoracic radiographs Abdominal radiographs Abdominal ultrasound Bone marrow Infectious disease

18 Red blood cell transfusion Immunosuppression (4-9 months) Thromboprophylaxis

19 70-90% of patients require transfusion Transfuse if clinical for anemia! Blood typing and crossmatching may be impossible Packed red blood cells preferred Whole blood

20 Predisone Glucocorticoid Inhibit phagocytosis of RBCs, decrease cytokine and immunoglobulin production 2-4mg/kg per day Dexamethasone can be substituted at mg/kg IV every hours

21 Azathioprine Cytotoxic purine analogue antimetabolite Suppresses T-cell function Suppresses macrophage function 2mg/kg PO daily for 7-14 days then every 48 hours Slow onset of action (7-14 days) Adverse side effects Gastrointestinal upset Myelosupression

22

23 Cyclosporine Immune modulator Inhibits T-cell function by preventing production of interleukin mg/kg every hours (modified) Expensive Adverse side effects Gastrointestinal upset Gingival hyperplasia Malignancies

24

25

26 Mycophenolate mofetil Immunomodulator Inhibitor of purine synthesis mg/kg/day divided between 2-3 doses Oral and IV Expensive Adverse side effects GI upset Bone marrow suppression

27 Leflunomide Immunomodulator Inhibitor of pyrimidine biosynthesis 4mg/kg/day Adverse side effects Bone marrow suppression Liver enzyme elevations Do not give with Azathioprine!

28 Cyclophosphamide Alkylating agent Associated with decreased survival No longer recommended

29 As much as necessary to achieve remission, as little as possible to minimize side effects (and maximize compliance) Immunosuppressants 3-6 months 6-12 months if relapse of difficult to get into remission

30 Prednisone or injectable dexamethasone Days 1-3 Add mycophenolate at discharge or when eating Add in cyclosporine or leflunomide If day 3-5 and still transfusion dependent or hematocrit not stable at first recheck Add in the other If day 5-7 and no remission Add in cyclosporine or leflunomide if > 7 days and no remission

31 Start taper, once PCV is normal and has been stable for 7-14 days Taper prednisone by 25% every 3-4 weeks In relapsed patients or in patient that were difficult to get into remission, taper even slower in 4-6 weeks increments Discontinue Prednisone, once receiving 0.25mg/kg every other day for 3-4weeks Once off Prednisone, SLOWLY taper other s

32 Intravenous Immunoglobulin Immunoglobulin from human donors Binds to macrophage Fc receptors g/kg infused over 6-12 hours Expensive Potentially immunogenic IVIG study at Tufts

33 Prospective, blinded, randomized clinical trial 28 dogs 14 dogs treated with prednisone alone 14 dogs treated with prednisone and hivig No difference in response, survival or length of hospitalization between the groups

34 Spleen Major site of autoantibody production Destruction of IgG-coated RBCs Splenectomy May decrease extravascular hemolysis Small prospective study High risk Can not be routine advocated Further studies are needed Need picture of spleen

35 Thromboembolism is the most common complication in dogs with IMHA Thromboemboli identified in up to 80% of dogs on necropsy Routine anticoagulation remains controversial

36 Primary IMHA Presence of anemia Autoagglutination and/or spherocytosis No underlying cause for IMHA No prior administration of anticoagulants, blood products, or immunosuppressants 11 dogs enrolled

37

38

39 All 11 dogs with IMHA were hypercoagulable Hypercoagulability may be a precursor to thrombosis Results suggest that thromboprophylaxis may be warranted early in the disease process Corticosteroids and hypercoagulability

40 Unfractionated heparin U/kg IV or SQ every 6-8 hours U/kg/hr CRI Low-molecular-weight heparin Dalteparin (Fragmin) 150units/kg SQ every 8-12 hours Enoxaparin (Lovenox) 0.8 mg/kg SQ every 6 hours Platelet inhibitor Clopidogrel (Plavix) 1-3 mg/kg PO every 24 hours Ultra-low dose aspirin 0.5mg/kg/day

41

42

43

44

45 Mortality rate was 58% Thromboemboli found in 80% on post-mortem Risk factors for thromboembolism Severe thrombocytopenia (<50,000) Serum bilirubin > 5mg/dl Hypoalbuminemia Higher risk of thrombosis Increased alkaline phosphatase Increased bilirubin Decreased albumin Risk factors for mortality Thrombocytopenia (<200,000) Serum bilirubin > 5mg/dl

46 Dogs that died Lower platelet counts Higher median neutrophil counts Lower median albumin Lower median potassium Higher median creatinine kinase Higher bilirubin (>1.5mg/dl) Improved long and short-term survival when treated with prednisone, azathioprine, and ultra-low dose aspirin

47 Prednisolone and Azathioprine for 3 months Overall half-year survival 72.6% If survived first 2 weeks, 92.5% Major predictors of mortality Increased blood urea nitrogen Increased bands Thrombocytopenia Petechiae Predictors of mortality during 1 st two weeks Increased blood urea nitrogen Icterus Petechiae

48 Relapse rate 12-24% Can occur anytime Some relapses require hospitalization, transfusions Avoid tapering medications too quickly! Consider other causes of decreasing PCV Avoid vaccinations!

49

50 Taper immunosuppressants slowly Transfuse if clinical for anemia Thromboembolism is a major contributor to morbidity and mortality Consider anticoagulant or anti-platelet therapy

51