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Anemia – What do you mean it’s not IMHA???

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Presentation on theme: "Anemia – What do you mean it’s not IMHA???"— Presentation transcript:

1 Anemia – What do you mean it’s not IMHA???
Jason M. Eberhardt DVM, MS, DACVIM

2 Overview One of the most common CBC abnormalities Back to basics
10-30% of patients Why is it still so confusing? Back to basics Systematic approach to anemia Avoiding common pitfalls

3 Some thoughts… “You need to have the correct diagnosis before you can recommend the correct treatment.” “If you always have the correct diagnosis then you’re not a really veterinarian…you’re probably a breeder.” “You need to run a minimum of 5 diagnostic tests prior to starting steroids…”

4 Definitions Mean Corpuscular Volume (MCV) – Avg. RBC size
Macrocytosis Microcytosis Normocytic Mean corpuscular Hgb concentration (MCHC) – [ ] of Hgb vol. RBC Hypochromic Normochromic Macrochromic Reticulocytes – Immature RBCs released from B.M. early Normoblasts/metarubricytes – nucleated erythrocytes Reduction in # of circulating RBCs, HCT and HB Erythrocyte indices – remember they are MEAN calculations – a large # of cells have to be abnorm. To pull value out of ref. range – IMHA only 8.3 % are actually hypochromic on blood work Macrochromic – almost all lab errors (due to heinz bodies or hemolysis or severe lipemia– people sickle cell anemia, hereditary spherocytosis MCH – mean corpuscular hemoglobin Hgb x 10/PCV

5 Definitions continued…
Poikilocytosis – Variation of RBC shape Rouleaux – Stacks of coins Small amount is normal Increased fibrinogen or acute phase proteins Typically seen in inflammatory conditions Autoagglutination – Aggregate in grapelike clusters Must be differentiated from rouleaux Rouleaux disperses when blood is mixed with saline Spherocytes (RBCs lack central pallor near feather edge), Echinocytes, Acanthocytes (HAS, hepatic dz), Schistocytes (DIC, Fe def, CHF, myelofibrosis, HAS, malig. Histo)

6 Rouleaux or Autoagglutination

7 Before I go any further…
Where do I start……. Back to basics!!!


9 The first step… Remember the Total Protein!!! DO NOT OVERLOOK!
It’s the other half of “blood” It’s cheap! It’s fast DO NOT OVERLOOK! Are just the RBCs being affected or the plasma as well?

10 The next steps… Morphologic classification Bone marrow response
RBC indices Bone marrow response Regenerative vs. Non-regenerative Description of poikilocytosis? Macrocytic, hypochromic, regenerative anemia with marked spherocytosis

11 Morphological classification
Usage of RBC indices (MCV/MCHC) to “describe” the RBCs. Remember MCV/MCHC are MEAN calculations Large # of RBCs affected prior to increases/decreases Allows characterization of anemia into a category Helps with ranking differential diagnoses Are found on nearly all in-house CBC units Normocytic, normochromic, Macrocytic hypochromic, Microcytic hypochromic

12 Normocytic normochromic
Most common “Normal” RBCs Most commonly denotes a non-regenerative anemia Usually lacks RBC morphology changes “Pre-regenerative” First 1-3 days of acute loss/lysis Total Protein can assist…

13 Macrocytic hypochromic
Usually indicates a regenerative anemia Reticulocytes are relatively larger then mature RBCs Hypochromic because Hgb synthesis is not complete Only 8% of 6752 patients with reg. anemia had both increased MCV & decreased MCHC DiNicola et al.

14 Macrocytic normochromic
Usually misclassification due to insensitivity of MCV/MCHC Autoagglutination? Feline Leukemia Poodles – Congenital dyserythropoiesis Not anemic Large problem in humans B12 &/or folate deficiency Role in veterinary medicine is questionable FelV – usually no retics Great Schnauzers

15 Microcytic hypochromic
Consistent with an iron deficiency anemia Inadequate amount of Hgb is produced Typically seen in chronic conditions GI blood loss Severe parasitism PSS & Hepatic atrophy Myelodysplastic syndromes Congenital: Akitas, Shiba Inu, Chow breeds Not typically hypochromic Small RBCs (low MCV) Insufficient Hgb (low MCHC) Young dogs – GI parasites; Old dogs – GI masses Initially strongly reg. then non Look at TP Thrombocytosis can be marked

16 Bone marrow response Is there a regenerative response?
Evaluation of reticulocytosis No reticulocytosis/polychromasia expected during first 1-3 days (maybe not at all if anemia stays mild) Response peaks 4-5 days (with normal B.M.) Erythrocyte indices start to change 7-14 days Which species do not release produce reticulocytes (horses)

17 What is consider regenerative???
Normal patient should have <45,000-60,000 absolute retic count Absolute counts 60, ,000 Early/mild response 150, ,000 Mild-moderate >250, ,000 Moderate-Marked Relative % 1-4 % - Mild 5-20 % - Moderate > 20 % - Marked Define relative

18 Regenerative anemia Loss vs. Lysis External blood loss
LOOK AT TOTAL PROTEIN!!!! External blood loss Low to low-normal T.P. Hemolytic disease High to high-normal T.P.

19 Acute external blood loss
PCV does not fully reflect severity first 1-3 days Reticulocytosis should start by day 3 Peak reticulocytes day 4-7 PCV increases to low normal w/in 2 wks May take up to 4-5 weeks to return to normal Mild anemia does not stimulate strong erythropoietin release Splenic contraction Blood draws OBVIOUS – Urinary, nasal, hemoabdomen, hemothorax

20 Chronic blood loss Iron deficiency and negative protein balance develops after “several” weeks in adults Occurs more rapidly in young animals (low iron stores) Initially non/”pre” regenerative Period of regenerative anemia depending on severity Eventually returns to being poorly/non-regenerative Often have thrombocytosis Remember RBC indices do not change for 7-14 days Getting blood transfusions???

21 Hemolytic anemia Hemolysis is a mechanism NOT a “disease”
Lots of “non” immune mediated causes Low serum phosphorus Normal to increased T.P. Spherocytosis and/or autoagglutination Over interpretation is common Can be seen in diseases that are not “primary” Positive Coomb’s Test? Icterus occurs

22 Direct Coomb’s Test Identifies presence antibodies/compliment on RBCs
They may/may not actually be directed towards RBCs This may/may not actually cause damage to RBCs Neither highly specific or sensitive for IMHA Positive in 60-70% of cases Positive results – should have other evidence of IMHA Effect of steroids? **NOTE** – What is the end point of the test????? FP seen in blood transfusions, drug reactions, RBC parasitic infections

23 Breaking it down… Try to subclassify into intravascular vs. extravascular Alters differential diagnosis Intravascular – Rapid breakdown in vascular system Pink urine, pink serum Hemoglobinuria best indicator Hyperbilirubinemia typically more profound then in extravascular Extravascular – removal of RBCs by spleen, liver, B.M. More common Often has icterus, splenomegaly, hepatomegaly

24 Immune mediated “Immune-mediated” is a mechanism NOT a disease.
Can be 2nd to a number of possible causes Infectious – Babesiosis, Ehrlichiosis, Leishmaniasis, Rickettsioses, Mycoplasma haemofelis, FeLV Neoplasia Drugs Can be initially non-regenerative (esp. in cats) Drugs: Sulfas, Carprofen, cephalosporins Vax??? Look alikes – ie low phosphorus Also snake envenomation

25 “Penny” 6 year FS Cocker Presented for severe lethargy, “yellow skin” and “peeing blood” Severe, macrocytic, normochromic strongly regenerative anemia with mild-moderate spherocytosis Slide agglutination negative High total protein Abdominal ultrasound WNL Infectious disease titers all negative

26 The “Penny” dilemma Needed multiple transfusion in a 5-6 day period
Continued to have hemolysis despite aggressive immunosuppressive therapy Where do we go from here??? “Peeing” blood – hemoglobinuria Intravascular hemolysis Pred, cyclosporine, IVIG

27 Intravascular hemolysis
Immune mediated Phosphofructokinase deficiency Eng. Springers, Amer. Cockers Babesia infection Snake envenomation Heavy metal to toxicity Zinc Copper Zinc dogs can have spherocytes!!!! PFK – Strenuous exercise with hyperventilation – leads to alkalosis, high pH inhibits PFK and RBC lysis

28 “Penny” 6 yr FS Cocker Spaniel
Presented for severe lethargy, yellow skin and “peeing blood” Severe, macrocytic, normochromic strongly regenerative anemia with mild-moderate spherocytes Abdominal ultrasound WNL Infectious disease titers all negative


30 “Sheldon” 9 yr MC Jack Russell
Presented with clinical evidence of anemia Severe leukocytosis (54,000), severe anemia (9%), high normal platelets, mild-moderate reticulocytosis Total Protein – 4.9 g/dL VF, Ehr. Neg. Weakness, severe lethargy, decreased appetite Pale mm, tachycardia, grade 2/6 systolic murmurs

31 IHMA??? Started on prednisone, cyclosporine, doxycycline
Needed 2nd transfusion 1 week later Added azathioprine PCV still low 2 weeks later Chest rads and abd. u/s WNL Increased prednisone, continued on cyclosporine and azathioprine 3rd transfusion in 4 weeks Added leflunomide Repeat abdominal ultrasound WNL

32 More anemia!!! Initial PCV/TP at EAC Reference lab work 12%/4.8
Hypoalbuminemia (2.6 g/dL), globulin WNL (1.7 g/dL), BUN increased (mild), Total bilirubin (mild) Inflammatory leukogram Severe reticulocytosis

33 What’s going on??? Horrible IMHA??? Another type of hemolytic anemia?
GI bleeding (from prednisone?, GI mass?) Diagnostic plan??????????? Explain the decreased total protein


35 Non-regenerative anemia
Very common!!! Usually normocytic normochromic Microcytic, hypochromic anemias Usually no poikilocytosis Huge majority are mild-moderate in severity 2nd to systemic disease

36 Before going any further…
Is neutropenia and/or thrombocytopenia also present? What is the duration of clinical signs? How severe are the clinical signs? Supports bone marrow disease

37 I need more RBCs… Mild-moderate NR anemia
Search for an underlying disease first Anemia of chronic/inflammatory disease Neoplasia, renal disease, hepatic disease, infectious, inflammatory, endocrine Drugs Phenobarb, sulfas, methimazole, chlorambucil, azathioprine

38 Severe non-regenerative anemia
Toxicity Estrogen? Drugs Renal disease More than just decreased erythropoietin Chronic dz, decr. RBC lifespan, ineffective production, blood loss Phenobarb, sulfas, methimazole

39 Why can’t it be easy??? Bone marrow exam Took a long time to develop
Can take even longer to resolve Can still be very confusing and frustrating

40 Bone Marrow disease Immune mediated
Maturation arrest vs. Pure Red Cell Aplasia Myelophthisic syndromes - multiple cell lines often affected Aplastic anemia – B.M. replaced by fat Can be 2nd to chronic ehrlichiosis Myelofibrosis – B.M. replaced by fibrous Myelonecrosis – Drugs, toxins, viral Neoplasia

41 “Howard” 9 yr MN DSH Progressive lethargy, wt. loss for several weeks
Marked (12%), macrocytic, normochromic anemia Total protein 6.2 g/dL Absolute reticulocyte count 40,000 Retic. total 2% Corrected 0.65% FelV/FIV negative Chest radiographs, abdominal ultrasound WNL

42 Why cats are not small dogs…
50% of cats with immune mediated disease initially had a non-regenerative response Kohn et al. 2006 2/3 were <3 years (range was 1-9 yr) Bone marrow disease – 53% Infectious – 22% Hemolysis – 11% Immune Mediated – 6% Severity of anemia associated with B.M. disease Korman et al. 2013

43 Bone marrow or bust Owner noticed gradual decline Transfusion
More consistent with non-regenerative disease Transfusion Recheck 2-3 days later vs. bone marrow now Marked erythroid hypoplasia/aplasia Immune mediated vs. FelV Bone marrow IFA positive for FelV Stutzer et al. 2010

44 RBC shape descriptions
Many have little/no clinical significance Anisocytosis, elliptocytes, codocytes, leptocytes, *echinocytes* Spherocytes – Evidence of hemolysis Acanthocytes - Hemangiosarcoma, hepatic dz Schistocytes - DIC, Fe def, CHF, myelofibrosis, hemangiosarcoma, other neoplasia

45 Summary Anemia is a common abnormality
Cause can often be elusive Vital to approach systematically RBC indices, bone marrow response, poikilocytosis DON’T FORGET THE TOTAL PROTEIN!!!


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