section name header

Basics ⬇

Basics

Definition

Decreased circulating RBC mass (indicated by low PCV, hemoglobin, and total RBC count) accompanied by appropriate, compensatory increase in RBC production by the bone marrow (e.g., reticulocytosis in the peripheral blood and RBC hyperplasia in the bone marrow).

Pathophysiology

  • Caused by blood loss or hemolysis.
  • Hemolysis-caused by intrinsic RBC defects (e.g., congenital RBC membrane defects or enzyme deficiencies) or extrinsic factors (e.g., RBC parasites, oxidative injury, hemolysins, osmotic changes, immune-mediated RBC destruction, heat stroke, and severe hypophosphatemia.
  • Intravascular hemolysis may lead to DIC.

Systems Affected

  • Cardiovascular-murmurs with marked anemia; tachycardia.
  • Hemic/Lymph/Immune-erythroid hyperplasia in bone marrow; splenic EMH; splenomegaly due to EMH and histiocytic hyperplasia can be feature of extravascular hemolytic anemia.
  • Hepatic-anoxia causes centrilobular degeneration of the liver; hemosiderosis ± hemochromatosis possible with chronic hemolytic anemia (e.g., PK-deficient dogs) especially following repeated transfusions.
  • Renal-severe intravascular hemolysis rarely leads to renal tubular necrosis and acute renal failure.
  • Musculoskeletal-progressive osteoclerosis seen in PK-deficient dogs.

Signalment

  • PK deficiency-basenji, beagle, cairn terrier, Chihuahua, dachshund, Labrador retriever, miniature poodle, pug, West Highland white terrier, and American Eskimo; and Somali, Abyssinian, and domestic shorthair cats.
  • PFK deficiency-English springer spaniel, American cocker spaniel, whippet, wachtelhund, and mixed breed dogs with spaniel parentage.
  • Marked RBC osmotic fragility-English springer spaniel and Abyssinian, Somali, Siamese, and domestic shorthair cats.
  • Feline congenital porphyria-Siamese and domestic shorthair cats.
  • Some dog breeds have a genetic predisposition for heritable coagulopathies such as factor VIII deficiency and von Willebrand disease.
  • Middle-aged female dogs, especially American cocker spaniel, English springer spaniel, Irish setter, Old English sheepdog, poodle, and Shetland sheepdog, are predisposed to immune-mediated syndromes, such as SLE and immune-mediated hemolytic anemia.

Signs

  • Pallor.
  • Weakness, exercise intolerance.
  • Anorexia.
  • Possible heart murmur, tachycardia, bounding pulses.
  • Possible jaundice and hemoglobinuria.
  • Petechiae, epistaxis, melena suggest blood loss due to vasculitis or a platelet problem.
  • Hematomas or cavity bleeds suggest a coagulation factor deficiency.
  • Clinical signs depend on degree of anemia and rapidity of onset.
  • Rapid loss of 15–25% blood volume or acute hemolysis results in shock and possible death.
  • With chronic anemia, compensatory increases in heart rate, and eventually heart size, lessens RBC circulation time; hemoglobin can drop to as low as 50% of minimum normal value without overt signs of hypoxia.

Causes

Immune Mediated

  • Antibodies ± complement on membrane shorten RBC lifespan. Antibodies may target RBC membrane components or may be directed against tumor antigens, infectious agents, vaccines, or drugs (e.g., sulfonamides, penicillins, cephalosporins, methimazole, amiodarone) that are either directly adherent to RBC surface or part of immune complexes adherent to RBCs.
  • Anemia is usually regenerative, but up to 30% of cases will be nonregenerative due to immune-mediated destruction of erythroid precursors in bone marrow.
  • Hemolysis may be either intravascular, through IgM-mediated activation of complement, or extravascular, through IgG-mediated phagocytosis.
  • Hemolytic antibodies are generally reactive at body temperature; rarely cold-acting antibodies cause in vivo hemolysis and/or RBC agglutination in cooler, peripheral vasculature.
  • Transfusion of a blood type B cat with type A blood can result in rapid, severe, intravascular hemolysis; neonatal isoerythrolysis seen in kittens born to a blood type B queen mated to a blood type A tom.
  • Canine blood type DEA 1.1 can cause hemolysis in a DEA 1.1-negative dog, although a single incompatible transfusion can be tolerated.
  • The newly identified blood types Mik (cats) and Dal (dogs) can cause significant hemolytic transfusion reactions in animals lacking these common RBC antigens.

Oxidant Injury

  • Oxidants can cause Heinz body formation (aggregates of oxidized hemoglobin), eccentrocytes (oxidation of RBC membranes), and methemoglobinemia.
  • Heinz bodies are removed through extravascular hemolysis, while oxidized membrane components cause intravascular hemolysis.
  • Oxidants include onions, garlic, acetaminophen (especially in cats), zinc (from pennies minted after 1982, zinc oxide ointment, and zinc bolts), acute copper toxicosis, benzocaine, vitamin K3 (dogs), propofol, phenolic compounds (moth balls), skunk musk, and phenazopyridine (cats).
  • In cats, some systemic diseases (e.g., diabetes mellitus, hyperthyroidism, lymphoma) enhance Heinz body formation but do not necessarily cause anemia.

Erythrocyte Parasites

  • Cats: Mycoplasma haemofelis, M. haemominutum, M. turicensis, and M. haematoparvum, Cytauxzoon felis.
  • Dogs: Mycoplasma haemocanis, Babesia canis, and B. gibsoni.

Mechanical RBC Fragmentation

  • Caused by vasculitis, thromboembolic disease or disease of any vascular organ (e.g., liver, kidney, spleen, heart).
  • Rare cause of anemia unless accompanied by hemorrhage.

Inherited RBC Abnormalities

  • PK deficiency-impaired ATP formation, leading to premature RBC destruction; autosomal recessive trait.
  • PFK deficiency-marked alkaline fragility caused by impaired synthesis of 2,3-diphosphoglycerate; hemolytic episodes triggered by hyperventilation-induced alkalemia, especially after vigorous exercise; autosomal recessive trait.
  • Increased RBC osmotic fragility, (unknown RBC defect) leads to recurrent severe anemia and splenomegaly.
  • Feline congenital porphyria-enzyme deficiency in heme synthetic pathway leads to accumulation of heme precursors, hemolytic anemia and brown-red discoloration of teeth and bones. Siamese tend to have severe hemolytic anemia, while domestic shorthair cats have a less severe autosomal dominant trait that causes mild anemia.

Hypophosphatemia

Severe hypophosphatemia, secondary to treatment with insulin or phosphate binders, impairs ATP production, leading to increased erythrocyte fragility and hemolysis.

Blood Loss

  • Trauma
  • Bleeding neoplasms (e.g., hemangiosarcoma, intestinal adenocarcinoma)
  • Coagulopathies (e.g., warfarin poisoning, hemophilia, thrombocytopenia)
  • Bloodsucking parasites (e.g., fleas, ticks, and Ancylostoma)
  • Gastrointestinal ulcers

Diagnosis ⬆ ⬇

Diagnosis

Differential Diagnosis

Differentiated from nonregenerative anemia by high reticulocyte count.

Laboratory Findings

Disorders That May Alter Laboratory Results

  • Lipemia can cause mild in vitro hemolysis, without appreciable anemia, and may falsely elevate MCHC.
  • Autoagglutination may falsely decrease the RBC count.
  • Intraerythrocytic inclusions (e.g. basophilic stippling or intraerythrocyte parasites may falsely increase automated reticulocyte count.
  • Exercise and excitement can increase RBC count, PCV, and reticulocyte count through splenic contraction.

Valid If Run in Human Laboratory?

  • Dogs-yes.
  • Cats-yes, if hematology instrument uses species-specific parameters; instruments designed for analysis of human specimens may under-count small feline RBCs.

CBC/Biochemistry/Urinalysis

  • PCV, RBC count, and hemoglobin low.
  • Total protein often low with blood loss anemia and may be the only sign with acute blood loss; normal PCV may be maintained through transient splenic contraction.
  • Severity of acute blood loss may be underestimated until the plasma volume has been restored by fluid administration and/or internal fluid shifts.
  • RBC indices vary depending on the cause of anemia and degree of regenerative response-MCV, normal to high; MCHC, normal to low in most patients; MCHC, artificially high with intravascular hemolysis and hemoglobinemia.
  • With iron deficiency, dogs may have a low MCV, MCH, and MCHC; cats have a low MCV but normal MCH and MCHC.
  • Specific RBC morphologies may suggest cause of hemolysis: marked spherocytosis suggests immune-mediated disease (not as easily detected in cats whose RBCs generally lack central pallor); Heinz bodies or eccentrocytes suggest oxidant injury; numerous schistocytes suggest microangiopathy.
  • Agglutinated RBCs indicate anemia is immune mediated; distinguish autoagglutination from rouleaux by generous sample dilution with saline.
  • Hemolysis may cause inflammatory leukogram (neutrophilia with a left shift and monocytosis). Acute blood loss may be associated with stress leukogram (mild neutrophilia and lymphopenia).
  • Blood loss may be accompanied by either thrombocytopenia or rebound thrombocytosis; iron deficiency is often accompanied by thrombocytosis.
  • Hyperbilirubinemia and bilirubinuria accompany marked hemolysis; hemoglobinemia and hemoglobinuria seen with intravascular hemolysis.

Other Laboratory Tests

  • In anemia automated absolute reticulocyte count (RBC count × reticulocyte %) >60,000/µL (cats) or >95,000/µL (dogs) suggests regenerative anemia.
  • It takes 3–5 days for bone marrow to mount a peak regenerative response, so reticulocytosis may initially be absent with blood loss or hemolysis.
  • Direct antiglobulin test (Coombs' test) indicated when immune-mediated hemolytic anemia suspected; a positive test and evidence of spherocytosis (canine) in the peripheral blood is confirmatory; false negatives and false positives are possible.
  • PCR test for PK deficiency: young Basenji, beagle, dachshund, Toy Eskimo, West Highland white terrier, and cairn breeds with persistent anemia, massive reticulocytosis and a negative Coombs' test.
  • PCR test for PFK deficiency: spaniels and whippets with recurrent hemolytic crises.

Diagnostic Procedures

  • Bone marrow aspirate-needed only when reticulocytosis is lacking; RBC hyperplasia confirms regenerative response.
  • Bone marrow biopsy-useful in evaluation of bone marrow architecture and overall cellularity; important for confirmation of nonregenerative process.

Treatment ⬆ ⬇

Treatment

Blood Loss Anemias

  • Traumatic blood loss leading to shock-crystalloid fluids can rapidly correct hypovolemia and restore circulation.
  • RBC replacement (packed RBCs or whole blood) indicated if PCV <15–20% and signs of severe hypoxia (i.e., extremely pale mucous membranes, weakness, tachycardia, pounding pulses, tachypnea). Initial dosage depends on product selected; 6–10 mL/kg for packed RBCs; 10–20 mL/kg for whole blood. Less blood may be needed in animals with chronic anemia. Determine blood type prior to transfusion, to ensure compatibility. Cross match against donor blood if blood typing reagents not available, or if patient requires second transfusion more than 4 days after first transfusion.
  • Animals with chronic blood loss are normovolemic with increased cardiac output, therefore transfusion volumes and rates should be conservative to avoid cardiac failure.

Hemolytic Anemias

Blood transfusion may be indicated; in patients with immune-mediated process, RBCs probably survive similarly to patient's own RBCs, so transfusion should not be withheld if marked signs of anemia present.

Medications ⬆ ⬇

Medications

Drug(s)

  • Iron may benefit animals with chronic blood-loss anemia (see Anemia, Iron-Deficiency).
  • Hemolytic anemias-varies with cause of hemolysis.

Follow-Up ⬆ ⬇

Follow-Up

Patient Monitoring

  • Initially, monitor of RBC mass (e.g., PCV, RBC count, and hemoglobin) and morphologic features on a blood film (i.e., polychromasia) every 24 hours to evaluate effectiveness of treatment and bone marrow responsiveness.
  • As regeneration becomes apparent (rising RBC values and polychromasia), recheck patients every 3–5 days; return to normal values occurs about 14 days after acute hemorrhage but may take longer with immune-mediated process.
  • Following transfusion, monitor for complications (see Blood Transfusion Reactions).

Miscellaneous ⬆

Miscellaneous

Abbreviations

  • ATP = adenosine triphosphate
  • DIC = disseminated intravascular coagulation
  • EMH = extramedullary hematopoiesis
  • MCH = mean corpuscular hemoglobin
  • MCHC = mean corpuscular hemoglobin concentration
  • MCV = mean cell volume
  • PCV = packed cell volume
  • PFK = phosphofructokinase
  • PK = pyruvate kinase
  • RBC = red blood cell
  • SLE = systemic lupus erythematosus

Internet Resources

Erythrocytes: Overview, Morphology, Quantity; A.H. Rebar, P.S. MacWilliams, B.F. Feldman, et al.: http://www.ivis.org/advances/Rebar/Chap4/chapter.asp?LA=1.

Suggested Reading

Mitchell K, Krush S. Immune-mediated haemolytic anemia and other regenerative anemias. In: Ettinger SJ, Feldman EC, eds., Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat, 7th ed.St Louis, MO: Elsevier Saunders, 2010, pp. 761–772.

Author Joyce S. Knoll

Consulting Editor Alan H. Rebar