SUBJECT:

ANEMIA . DEFECTS OF RED BLOOD CELL MEMBRANE PRODUCTION

DISCIPLINE: PHYSIOPATHOLOGY

PROFESSOR :
STUDENT:
 Anemia is a condition in which you don't have enough healthy red blood
cells to carry adequate oxygen to the body's tissues. Having anemia may make you
feel tired and weak.
There are many forms of anemia, each with its own cause. Anemia can be
temporary or long term, and it can range from mild to severe.
 Hemolytic anemia or haemolytic anaemia is a form of anemia due
to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in
the blood vessels (intravascular hemolysis) or elsewhere in body (extravascular,
but usually in the spleen).
1.Abnormal and accelerated destruction of red cells and, in some anemias, their precursors
2.Increased breakdown of hemoglobin, which may result in:
-increased bilirubin level (mainly indirect-reacting) with jaundice
-increased fecal and urinary urobilinogen
-Hemoglobinemia, methemalbuminemia, hemoglobinuria and
3.Bone marrow compensatory reaction:
-erythroid hyperplasia with accelerated production of red cells, reflected
by reticulocytosis and slight macrocytosis in peripheral blood
-expansion of bone marrow in infants and children with severe chronic hemolysis
4.The balance between red cell destruction and marrow compensation determines the severity of
anemias.
Symptom Sign/lab finding Mechanism
Weakness/fatigue Anemia Hemolysis
Jaundice Accumulation of unconjugated bilirubin

Splenomegaly Not usually expected, consider coexisting disease

Dark urine Hemoglobinuria Hemolysis resulting in hemoglobin filtering into the

urine
Low or absent haptoglobin Haptoglobin binds hemoglobin after hemolysis and
the complex is cleared from circulation
High LDH LDH is an intravascular enzyme released from
erythrocytes during hemolysis
Heinz bodies: circular inclusions Form from precipitated hemoglobin due to oxidation
inside red cells and denaturation.
Bite cells: red cells with ‘bites’ ‘Bites’ are from splenic macrophages removing the
taken out part of the red blood cell with a Heinz body.
Blister cells: red cells with a Arises when bite cells undergo repair of the cell
clearing at the periphery, like a membrane, resulting in a clearing within the red cell
blister where the Heinz body previous was.
Anisocytosis: unequal red cells Hemolysis leads to increased cell fragments.
sizes as indicated by increased red
cell distribution width (RDW)

Polychromasia: immature red Hemolysis leads to increased reticulocytes.

cells on peripheral smear Immature red cells have a grey-blue tinge, and this
difference in colour is referred to as polychromasia.
 They may be classified according to the means of hemolysis, being either
intrinsic in cases where the cause is related to the red blood cell (RBC) itself, or
extrinsic in cases where factors external to the RBC dominate.
 Immune
Spur cell mediated

Poisoning
by arsine or
stibine
Hypersplenism

Encountered
in burns and as
a result of Lead poisoning
certain
infections
 Paroxysmal
nocturnal
hemoglobinuria

Defects of red
blood cell Defective red
membrane cell metabolism
production

Defects in
hemoglobin
production
 Primary abnormalities of the erythrocyte membrane, including the
hereditary spherocytosis and hereditary elliptocytosis syndromes, are an important
group of inherited hemolytic anemias.
Classified by distinctive morphology on peripheral blood smear, these
disorders are characterized by clinical, laboratory, and genetic heterogeneity.
Clinical and laboratory manifestations, as well as associated molecular
defects, of these disorders vary widely. Abnormalities of erythrocyte shape on
peripheral blood smear often provide clues to the underlying pathobiology and
clinical diagnosis of the underlying disorder.
Hereditary Elliptocytosis
 The principal defect in HE/HPP erythrocytes is mechanical weakness or fragility
of the erythrocyte membrane skeleton due to defects in various membrane
proteins, including α- and β-spectrin, protein 4.1, and glycophorin C.
Most cases of HE and HPP are due to defects in spectrin, the principal structural
protein of the erythrocyte membrane skeleton. Spectrin integrity is dependent on the self-
association of heterodimers of α- and β-spectrin into mature spectrin molecules that are
critical for membrane stability and erythrocyte shape and function.
HE is inherited in an autosomal dominant pattern with rare cases of de
novo mutations. Mutations in the regions of spectrin where the α- and β-spectrin chains self-
associate cause the majority of cases of HE/HPP. Most of these mutations are missense
mutations at residues critical for spectrin function.In contrast to HS, the HE/HPP
syndromes, while also heterogeneous, have been associated with distinct spectrin mutations
in persons of similar genetic backgrounds, suggesting a “founder effect” for these
mutations.
The hereditary elliptocytosis (HE) syndromes are a heterogeneous group of disorders
characterized by the presence of elliptical-shaped erythrocytes on peripheral blood smear.
Clinical manifestations range from the asymptomatic carrier state to severe, transfusion-
dependent hemolytic anemia.
Hereditary pyropoikilocytosis (HPP) is an uncommon severe hemolytic anemia
characterized by erythrocyte morphology reminiscent of that seen in patients after a
thermal burn .There is a strong association between HE and HPP, with a third of family
members of HPP patients exhibiting typical HE.
Imaging Studies
In hemolytic HE and HPP, splenomegaly is typically detected on abdominal
ultrasound examination or radionuclide scanning. Cholelithiasis may be detected on
abdominal ultrasound.
Differential Diagnosis
Conditions with elliptocytes on peripheral smear include the megaloblastic
anemias, the hypochromic microcytic anemias (iron deficiency anemia and thalassemia),
myleodysplasic syndromes, and myelofibrosis. In these conditions, elliptocytes generally
number less than one-third of erythrocytes. History and additional laboratory testing
usually clarify the diagnosis of these disorders.
Hereditary Spherocytosis
The principal abnormality in HS erythrocytes is loss of membrane surface area relative to
intracellular volume, which leads to spherically shaped erythrocytes with decreased
deformability.
-The loss of surface area results from increased membrane fragility due to primary and
secondary abnormalities in erythrocyte membrane proteins, particularly ankyrin, α- and β-
spectrin, band 3, and protein 4.2 .
-Increased erythrocyte fragility leads to vesiculation and membrane loss.
-Splenic destruction of poorly deformable HS erythrocytes is the primary cause of hemolysis
experienced by HS patients
HS is inherited as in autosomal dominant manner in ∼two thirds of patients, associated with
mutations in the ankyrin, β-spectrin, or band 3 genes.2 In the remaining patients, inheritance
is non-dominant due to autosomal recessive inheritance or a de novo mutation.3Autosomal
recessive inheritance is associated with mutations of either the α-spectrin or protein 4.2
genes. A number of de novo mutations have been reported in the HS genes.
 The hereditary spherocytosis (HS) syndromes are a group of disorders
associated with a primary defect in erythrocyte membrane proteins.
HS was first described based on the finding of spherocytes, characteristic
erythrocytes lacking central pallor, on peripheral blood smear. HS occurs
worldwide in all racial and ethnic groups. It is the most common inherited anemia
 Classification of hereditary spherocytosisa
Moderate
Carrier Mild spherocytosis spherocytosis Severe spherocytosisb

Hemoglobin (g/dl) Normal 11–15 8–12 6–8

Reticulocytes (%) ≤3 3–6 ≥6 ≥10

Bilirubin (mg/dl) 0–1 1–2 ≥2 ≥2

Spectrin content (% of
normal) 100 80–100 50–80 40–60

Peripheral smear Normal Mild spherocytosis Spherocytosis Spherocytosis

Osmotic fragility Normal or slightly

fresh blood Normal increased Distinctly increased Distinctly increased

Incubated blood Slightly increased Distinctly increased Distinctly increased Distinctly increased
Imaging Studies
Splenomegaly is typically detected on abdominal ultrasound examination or
radionuclide scanning. Cholelithiasis may be detected on abdominal ultrasound.
Differential Diagnosis
Hemolytic anemia with spherocytes on peripheral blood smear is found in a
number of conditions including autoimmune hemolytic anemia, liver disease, thermal
injury, micro- and macroangiopathic hemolytic anemias, Clostridial sepsis, transfusion
reaction with hemolysis, severe hypophosphatemia, ABO incompatibility, and poisoning
with certain snake, spider, and hymenoptera venoms. It is usually not difficult to
distinguish HS from other disorders by additional diagnostic testing, such as autoimmune
hemolytic anemia via a Coombs' test (the direct anti-globulin test or DAT), or by viewing
the condition in the appropriate clinical context.
 Clinical manifestations of the spherocytosis syndromes vary
widely. Typical HS is associated with pallor, jaundice, splenomegaly, anemia,
reticulocytosis, spherocytes on peripheral blood smear, positive osmotic fragility or
flow cytometric analysis of eosin-5-maleimide-labeled erythrocytes
Clinical manifestations of the HE syndromes vary widely, from
asymptomatic carriers to patients with severe, transfusion-dependent anemia.
How are IMHA in animals diagnosed?

 One of the first things veterinarians might do is ask

for a history of symptoms and activities;

Veterinarian may recommend a series of diagnostics,

including a blood test, fecal test, urinalysis, and
diagnostic imaging tests like radiographs and
ultrasounds.
 Most common blood test is the packed cell
volume (PCV) test ;

A red blood cell count (RBC) and a

hemoglobin count ;

A blood smear may reveal;

Reticulocyte count;
 Slide agglutination test

Urinalysis, biochemical profile, fecal parasite

exam.

EMA binding and osmotic fragilitys

How are IMHA treated in animals?

Treating anemia is a two-step process.

First, veterinarian will need to assess if the anemia itself is severe enough to require a
blood transfusion ;
 Then will make a plan for treating the underlying disease or condition.
The treatment options for the underlying condition will vary, depending on the
disease, and could include medications or care involving corticosteroids, chemotherapy, or
even surgery.
 The severity of clinical signs will determine the course of treatment needed for
the animal. Hospitalization frequently is required for treatment, and needed for monitoring
and supportive care. Treatment is case-by-case and follows four main principles:
preventing hemolysis, treating tissue hypoxia, deterring the formation of thromboemboli
and providing continuous supportive care to the patient. Treatment of HS encompasses
supportive care and when appropriate, splenectomy.
Veterinarians will provide a combination of medications, valuable nutrition and
constant monitoring of progress in the patient. Treatments take up to at least three months
or longer. At times, the severity of the blood disease is caught early, and in this case the
patient will be treated as an ongoing outpatient;
gallbladder disease;
hemolytic crisis;
aplastic crisis;
megaloblastic crisis;
uncommon: chronic leg ulceration, cardiomyopathy, neuromuscular
abnormalities, “tumors” due to extramedullary erythropoiesis
• Gallbladder disease, chronic hemolysis may lead to the formation of bilirubinate
gallstones, the most complication in HS patients.
• Hemolytic crises present with jaundice, increased splenomegaly, decreased hematocrit,
and reticulocytosis. They are generally mild and are associated with viral infection.
• Aplastic crises are typically due to viral bone marrow suppression by parvovirus B19
infection, which selectively infects erythropoietic progenitor cells and inhibits their growth.
During the aplastic phase, the hemoglobin and reticulocyte count fall, paralleling a decrease
in production of new red blood cells. Parvovirus infection may be the first manifestation.
• Megaloblastic crises with exaggeration of anemia occur due to exhaustion of folate
reserves by the sustained increase in net DNA synthesis associated with increased folate.
Is IMHA life threatining!?

Anemia can be caused by a wide array of conditions, from infectious diseases

and autoimmune conditions to trauma and dangerous toxins. Since some of the causes are
very serious. The prognosis for anemia depends on the cause and, if applicable, treatment.