HEMOLYTIC ANEMIA

Hemolytic Anemias
 Anemias due to increased destruction of red cells :
 Called hemolytic anemias (HAs), may be :  Site of hemolysis :
1. Inherited 1. Intravascular
2. Acquired 2. Extravascular
 May be :  Mechanisms :
1. Acute 1. Intracorpuscular
2. Chronic 2. Extracorpuscular

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 Classification of Hemolytic Anemias
Intracorpuscular Defects Extracorpuscular Factors

 Hereditary  Hereditary
1. Hemoglobinopathies 1. Familial hemolytic uremic
2. Enzymopathies syndrome (HUS)
3. Membrane-cytoskeletal defects  Acquired
 Acquired 1. Mechanical destruction

1. PNH
(microangiopathic)
2. Toxic agents
3. Drugs

4. Infectious
5. Autoimmune

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 General Clinical and Lab Features of HA
 Greatly influenced by whether the  Whereas a patient with mild hereditary
onset is : spherocytosis or with cold agglutinin
 Abrupt or disease

 Gradual  May be diagnosed after years

 A patient with autoimmune hemolytic  Differentiating HA from other anemias

anemia or with favism :

 May be a medical emergency  Patient has signs and symptoms

 Arising directly from hemolysis

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 General Features of Hemolytic Disorders
 General examination : Jaundice, pallor
 Other physical findings : Spleen may be enlarged; bossing of skull in severe
congenital cases
 Hemoglobin : From normal to severely reduced
 MCV, MCH : Usually increased
 Reticulocytes : Increased
 Bilirubin : Increased (mostly unconjugated)
 LDH :Increased (up to 10X normal with intravascular hemolysis)
 Haptoglobin : Reduced to absent
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 Laboratory features of HA
 Laboratory features of HA are related to :
(1) Hemolysis per se and
(2) The erythropoietic response of the bone marrow
 Serum
 Increased unconjugated bilirubin,
 Increased lactate dehydrogenase (LDH),
 Increased aspartate transaminase,
 And reduced haptoglobin.
 Urobilinogen will be increased in both urine and stool
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 Hemolysis is mainly intravascular :
 The telltale sign is hemoglobinuria
 Often associated with hemosiderinuria
 An increase in serum hemoglobin
 In contrast, the bilirubin level : normal or only mildly elevated

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 The main sign of the erythropoietic response by the BM is :
 An increase in reticulocytes
 % age of reticulocytes and the absolute reticulocyte count
 The increased number of reticulocytes is associated with an :
 Increased mean corpuscular volume (MCV) in the blood count.
 Macrocytes, polychromasia and nucleated red cells on blood smear

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 General Pathophysiology of HA
 Cytochrome-mediated oxidative phosphorylation :
 Lost with the loss of mitochondria
 No backup to anaerobic glycolysis for the production of ATP
 With the loss of ribosomes, no protein synthesis
 Places the cell's limited metabolic apparatus at risk because if any protein
component deteriorates, it cannot be replaced as in most other cells
 Activity of most enzymes gradually decreases as red cells age

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 Any sort of metabolic failure will eventually lead either
 To structural damage to the membrane or
 To failure of the cation pump
 The life span of the red cell is reduced (= hemolytic disorder)
 Rate of red cell destruction exceeds the capacity of the bone marrow to produce
more red cells, the hemolytic disorder will manifest as hemolytic anemia.
 The essential pathophysiologic process
 Common to all HAs
 Is an increased red cell turnover

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 Transient Hemolytic Event :
 It does not usually cause any long-term consequences.
 Recurrent or Persistent Hemolytic Event:
 Increased bilirubin production
 Favors the formation of gallstones.

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 If considerable proportion of hemolysis occurs in spleen :
 As is often the case
 Splenomegaly: prominent feature
 Hypersplenism may develop
 Consequent neutropenia and/or thrombocytopenia.

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 The increased red cell turnover :
 Has metabolic consequences.
 In normal subjects : iron from effete red cells : recycled by the body
 Chronic Intravascular Hemolysis:
 Persistent Hemoglobinuria
 Cause considerable iron loss
 Needing replacement

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 Chronic Extravascular Hemolysis : opposite problem :
 Iron overload is more common
 Especially if patient needs frequent blood transfusions
 Chronic iron overload :
 Cause Secondary Hemochromatosis
 Damage to :
 Liver = cirrhosis
 Heart Muscle =heart failure

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 Compensated Hemolysis versus HA
 Red cell destruction :
 Potent stimulus for erythropoiesis
 Mediated by erythropoietin
 Mechanism is so effective :
 Increased output of red cells from the bone marrow
 Can fully balance an increased destruction of red cells
 Hemolysis is Compensated

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 pathophysiology of compensated hemolysis :
 similar to that just described
 except there is no anemia
 compensated hemolysis :
 may become "decompensated“
 anemia may suddenly appear in certain circumstances
Eg. : pregnancy/folate deficiency/ renal failure

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 Common causes of HA in the adult
Extravascular destruction of red blood cells
 Intrinsic red blood cell defects
 Enzyme deficiencies (eg, G6PD or pyruvate kinase deficiencies)
 Hemoglobinopathies (eg, sickle cell disease, thalassemias, unstable
hemoglobins)
 Membrane defects (eg, hereditary spherocytosis, elliptocytosis)
 Extrinsic red blood cell defects
 Liver disease
 Hypersplenism
 Infections (eg, bartonella, babesia, malaria)
 Oxidant agents (eg, dapsone, nitrites, aniline dyes)
 Other agents (eg, lead, snake and spider bites)
 Microangiopathic (eg, DIC, TTP-HUS)
 Autoimmune hemolytic anemia (warm- or cold-reacting, drugs)
 Intravenous immune globulin infusion
 Large granular lymphocyte leukemia
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 Intravascular destruction of red blood cells
 Microangiopathy (eg, aortic stenosis, prosthetic valve leak)
 Transfusion reactions (eg, ABO incompatibility)
 Infection (eg, clostridial sepsis, severe malaria)
 Paroxysmal cold hemoglobinuria
 Paroxysmal nocturnal hemoglobinuria
 Following intravenous infusion of Rho(D) immune globulin
 Following intravenous infusion with hypotonic solutions
 Snake bites

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 G6PD
 X– linked condition, so there will be a positive family history.
 No chronic hemolytic anemia & episodes of hemolysis occur only due to
oxidative stress from infection or drug.
 Ix: peripheral smear- normal, no splenomegally, plt & WBCs count are normal.
 G6PD levels are low b/n hemolytic episodes.

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 Hereditary Spherocytosis
 An AD condition, with positive family Hx.
 Peripheral smear: shows spherocytes with loss of central pallor & hemolysis
patterns is of extra-vascular type with normal LDH & serum haptoglobulin level

 A.I HA
 Hemolysis is of extra vascular type & peripheral smear may show spherocytes.
 Coomb`s test positive
 WBCs & platelates counts are normal.

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 PNH
 Acquired d/o of hematopoietic cells & may cause pancytopenia
 Should be considered in all patient with confusion + hemolytic anemia +
pancytopenia.
 Hemolysis is intravascular with low serum haptoglobulin & elevated LDH
 Loss of iron in the urine may result in IDA
 Congested splenomegally is one of the CPX of d/o.
 BM may be hypocellular.
 Flow cytometry is a better chioce & confirms the dx by showing absence of
CD59.

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 An acquired mutation in the PIG-A gene in a hematopoietic stem cell is
required for the development of PNH, but PIG-A mutations probably occur
commonly in normal individuals.
 If the PIG-A mutant stem cell proliferates, the result is a clone of progeny deficient
in glycosylphosphatidylinositol-linked cell surface membrane proteins.
 Such PNH cells are now accurately enumerated using fluorescence-activated flow
cytometry of CD55 or CD59 expression on granulocytes rather than Ham or sucrose
lysis tests on red cells.

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 Small clones of deficient cells can be detected in about half of patients with aplastic
anemia at the time of presentation [and PNH cells are also seen in MDS];
 Frank hemolysis and thrombotic episodes occur in patients with large PNH
clones (>50%).

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 Functional studies of bone marrow from PNH patients, even those with mainly
hemolytic manifestations, show evidence of defective hematopoiesis.
 Patients with an initial clinical diagnosis of PNH, especially younger individuals,
may later develop frank marrow aplasia and pancytopenia;
 Patients with an initial diagnosis of aplastic anemia may suffer from
hemolytic PNH years after recovery of blood counts.
 One popular but unproven explanation for the aplastic anemia/PNH syndrome is :
 Selection of the deficient clones because they are favored for proliferation in
the peculiar environment of immune-mediated marrow destruction.

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 SUSPECTING HEMOLYSIS
 Is not difficult in the classic patient, who may have many of the following findings:
 Rapid onset of pallor and anemia
 Jaundice with increased indirect bilirubin concentration
 History of pigmented (bilirubin) gallstones
 Splenomegaly
 Presence of circulating spherocytic red cells
 Increased serum LDH concentration
 Reduced (or absent) level of serum haptoglobin

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 A positive direct antiglobulin test (Coombs test)
 Increased reticulocyte percentage or absolute reticulocyte number, indicating the
bone marrow's response to the anemia

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 CONFIRMING HEMOLYSIS
 The combination of an increased serum LDH & a reduced haptoglobin is 90%
specific for diagnosing hemolysis,
 While the combination of a normal serum LDH & a serum haptoglobin >25 mg/dL
is 92% sensitive for ruling out the presence of hemolysis.

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 LDH (specifically the LD1 and LD2 isoforms),
 Released from hemolyzed RBCs, &
 Haptoglobin,
 Which binds to hemoglobin
 Released during intravascular or extravascular hemolysis or ineffective
erythropoiesis with release of Hgb from late erythroid precursors in the BM.
 Higher haptoglobin values in the presence of hemolysis can reflect either:
 A lesser degree of hemolysis or
 Concurrent inflammation, since haptoglobin is an acute phase reactant

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 Normal reticulocyte percentage is 0.5 to 1.5 %.
 In patients with an otherwise intact BM, the increase in erythropoietin
production induced in a patient with hemolytic anemia should raise the
reticulocyte percentage above 4 to 5 %.

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 Abnormalities on the peripheral
blood smear suggesting
extravascular hemolysis include:
 Spherocytes
 Fragmented red cells
 "Bite" or blister cells
 Acanthocytes, and
 Teardrop red cells
 Abnormalities which suggest that
the hemolysis is intravascular
include:
 Presence of free hemoglobin in
plasma or urine
 A urine sediment positive for iron
(hemosiderinuria), and
 In rare cases, presence of
circulating red cell "ghosts"
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 DETERMINING THE CAUSE
 A thorough history and physical examination is important, as many of these causes
include drugs and toxins or systemic disorders (eg, infection, autoimmune disease,
malignancy).

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 ATYPICAL PRESENTATION
 Hemolysis with out anemia
 Hemolysis with out reticulocytosis

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AIHA

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 Most common causes of acquired hemolytic anemia is immunologic destruction of
RBCs mediated by autoantibodies directed against antigens on the patient's RBCs.

 The clinical manifestations of this group of diseases, called AIHA, depend

greatly on the type of antibody that is produced by the abnormal immune
reaction.

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 Nature of The Autoantibodies
 In general, antibodies of two major types, each with specific characteristics, are
produced in AIHA:
1. IgG antibodies which generally react with protein antigens on the RBC surface at
body temperature. For this reason, they are called "warm agglutinins" even
though they seldom directly agglutinate the RBCs. Rarely, IgM antibodies have
these reaction characteristics and readily agglutinate red cells.
2. IgM antibodies which generally react with polysaccharide antigens on the RBC
surface only at temperatures below that of the core temperature of the body. They
are therefore called "cold agglutinins." Rarely, IgG antibodies have these reaction
characteristics. 36
 Antibodies of the IgA isotype are much less common and often of unknown
significance.
 They can produce AIHA with either of the above reaction characteristics.

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 Etiology
 Most cases of warm agglutinin AIHA are idiopathic.
 Causes or conditions which may be associated with AIHA include the following:
 Viral infections (usually in children)
 Autoimmune and connective tissue diseases (particularly SLE)
 Malignancies of the immune system (eg, NHL, chronic lymphocytic leukemia
(CLL), with a higher incidence in those treated with purine analogs)
 Prior allogeneic blood transfusion or hematopoietic cell transplantation
 Certain drugs

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 Pathophysiology
 AIHA is caused by an autoantibody directed against a red cell antigen, i.e., a
molecule present on the surface of red cells.

 The autoantibody binds to the red cells.

 Once a red cell is coated by antibody, it will be destroyed by one or more

mechanisms.

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 In most cases the Fc portion of the antibody will be recognized by the Fc receptor
of macrophages, and this will trigger erythrophagocytosis.
 Thus, destruction of red cells will take place wherever macrophages are
abundant, i.e., in the spleen, liver, and bone marrow.
 Because of the special anatomy of the spleen, it is particularly efficient in
trapping antibody-coated red cells, and often this is the predominant site of red
cell destruction.

 Although in severe cases even circulating monocytes can take part in this process,
most of the phagocytosis-mediated red cell destruction takes place in the organs just
mentioned, and it is therefore called extravascular hemolysis.
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 In some cases, the nature of the antibody (usually an IgM antibody) is such that the
antigen-antibody complex on the surface of red cells is able to activate complement
(C).
 As a result, a large amount of membrane attack complex will form, and the red
cells may be destroyed directly; this is known as intravascular hemolysis.

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 The direct Coombs' test
 The diagnosis of warm agglutinin AIHA is based upon detection of antibody on
the surface of the RBC, or of the consequences of its interaction with the red
cell.

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 The beauty of this test is that it directly detects the pathogenetic mediator of the
disease, i.e., the presence of antibody on the red cells themselves.

 When the test is positive, it clinches the diagnosis, and when it is negative, the
diagnosis is unlikely.

 However, the sensitivity of the Coombs test varies depending on the technology
that is used, and in doubtful cases a repeat in a specialized lab is advisable; the
term "Coombs-negative AIHA" is a last resort.

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 In some cases, the autoantibody has a defined identity: it may be specific for an
antigen belonging to the Rhesus system (it is often anti-e).

 In many cases it is regarded as "unspecific" because it reacts with virtually all types
of red cells.

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 The AIHA are usually diagnosed by demonstrating an abnormality in a single
clinical laboratory test, the direct antiglobulin test first described by Coombs and
therefore sometimes called the direct Coombs' test.
 In this test, the RBCs of the patient are washed free of adherent proteins and
reacted with antiserum or monoclonal antibodies prepared against the various
immunoglobulins, particularly IgG and a fragment of the third component of
complement, C3d.
 If either or both of these are present on the red cell surface, agglutination or
some other endpoint will be detected.

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 When these tests are accurately and specifically performed, over 99 % of pts with
warm agglutinin AIHA will exhibit a positive result compared to less than 1 % of
the normal population.

 It is important to know whether IgG or C3 or both are present on the red cells.

 The presence of C3 but not IgG can be explained by one of two

mechanisms:
 First, the antibody is not IgG; this is the case for IgM cold agglutinins and the
rare IgA antibodies.
 Second, the antibody is IgG but so poorly fixed to the RBC surface that it is
removed as the cells are washed in preparation for the test. This reduction in
affinity may be temperature-related. 46
 The indirect antiglobulin (Coombs') test, in which the patient's serum is
incubated with normal red cells in order to test for circulating antibodies, is
generally of little value except in two circumstances:

47
 Warm Agglutinin Disease
 The most common form of AIHA is that due to IgG antibody able to react with its
antigen at core body temperature, the so-called "warm agglutinins".

 These account for more than 80 percent of all cases of AIHA.

 It is not clear why autoantibody production should begin.

 IgM antibodies to autoantigens are normally present in the plasma, although at low
and nonpathologic levels.

48
 It has been suggested that the B-cell clones that normally produce these
autoantibodies are altered or de-repressed to produce IgG antibodies in high and
pathogenetic titer in AIHA.

 In some patients, autoantibody production is initiated or exacerbated by an immune

reaction to a microbial infection (heteroimmune response).

 This is most likely to occur in children with viral infections, and results in the
production of autoantibody beginning one to three weeks after the initial
infection and lasting for one to three months.

 A reaction to blood transfusion or transplantation may also initiate this process

(alloimmune response)
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 The production of antibodies to erythrocyte autoantigens is most frequently the sole
evidence of immune dysfunction; this syndrome is called "idiopathic" AIHA.

 However, AIHA may occur in a number of disease states characterized by other

abnormalities in the immune system; these conditions should be considered when
appropriate in any patient with AIHA:
1. Autoantibodies may be seen in babies and children with any of a variety of
congenital abnormalities of the immune system. Examples are the autoimmune
lymphoproliferative syndrome and common variable immunodeficiency.

50
2. Viral attack on the immune system may result in the production of
autoantibodies, as in HIV infection and infectious mononucleosis.
3. There is a much higher than normal incidence of autoantibodies in patients with
SLE or, to a lesser extent, rheumatoid arthritis, scleroderma, dermatomyositis,
ulcerative colitis, and other diseases thought to be autoimmune in origin.
4. Malignancies of the immune system have an increased incidence of AIHA due
to IgG antibody. As an example, the incidence of AIHA is estimated at 11 % in
patients with CLL and 3% in NHL.

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 Acquired Causes
 Infections:
 Malaria
 Life-threatening intravascular hemolysis, due to a toxin with lecithinase activity,
occurs with:
 Clostridium perfringens sepsis
 Most frequent cause is probably Shiga toxin–producing Escherichia coli
O157:H7, now recognized as the main etiologic agent of the hemolytic-
uremic syndrome, more common in children than in adults.
 Toxins: snake venom
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 Drugs:
 Drugs can cause hemolysis through at least two other mechanisms.
1. A drug can behave as a hapten and induce antibody production. In rare
subjects this happens, for instance, with penicillin. Upon a subsequent
exposure, red cells are caught, as innocent bystanders, in the reaction
between penicillin and antipenicillin antibodies. Hemolysis will subside as
soon as penicillin administration is stopped.

53
2. A drug can trigger, perhaps through mimicry, the production of an
antibody against a red cell antigen. The best known example is
methyldopa, an antihypertensive agent no longer in use, which in a small
fraction of patients stimulated the production of the Rhesus antibody anti-e.
In patients who have this antigen the anti-e is a true autoantibody, which
would then cause an autoimmune HA. Usually this would gradually
subside once methyldopa was discontinued.

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 A number of drugs have been found to elicit immune reactions that result in
hemolysis. In one series that included 71 patients with 73 episodes of drug-related
immune hemolytic anemia, the most commonly implicated agents were :
 Cephalosporins — 37 episodes
 Penicillin/penicillin derivatives — 12 episodes
 Nonsteroidal antiinflammatory drugs — 11 episodes
 Quinine/quinidine — 7 episodes
 All others — 6 episode

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 Clinical Features
 The clinical syndrome seen with AIHA of the warm-antibody type varies greatly
with the amount and effectiveness of the causative antibody.
1. When the amount is small or the antibody is inefficient at effecting hemolysis,
the patient may be asymptomatic even if slightly anemic.
2. More commonly, the patient may complain of shortness of breath and dyspnea
on exertion. If the hemolysis is severe and of sudden onset, symptoms may be
those of severe degrees of cardiac decompensation, including heart failure,
arrhythmia, and/or chest pain, constituting a medical emergency.
3. Physical examination usually reveals the presence of pallor and jaundice. The
spleen is usually enlarged to a moderate degree. 56
 Diagnosis
 Accurate diagnosis requires the documentation of the presence of hemolysis along
with demonstration of the presence of a warm-reacting autoantibody on the surface
of the patient's red cells .
1. Anemia is usually present and may be severe. The MCHC is increased,
reflecting the presence of spherocytes. If anemia has been present long enough,
the absolute reticulocyte count will be elevated, reflecting the bone marrow's
response to anemia.
2. Laboratory findings indicating the presence of hemolysis include elevated
levels of indirect bilirubin and LDH, along with reduced levels of haptoglobin.

57
3. The peripheral blood smear shows the presence of spherocytes, usually with an
increased number of polychromatophilic red cells (reticulocytes).
4. The diagnosis of warm agglutinin AIHA is based upon detection of antibody on
the surface of the RBC, usually by the direct antiglobulin (Coombs') test. Over
99 % of patients with warm agglutinin AIHA will exhibit a positive result with
anti-IgG, anti-C3, or both.

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 Disease Complications
 Two potential complications of warm AIHA are the development of:
 A lymphoproliferative disorder and
 Venous thromboembolic disease

59
 Treatment
 The course of warm agglutinin AIHA varies with age.
 In children, AIHA is usually a self-limited disease, arising one to three weeks
after a viral infection and disappearing within one to three months.
 In adults, the disease is usually chronic and may be variably manifest for months
to years. The patient should be told of the chronic nature of this disease at the
time of diagnosis, since the subsequent course may be complex and protracted.

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 Severe acute AIHA can be a medical emergency.
 The immediate treatment almost invariably includes transfusion of red cells.
 This may pose a special problem b/c if the antibody involved is unspecific, all
the blood units cross-matched will be incompatible (presence of auto Ab
directed at a core component of Rh locus, w/ch is present on RBCs of all
potential donors, regardless of Rh subtype).
 In these cases it is often correct, paradoxically, to transfuse incompatible blood,
the rationale being that the transfused red cells will be destroyed no less but no
more than the patient's own red cells, but in the meantime the patient stays
alive.

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 A part from emergency blood transfusion, the first-line treatment of AIHA is by
using corticosteroids.
 In at least one-half of the cases, prednisone (1 mg/kg per day) will produce a
remission promptly.
 Whereas some patients are then apparently cured, relapses are not uncommon.

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 Treatment of warm agglutinin AIHA is aimed at either reducing the amount of
antibody being produced or reducing its efficiency in destruction of the red cells.
 These objectives are often pursued at the same time and success in treatment of
warm agglutinin AIHA (about 95 percent of the time) depends upon the
successful balancing of the several means available.

 Success does not mean cure, since there is usually evidence of persistent activity of
the underlying process. Rather, it means control of the degree of anemia sufficient
for most activities without excessive compromise of immunologic responsiveness.

63
 Treatment should also be aimed at cessation of any possible offending drug (eg,
penicillin) and at any underlying disease that might be present, such as SLE or
CLL.

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 Reduction In Antibody Production
1. Corticosteroids — are frequently used as the first therapy for warm AIHA, as they
induce remission of antibody production in about 60 to 70 % of patients.
The initial doses used are usually quite high (1 mg/kg per day of prednisone or
its equivalent in adults).
Doses in children are generally similar.
The minimal prednisone dose capable of inducing remission has never been
established.
When successful, the effect on antibody production, manifest by a rising
hemoglobin concentration, is usually seen within one to three weeks.

65
 How corticosteroids act in this setting is not clear; some have suggested that the
simultaneous presence of steroid in its receptor and the antigen in its receptor
induces apoptosis of specifically-programmed T-cells.

 Once remission has been achieved, the steroid dose must be tapered.
 In children, this can be done quite rapidly since the disease process is often self-
limited. In adults, tapering should be more gradual in an attempt to find the
lowest dose that will maintain an adequate remission.
 This process must take into account the fact that evidence of an insufficient dose
will not be apparent for three to four weeks.
 Based on our experience, we have found the following schedule to be useful:
66
 After a sufficient hemoglobin concentration (usually >10 g/dL) has been
achieved, maintain the prednisone dose at 60 mg/day for one week.
 Rapidly taper the dose to 20 mg/day over a period of two weeks. This is the largest
dose that will be tolerable over time. Maintain this dose for 1 month.
 If remission persists, gradually reduce the dose on alternate days to 10 mg/day.
Maintain this regimen for 1 month.
 If remission persists, omit the dose on alternate days while maintaining the dose
at 20 mg every other day.
 If remission persists, reduce the dose to 10 mg/day on alternate days. This dose
should be maintained as long as remission persists and the direct Coombs' test
remains positive.
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 If, at any time during this dose tapering process, the remission is not maintained,
other measures (cytotoxic therapy or splenectomy) must be instituted.
 This approach is also warranted in patients who show no response to
prednisone after two to three weeks.

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2. Immunosuppressive drugs
3. Monoclonal antibodies — Multiple case reports have indicated success with use
of the monoclonal anti-CD20 antibody (rituximab) in patients with resistant AIHA
and/or Evans syndrome
4. Danazol

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 Reduction In Antibody Effectiveness
 The hemolytic process can be reversed either by removing the primary site of
destruction via splenectomy, or by reducing the interaction between splenic
macrophages and the antibody-coated RBCs with intravenous immune globulin.
1. Splenctomy
2. IVIG

70
 Monitoring Disease Response
 The magnitude of hemolysis and response to treatment can be serially monitored by
use of those laboratory tests initially employed for establishing the presence of
hemolysis (eg, LDH, haptoglobin, indirect bilirubin, Coombs test).

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 INHERITED
HEMOLYTIC ANEMIAS

72
 HA Due to Abnormalities of the Membrane-Cytoskeleton Complex

 Membrane-cytoskeleton complex:
 Is indeed so integrated
 An abnormality of almost any of its components will be disturbing or disruptive
 Cause structural failure
 Results ultimately in hemolysis
 These abnormalities are almost invariably inherited mutations

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 Before the red cells lyse :
 They often exhibit morphologic changes
 That alter the normal biconcave disc shape

 Majority of diseases in this group have been known as :

 Hereditary Spherocytosis (HS) and
 Hereditary Elliptocytosis (HE)

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 Hereditary Spherocytosis
 Relatively common type of hemolytic anemia
 Estimated frequency of at least 1 in 5000
 Inherited as an autosomal dominant condition
 Defined as an inherited form of HA associated with :
 Presence of Spherocytes in the peripheral blood
 Presence of osmotic fragility : main diagnostic test for HS:
 abnormally susceptible to lysis in hypotonic media

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 Clinical Presentation and Diagnosis of HS
 spectrum of clinical severity of HS is  The main clinical findings are:
broad  Jaundice
 Severe cases :  Enlarged spleen
 present in infancy with severe  Gallstones
anemia  Finding of gallstones in a young
 Mild cases : person triggers diagnostic
 present in young adults or even investigations.
later in life

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 Variability in clinical manifestations of HS :
 Due to different underlying molecular lesions
 In milder cases :
 Hemolysis is often compensated
 Cause variation even in the same patient
 Due to the fact that intercurrent conditions (e.g., infection) cause
decompensation

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 The anemia is usually normocytic :
 With the characteristic morphology gives the disease its name
 A characteristic feature :
 Increase in mean corpuscular hemoglobin concentration (MCHC):
 This is almost the only condition in which high MCHC is seen.

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 In most cases the diagnosis is confirmed :
 On the basis of red cell morphology and
 A test for osmotic fragility
 A modified version of which is called the "pink test.“
 In some cases a definitive diagnosis :
 Can be obtained only by molecular studies
 Demonstrating a mutation in one of the genes underlying HS

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 Treatment of Hereditary Spherocytosis
 Currently no treatment aimed at the cause of HS
 No way to correct the basic defect in the membrane-cytoskeleton structure
 Splenectomy :
 Prime and obligatory therapeutic measure in HS
 Reasons :
 Spleen plays a special role in HS through a dual mechanism :
 Spleen itself is a major site of destruction
 Transit through the splenic circulation makes the defective red cells more
spherocytic and therefore accelerates their demise
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 Splenectomy also increases the risk of certain infections : not evidence-based :
 Avoid splenectomy in mild cases.
 Delay splenectomy until at least 4 years of age
 Antipneumococcal vaccination before splenectomy is imperative ( penicillin
prophylaxis postsplenectomy is controversial)
 HS patients often may require cholecystectomy. It used to be considered
mandatory to combine this procedure with splenectomy, but this may not be
always necessary.

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