Hemolytic anemia

Common causes of hemolytic anemia 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
 Conti….
#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
• 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 , platelet & WBCs count
are normal.
- G6PD levels are low b/n hemolytic episodes.
• 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
-
• NB intravascular hemolysis: High LDH and low heptoglobulin.
• A.I HA- coombs test positive
• A.I HA
-Hemolysis is of extra vascular type & peripheral smear may show spherocytes.
-coomb`s test positive
-WBCs & platelates counts are normal.
• 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 Cx of d/o.
- BM may be hypocellular.
- Flow cytometry is a better chioce & confirms the dx by showing absence of CD59.
• 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 (Chap. 101). 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. 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 (see below)]; frank hemolysis and
thrombotic episodes occur in patients with large PNH clones (>50%).
• 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.
• 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
- A positive direct antiglobulin test (Coombs test)
- Increased reticulocyte percentage or absolute reticulocyte number,
indicating the bone marrow's response to the anemia
• Confirming hemolysis — The combination of an increased
serum LDH and a reduced haptoglobin is 90 percent specific
for diagnosing hemolysis, while the combination of a normal
serum LDH and a serum haptoglobin >25 mg/dL is 92 percent
sensitive for ruling out the presence of hemolysis.
• LDH(specifically the LD1 and LD2 isoforms), released from hemolyzed
RBCs, and haptoglobin, which binds to hemoglobin released during
intravascular or extravascular hemolysis or ineffective erythropoiesis with
release of hemoglobin from late erythroid precursors in the bone marrow.
• 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.
• 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 %.
• 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."
• Determining the cause — The different causes for hemolysis
are reviewed above . 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).
 Atypical presentation

• Hemolysis with out anemia

• Hemolysis with out reticulocytosis
 AIHA
• 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.
• 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.
3. 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
• Antibody detection: 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.
• 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.
• When these tests are accurately and specifically performed, over 99 % of
patients 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.
• 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. 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 [19,20] . A reaction to
blood transfusion or transplantation may also initiate this process
(alloimmune response)
• 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.
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.
• DRUG-RELATED IMMUNE HEMOLYSIS
- 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 [45] :
- Cephalosporins — 37 episodes
- Penicillin/penicillin derivatives — 12 episodes
- Nonsteroidal antiinflammatory drugs — 11 episodes
- Quinine/quinidine — 7 episodes
- All others — 6 episode
 C/f
• 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.
 Dx

• 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.
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.
 Etiology

• Most cases of warm agglutinin AIHA are idiopathic. Associated disorders

may include :
• Preceding viral infection, usually in children
• Autoimmune disorders, especially systemic lupus erythematosus
• Lymphoproliferative diseases (eg, chronic lymphocytic leukemia)
• Drugs (eg, penicillin, methyldopa)
• Allogeneic blood transfusion or hematopoietic cell transplantation
• DISEASE COMPLICATIONS — Two potential complications of warm AIHA
are the development of a lymphoproliferative disorder and venous
thromboembolic disease.
 Indications for treatment

•  Most patients with AIHA present with an acute onset of severe hemolysis
with symptomatic anemia, requiring immediate treatment. In patients with
underlying cardiac disease, AIHA can present as a medical emergency,
requiring immediate packed red cell transfusion.
• Initial treatment — Once the diagnosis of symptomatic warm agglutinin
AIHA is confirmed, we recommend immediate institution of treatment with
corticosteroids over splenectomy or use of other immunosuppressive agents
• Poorly responsive or resistant disease -For patients not responding to
corticosteroids, or for those who require large doses of corticosteroids to
maintain their response, we suggest elective splenectomy . For patients
unwilling or unable to undergo splenectomy, we suggest the institution of
immunosuppressive or cytotoxic agents (eg, azathioprine,
cyclophosphamide, cyclosporine, rituximab) . At the present time, there is
not sufficient information to choose one of these agents over another.
 TREATMENT OVERVIEW

• 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.
• Of importance, AIHA can present as a medical emergency in some
patients, especially those with underlying cardiac disease. Immediate
transfusion of blood, which requires urgent discussion with blood bank
personnel, can be life-saving.
• 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.
• 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. An extensive list of drugs associated with immune
hemolytic anemia and/or a positive direct Coombs test is available .
 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).
 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.
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:
• 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
one month.
• If remission persists, gradually reduce the dose on alternate days to 10
mg/day. Maintain this regimen for one 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.
• 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.

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 
 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
 Harrision
• Coombs and known since by his name. 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. 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.
 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. In most cases the Fc portion of the antibody will
be recognized by the Fc receptor of macrophages, and this will trigger
erythrophagocytosis (Fig. 106-7). 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. 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.
 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
• 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.
(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 (see below). Usually this
would gradually subside once methyldopa was discontinued.
 Treatment: Autoimmune Hemolytic Anemia

• 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. 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. Clearly, this rather unique situation
requires good liaison and understanding b/n the clinical unit treating the
patient and the blood transfusion/serology lab.
• Transfusion is due to:
- Presence of autoAb directed at a core component of Rh locus, w/ch is
present on RBCs of all potential donors, regardless of Rh subtype.
• 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
• Although unfortunately most of the management of AIHA is not evidence-
based, for patients who do not respond and for those who have relapsed (or
who require more than 15 mg/d of prednisone to prevent relapse), it is
highly recommended to consider a second-line treatment option, which
might be either splenectomy or rituximab (anti-CD20).
• Splenectomy, although it does not cure the disease, can produce significant
benefit by removing a major site of hemolysis, thus improving the anemia
and/or reducing the need for other therapies (e.g., the dose of prednisone).
• Rituximab has emerged as a significant alternative to splenectomy b/c it can
produce remissions in up to 80% of patients and it can be used repeatedly,
even though progressive multifocal leukoencephalopathy is a dreaded if rare
side effect.
• Azathioprine, cyclophosphamide, cyclosporine, and IV immunoglobulin have
become third-line agents since the introduction of rituximab.
• In severe refractory cases, either auto- or allohematopoietic stem cell
transplantation has been used, sometimes successfully.
• presence of warm agglutinins is almost always due to IgG antibodies that
react with protein antigens on the red blood cell (RBC) surface at body
temperature. For this reason, they are called "warm agglutinins" even
though they seldom directly agglutinate the RBCs.
• causes or conditions which may be associated with AIHA include the
following:
- Viral infections (usually in children)
- Autoimmune and connective tissue diseases (particularly systemic lupus
erythematosus)
- Malignancies of the immune system (eg, non-Hodgkin lymphoma, chronic
lymphocytic leukemia (CLL), with a higher incidence in those treated with
purine analogs)
- Prior allogeneic blood transfusion or hematopoietic cell transplantation.
- Certain drugs .
• Direct Coombs' test — 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.
• When these tests are accurately and specifically performed, 97 to 99
percent of patients with warm agglutinin AIHA will exhibit a positive result
with anti-IgG, anti-C3, or both, compared to less than 1 percent of the
normal population

• 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:
DISEASE COMPLICATIONS — Two potential complications of warm AIHA are
the development of a lymphoproliferative disorder and venous
thromboembolic disease.

• Lymphoproliferative disorder — The onset of AIHA may either precede or

follow the diagnosis of a lymphoproliferative disorder [28] . In one series
of 107 patients with idiopathic AIHA, 18 % developed a malignant
lymphoproliferative disorder (LPD) after a median time of approximately
two years (range: 9 to 76 months) [29] . The following were risk factors for
development of LPD in this group of patients: Advanced age Underlying
autoimmune disease The presence of a monoclonal IgM gammopathy

• AIHA may also follow the use of purine analog therapy in patients with CLL
or other indolent NHL variants.
• The laboratory features of HA are related to hemolysis per se and the
erythropoietic response of the bone marrow.
• Hemolysis regularly produces in the serum an increase in unconjugated
bilirubin and aspartate transaminase (AST); urobilinogen will be increased
in both urine and stool.
• If hemolysis is mainly intravascular, the telltale sign is hemoglobinuria
(often associated with hemosiderinuria); in the serum there is increased
hemoglobin, LDH is increased, and haptoglobin is reduced.
• In contrast, the bilirubin level may be normal or only mildly elevated. The
main sign of the erythropoietic response by the bone marrow is an
increase in reticulocytes ; a test all too often neglected in the initial
workup of a patient with anemia.
• Usually the increase will be reflected in both the percentage of
reticulocytes (the more commonly quoted figure) and the absolute
reticulocyte count (the more definitive parameter). The increased number
of reticulocytes is associated with an increased MCV in the blood count.
• On the blood smear, this is reflected in the presence of macrocytes; there
is also polychromasia and sometimes one sees nucleated red cells.
• In most cases, a bone marrow aspirate is not necessary in the diagnostic
workup; if it is done, it will show erythroid hyperplasia. In practice, once a
HA is suspected, specific tests will usually be required for a definitive
diagnosis of a specific type of HA.
• On peripheral blood smears, lymphoblasts vary from small
cells with scant cytoplasm, condensed nuclear chromatin,
and indistinct nucleoli to larger cells with moderate amounts
of cytoplasm, dispersed chromatin, and multiple nucleoli. A
few azurophilic cytoplasmic granules may be present. Auer
rods are never present.

• AIHA: Spherocyte is due to interaction b/n splenic

macrophage and Ab coated RBCs resulted in removal of
portion of red cell mrn.
• Aspirin treatment failure — Treatment failure following the use of
aspirin is a clinical observation, which can be operationally defined as the
failure of aspirin to prevent clinical atherothromboembolic ischemic
events. However, treatment failure does not necessarily imply
"resistance," since no effective cardiovascular drug prevents ALL events.

• Aspirin resistance — Aspirin resistance is a laboratory phenomenon, in

which there is the inability of aspirin to inhibit one or more in vitro tests of
platelet function
• Until further data are forthcoming, we suggest against laboratory testing
of patients for "aspirin resistance" and we suggest against use of
alternative agents such as clopidogrel in patients with aspirin nonresponse
based upon the results of in vitro assays (Grade 2C). Similar conclusions
have been reached by others, including the 2005 Working Group on
Aspirin Resistance, a 2005 review of the available evidence, and the 2008
American College of Chest Physicians Clinical Practice Guidelines
• Possible mechanisms — The biologic mechanisms by which aspirin
nonresponse might occur are not well understood . The following are
among the hypotheses that have been proposed in addition to
noncompliance with aspirin
- Platelet function inhibition by aspirin may be a matter of degree, rather
than being "all or none." Accordingly, underdosing or poor absorption of
aspirin may also be a factor in aspirin nonresponse
- Drug interactions, such as with nonaspirin NSAIDs (eg, ibuprofen)
- There may be an intrinsic platelet mechanism that allows thromboxane
production despite the presence of aspirin. Such an effect could be related
to polymorphisms in the COX-1 gene that confer relative nonresponse to
low dose aspirin or to residual thromboxane production that may be
independent of COX-1 and COX-2
 Diarrhea w/o blood ,fever ,abdominal pain but no
vomiting: etiology
1. Invasive organisms
- Salmonella, Campylobacter, and Aeromonas species, Vibrio
parahaemolyticus, Yersinia 

2. Enteroadherent
- Enteropathogenic and enteroadherent E. coli, Giardia organisms,
cryptosporidiosis, helminths 

3. Cytotoxin producers
- C. difficile