Transcript ACQUIRED HEMOLYTIC ANEMIAS: Immunologic Causes of

Hemolysis:
premature destruction
of the red cells
RBC normally survive 90 to 120 days in the circulation.
Kind of hemolysis:
Extravascular Hemolysis:
RBC prematurely removed from the
circulation by macrophages, particularly those
of the spleen and liver
intravascular hemolysis:
 less commonly, by disruption of their
membranes during their circulation
------------------------------------------------The level of unconjugated bilirubin never exceeds
70 to 85 umol/L (4 to 5 mg/dL), unless liver function
is impaired.
Hemoglubin
Heme
Protopurphyrin
Unconjugated bil
Conjugated bil
Fe
globulin
Aminoacide
(LDH), particularly LDH-2, is elevated
Serum AST (SGOT) may be somewhat elevated,
whereas ALT (SGPT) is not.
Haptoglobin :
High concentration (~1.0 g/L) in the plasma (and serum)
It binds specifically and tightly to the globin in
hemoglobin
Cleared within minutes by the mononuclear phagocyte
system.
Is decreased in patients with hepatocellular
disease and increased in inflammatory states
plasma hemoglobin is increased in proportion to
the degree of hemolysis
Plasma hemoglobin may be falsely elevated due to
lysis of RBC in vitro
Hemosiderin appears 3 to 4 days after the onset of
hemoglobinuria and may persist for weeks after
its cessation.
glomerular permeability than myoglobin and is
less rapidly cleared by the kidneys.
the urine is positive with the benzidine reaction:
Hemoglobinuria , Hematuria , myoglobinurea
The distinction between hemoglobinuria and myoglobinuria:
Can best be made by specific tests that exploit immunologic differences
Differences in solubility:
After centrifugation of an anticoagulated blood
specimen, a reddish-brown color (Hb)
normal in color (myoglobin)
Because of its higher molecular weight, hemoglobin
has lower glomerular permeability than myoglobin
and is less rapidly cleared by the kidneys.
Classification of Hemolytic Anemias
Intra
corpuscular
1. Abnormalities of RBC interior
a. Enzyme defects
b. Hemoglobinopathies (Chap. 106)
2. RBC membrane abnormalities
a. Hereditary spherocytosis etc.
b. Paroxysmal nocturnal hemoglobinuria
Extra
corpuscular
c. Spur cell anemia
3. Extrinsic factors
a. Hypersplenism
b. Antibody: immune hemolysis
c. Microangiopathic hemolysis
d. Infections, toxins, etc.
Heredtary
Acquired
In intracorpuscular types of hemolysis, the patient's RBC have an abnormally
short life span in a normal recipient (with a compatible blood type), while
compatible normal RBC survive normally in the patient. The opposite is true in
extracorpuscular types of hemolysis.
INHERITED HEMOLYTIC ANEMIAS
Defects are often known at the genomic level
1- The membrane
2-The enzyme
3-Hemoglobin
Red Cell Membrane Disorders These are usually
readily detected by morphologic abnormalities of
the RBC on the blood film
Three types of inherited RBC membrane abnormalities:
1- Hereditary spherocytosis
2- Hereditary elliptocytosis
4- hereditary stomatocytosis.
3- pyropoikilocytosis
This condition is characterized by :
DEFECT OF ONE PROTEIN OF CYTOSKELATON
LOSS OF RBC MEMBRANE 
S/V DECREASE 
SPHEROCYTOSIS
 usually has an autosomal dominant
1:1000 to 1:4500
~20% autosomal recessive inheritance or a spontaneous mutation
The disorder is sometimes clinically apparent in early infancy but
often escapes detection until adult life.
Hereditary spherocytosis
CLINICAL MANIFESTATIONS
•
Anemia
1. anemia is usually mild or moderate and may even be
absent in an otherwise healthy individual
2. erythroid hyperplasia of the bone marrowextramedullary
3.
erythropoiesis paravertebral masses visible on chest x-ray
episodes of relative erythroid hypoplasia precipitated by infections,
particularly parvovirus, trauma, surgery, and pregnancy
• Splenomegaly
4.
Splenomegaly is very common
5.
The hemolytic rate may increase transiently during systemic infections, which
induce further splenic enlargement.
• Jaundice("congenital hemolytic jaundice“)
Jaundice may be intermittent and tends to be less pronounced in early childhood
pigmented gallstones are common
• Chronic leg ulcers
Hereditary spherocytosis
Laboratory:
•MCV: is usually normal or slightly decreased
•MCHC : is increased to 350 to 400 g/L
•Osmotic fragility test: increased
• PBS :spherocytes are usually detected as small cells
without central pallor
•They will ordinarily not influence the osmotic
fragility test unless they constitute more than 1 or 2%
of the total cell population
•The autohemolysis test is also useful.
Hereditary spherocytosis
OSMOTIC FRAGILITY TEST
Hereditary spherocytosis
Hereditary spherocytosis
PATHOGENESIS :
PROTEIN DEFICIENCY
Nearly all patients have a significant deficiency of spectrin
50% of patients have a defect in ankyrin
25% of patients have a mutation of protein 3
remaining 25% have mutations of spectrin, leading to impaired synthesis or selfassociation
b-spectrin deficiency is generally mild, with dominant inheritance
a-spectrin deficiency is severe, with a recessive inheritance pattern.
"conditioning“: the lipid bilayer is not well anchored when these proteins are defective part
of it is lost by vesiculation resulting in a more spherical less deformable cell.
DESTRUCTION ON SPLEEN
"conditioning" produces a subpopulation of hyperspheroidal RBC in the peripheral
blood.
DIFERENTIAL DIAGNOSIS:
1. Immune spherocytosis
2. Cirrhosis
3. In clostridial infections,
4. Certain snake envenomations
5. Glucose -6-phosphate dehydrogenase (G6PD)
deficiency.
Hereditary spherocytosis
TREATMENT:
1- Splenectomy
•corrects the anemia, although the RBC defect and its consequent
morphology persist
•The operative risk is low
•splenectomy should be performed in symptomatic individuals
• cholecystectomy should not be performed without
splenectomy, as intrahepatic gallstones may result
•Splenectomy in children should be postponed until age 4
•Polyvalent pneumococcal vaccine should be administered at least 2
weeks before splenectomy
2- folic acid (1 mg/d) should be administered prophylactically.^
Hereditary elliptocytosis :
Oval or elliptic RBC are normally found in birds, reptiles, camels, and llamas
autosomal dominant trait
1 per 4000 to 5000 people (similar to that of hereditary
acquired elliptocytosis : rarely in patients with MDS
PATOGENESIS :
1- Spectrin Def.
2- protein 4.1 Def.
PRESENTATION :
MILD ANEMIA (HB>120 RET<4%
In 10 to 15% of patients with more severe abnormalities, the rate of hemolysis is
substantially increased, with median survival times of RBC as short as 5 days
and reticulocytes ranging up to 20%.
RBC destruction occurs predominantly in the spleen, which is enlarged in
patients with overt hemolysis
Hemolysis is corrected by splenectomy.
Hereditary elliptocytosis
at least 25% and, more commonly, >75% of RBC are elliptic, with
an axial ratio (width/length) of <0.78. Patients with hemolysis
frequently have microovalocytes, bizarre-shaped RBC, and RBC
fragments, all of which increase in number after splenectomy.
The degree of hemolysis does not correlate with the percentage of
elliptocytes.
Osmotic fragility is usually normal but may be increased in
patients with overt hemolysis.
Hereditary pyropoikilocytosis:
• rare disorder
• bizarre-shaped, microcytic RBC that undergo
disruption at temperatures of 44 to 45°C
• normal RBC are stable up to 49°C
• Hemolysis is usually severe
• recognized in childhood, and is partially responsive to
splenectomy.
Hereditary Stomatocytosis:
cup-shaped RBC (concave on one face and convex on the other).
This formation results in a slitlike central zone of pallor on dried smears.
autosomal dominant pattern.
RBC have an increased permeability to sodium and potassium
overhydrated stomatocytes, "hydrocytosis“
In some patients, the RBC are swollen with an excess of ions and water and a
decreased mean corpuscular hemoglobin concentration (many of these patients lack
the RBC membrane protein 7.2 (stomatin)
These are true stomatocytes on dried smears.
dehydrated stomatocytes, "desiccytosis" or "xerocytosis"
In other patients, the RBC are shrunken, with a decreased ion and water content and
an increased mean corpuscular hemoglobin concentration
Theas assume the morphology of target cells on dried smears
Osmotic fragility is increased in overhydrated stomatocytes and decreased
in underhydrated stomatocytes
RBC lacking Rh proteins (Rhnull cells) are stomatocytic and have a shortened life
span
Sign & symptom :splenomegaly and mild anemia
Treatment: Splenectomy decreases but does not totally correct the hemolytic
process.
Red Cell Enzyme Defects
The RBC loses its nucleus, ribosomes, and mitochondria and
thus its capability for protein synthesis and oxidative
phosphorylation.
ATP must be generated from the Embden-Meyerhof pathway to:
•
•
•
Drive the cation pump that maintains the ionic milieu in the
RBC. Preservation of hemoglobin iron in the ferrous (Fe2+)
state
For the renewal of the lipids in the RBC membrane.
About 10% of the glucose consumed by the RBC is metabolized
via the hexose-monophosphate shunt which protects both
hemoglobin and the membrane from exogenous oxidants,
including certain drugs
Red Cell Enzyme Defects
Defects in the Embden-Meyerhof Pathway
may be restricted to RBC or not
Mutations can result in no protein product, a dysfunctional product,
or an unstable product
These enzymopathies have similar pathophysiologic and clinical
features
Patients present with a congenital nonspherocytic hemolytic anemia
of variable severity
The RBC are often relatively deficient in ATP, resulting in a leak of
potassium ion out of these cells
These RBC are rigid and thus more readily sequestered by the
mononuclear phagocyte system.
pyruvate kinase (PK) deficiency and hexokinase deficiency are
localized to the RBC
Glucose phosphate isomerase deficiency and phosphoglycerate
kinase deficiency also involve leukocytes
Red Cell Enzyme Defects
Defects in the Embden-Meyerhof Pathway
Individuals with deficiency of triose phosphate isomerase
have decreased levels of enzyme in leukocytes, muscle cells,
and cerebrospinal fluid, and they have a progressive
neurologic disorder.
Some patients with phosphofructokinase deficiency have a
myopathy.
Incidence: defects in the glycolytic pathway
PK deficiency :
95%
glucose phosphate isomerase deficiency: 4%
Other
1%
Red Cell Enzyme Defects
Defects in the Embden-Meyerhof Pathway
A number of different mutations result in PK deficiency.
There is considerable variability in the clinical
manifestations and laboratory findings among
individuals reported as having PK deficiency
Most of these patients are compound heterozygotes who
have inherited a different defective enzyme from each
parent.
autosomal recessive pattern: most ofen (the parents are
entirely asymptomatic)
Phosphoglycerate kinase deficiency is inherited as a sexlinked disorder|(male sever anemia
female mild
hemolytic anemia )
Red Cell Enzyme Defects
Defects in the Embden-Meyerhof Pathway
CLINICAL MANIFESTATIONS
Anemia
jaundice
splenomegaly
LABORATORY FINDINGS
•PBS normocytic (or slightly macrocytic), normochromic anemia with reticulocytosis.
• In those with PK deficiency, bizarre erythrocytes, including spiculated cells, are noted
on the peripheral smear, especially after splenectomy.
•Spherocytes are usually absent; hence the term congenital nonspherocytic hemolytic
anemia
• the osmotic fragility of freshly drawn blood is usually normal
•AUTOHEMOLYSIS TEST
• Incubation brings out an osmotically fragile population of RBC, an abnormality not
corrected by the addition of glucose.
• specific enzymatic assays
Red Cell Enzyme Defects
Defects in the Embden-Meyerhof Pathway
TREATMENT:
•Most patients do not require therapy
•Those with severe hemolysis should be given folic acid (1 mg/d)
•Blood transfusions may be necessary during a hypoplastic crisis
•Women with PK deficiency may become very anemic during pregnancy
sometimes leading to the diagnosis for the first time
splenectomy
•PK
•glucose phosphate isomerase
•not been proven effective in individuals with other glycolytic enzymopathies.
Red Cell Enzyme Defects:
Defects in the hexose-monophosphate shunt
Glucose metabolism via the hexose-monophosphate shunt
Reduced glutathione
protecting the sulfhydryl groups of hemoglobin and the RBC
membrane from oxidation
inherited defect in the hexose-monophosphate shun
unable to maintain an adequate level of reduced
glutathione in their RBC
Hemoglobin sulfhydryl groups become oxidized
The hemoglobin precipitates within the RBC
forming Heinz bodies.
Red Cell Enzyme Defects
Defects in the hexose-monophosphate shunt :G6PD DEFICIENCY
most common congenital shunt defect
defective home for the merozoite
over 400 variants of G6PD
In most cases, the alteration is a base substitution, leading to an amino acid
replacement
DIFERENT SEVERITY:
nonspherocytic hemolytic anemia without demonstrable oxidant stress (particularly
shortly after birth)
through hemolytic anemia only when stimulated by marked to mild oxidant stress,
to no clinically detectable abnormality
TYPE B: The normal G6PD
TYPE A+: About 20% of individuals of African descent have a G6PD (that differs
by a single amino acid and is electrophoretically distinguishable but functionally
normal. .
type A- : same electrophoretic mobility as the A+ type, but it is unstable and has
abnormal kinetic properties 11% of African American males
Mediterranean type more severe than the AChinesetype : less severe variant
Red Cell Enzyme Defects
Defects in the hexose-monophosphate shunt :G6PD
FICIENCY:
sex-linked trait( x linked )
males (hemizygotes)
female carriers (heterozygotes):Lyon hypothesis
Most female carriers are asymptomatic
G6PD activity normally declines ~50% during the 120-day life span of the RBC
A-Varien( mild non clinical anemia )
Stess factor:some type of environmental stress
viral and bacterial infections(most often)mechanism is
unknown
most commonly sulfa drugs, antimalarials, and
nitrofurantoin
Although aspirin is frequently mentioned as a likely offender,
Red Cell Enzyme Defects
G6PD FICIENCY :
CLINICAL AND LABORATORY FEATURES
acute hemolytic crisis within hours of exposure to the oxidant stress
leading to hemoglobinuria and peripheral vascular collapse
hemolytic crisis is usually self-limited
Since only the older population of RBC is rapidly destroyed
A- variant, the RBC mass decreases by a maximum of 25 to 30%
laboratory
HCT
rise in plasma hemoglobin
unconjugated bilirubin
decrease in plasma haptoglobin
Heinz bodies, visualized by means of a supravital stain such as crystal violet.
Heinz bodies are usually not seen after the first day or so, since these inclusions
are readily removed by the spleen
 "bite cells" (RBC that have lost a peripheral portion of the cell)
Multiple bites cause the formation of fragments
Red Cell Enzyme Defects
Defects in the hexose-monophosphate shunt :G6PD
FICIENCY:
Mediterranean type G6PD:
much lower overall enzyme activity
more severe clinical manifestations
sensitive to fava beans:favism 
he oxidants in Vicia fava are two b-glycosides whose aglycones, when
autooxidized, produce oxygen free radicals.
Favism is not encountered in individuals with the A- variant.
Red Cell Enzyme Defects
Defects in the hexose-monophosphate shunt :
G6PD FICIENCY
The diagnosis of G6PD deficiency:
•In any individual, particularly a male of African or
Mediterranean descent, who experiences an acute
hemolytic episode.
•The enzyme activity or the effects of its deficiency.
•A false-negative result during a hemolytic episode when
the old RBC containing the defective enzyme have already
lysed.
Red Cell Enzyme Defects
Defects in the hexose-monophosphate shunt :G6PD
FICIENCY:
TREATMENT:
•no specific treatment is necessary.
•Since hemolysis in patients deficient in A- G6PD is usually
self-limited
•Splenectomy does not benefit
•Blood transfusions are rarely indicated
• Adequate urine flow
•Prevention of hemolytic episodes is best
•Infections ought to be treated promptly.
•warned about risks posed by oxidant drugs and fava beans
•Any patient of African or Mediterranean ancestry about to be
given an oxidant drug should be screened for G6PD deficiency
Red Cell Enzyme Defects
Table 108-4. Drugs Causing Hemolysis in
Subjects Deficient in G6PD
Antimalarials: Primaquine, pamaquine, dapsone
Sulfonamides: Sulfamethoxazole
Nitrofurantoin
Analgesics: Acetanilid
Miscellaneous: Vitamin K (water-soluble form), doxorubicin,
methylene blue, nalidixic acid, furazolidone, niridazole,
phenazopyridine
ACQUIRED HEMOLYTIC ANEMIAS:
RBC are made normally but are prematurely destroyed
because of damage acquired in the circulation.
he exceptions are rare disorders characterized by
acquired dysplasia of the cells of the bone marrow
Causes of Acquired Hemolytic Anemia
II. Immune
A. Warm-reactive (IgG) antibody
B. Cold-reactive IgM antibody (cold agglutinin disease)
C. Cold-reactive IgG antibody (paroxysmal cold
hemoglobinuria)
D. Drug-dependent antibody
1. Autoimmune
2. Haptene
III. Traumatic hemolytic anemia
A. Impact hemolysis
B. Macrovascular defects¾prostheses
C. Microvascular causes
1. Thrombotic thrombocytopenic purpura/hemolytic-uremic
syndrome
2. Other causes of microvascular abnormalities
3. Disseminated intravascular hemolysis
IV. Hemolytic anemia due to toxic effects on the
membrane
A. Spur cell anemia
B. External toxins
1. Animal or spider bites
2. Metals (e.g., copper)
3. Organic compounds
V. Paroxysmal nocturnal hemoglobinuria
ACQUIRED HEMOLYTIC ANEMIAS
Hypersplenism
blood circulatingspleenarterioleswhite pulp to sinuses(98%)
red pulpvenous
system
1 to 2%
"marginal zone" of the lymphatic white pulp
cells that occupy this zone are not phagocytic
serve as a mechanical filter
ACQUIRED HEMOLYTIC ANEMIAS
Hypersplenism:
The normal spleen retains reticulocytes for 1 to 2 days
In infiltrative diseases of the spleen, substantial splenomegaly may
exist with no apparent hemolysis;
inflammatory and congestive splenomegaly is commonly associated
with modest shortening of RBC survival time, along with more
marked granulocytopenia and thrombocytopenia.
ACQUIRED HEMOLYTIC ANEMIAS:Immunologic
Causes of Hemolysis
The Coombs antiglobulin test is the major tool for diagnosing
autoimmune hemolysis.
neither IgG nor complement may be found on the RBC of the
patient (Coombs-negative immune hemolytic anemia)
IgG anti c3 = warm Ab
IgM
= cold Ab
ACQUIRED HEMOLYTIC ANEMIAS
Table 108-6. Use of the Direct Coombs Test in Diagnosing the
Cause of Autoimmune Hemolytic Anemia
Reaction with
Anti-IgG
Anti-C3
Causes
Yes
No
Antibodies to Rh proteins, hemolysis
caused by a-methyldopa or penicillin
Yes
Yes
Antibodies to glycoprotein antigens, SLE
No
Yes
Cold-reacting antibodies (agglutinins or
Donath-Landsteiner antibody), most
drug-related antibodies, IgM antibodies,
IgG antibodies of low affinity, activation of
complement by immune complexes
ACQUIRED HEMOLYTIC ANEMIAS
:
Immunologic Causes of Hemolysis
"Warm" antibodies
nearly always IgG occasionally, they are IgA and rarely IgM
Hemolysis due to autologous antibodies is called autoimmune
hemolytic (or immunohemolytic) anemia, warm antibody type
ACQUIRED HEMOLYTIC ANEMIAS:Immunologic
Causes of Hemolysis
Warm" antibodies
CLINICAL MANIFESTATIONS
occurs at all ages, but it is more common in adults, particularly women.
one-fourth an underlying disease: next slide
The presentation quite variable
severe anemia [hemoglobin levels 60 to 100 g/L and reticulocyte counts
10 to 30%
spherocytosis
Splenomegaly
fulminant hemolysis associated with hemoglobinemia, hemoglobinuria,
and shock; this syndrome may be rapidly fatal unless aggressively
treated.
The direct Coombs test is positive in 98% of patients
usually IgG is detected with or without C3
Evans's syndrome : immune throbocytopenia + anemia
Occasionally, venous thrombosis occurs
ACQUIRED HEMOLYTIC ANEMIAS:
Immunologic Causes of Hemolysis
CLINICAL MANIFESTATIONS
Hemolysis due to Antibodies
WARM-ANTIBODY IMMUNOHEMOLYTIC ANEMIA
Idiopathic , Lymphomas: Chronic lymphocytic
leukemia, non-Hodgkin's lymphomas, Hodgkin's
disease (infrequent) ,SLE and other collagenvascular diseases Drugs , a-Methyldopa type
(autoantibody to Rh antigens) , Penicillin type
(stable hapten)
Quinidine type (unstable
hapten) , Postviral infections Other tumors (rare)
1.
COLD-ANTIBODY IMMUNOHEMOLYTIC ANEMIA
cCold agglutinin disease , Acute: Mycoplasma infection,
infectious mononucleosis , Chronic: Idiopathic,
lymphoma , Paroxysmal cold hemoglobinuria
ACQUIRED HEMOLYTIC ANEMIAS:Immunologic
Causes of Hemolysis
Warm" antibodies
PATHOGENESIS
IgG antibodies lyse RBC by two mechanisms
(1) immune adherence of RBC to phagocytes mediated by the
antibody and by complement components that become fixed to
the membrane (by far the more important mechanism of
destruction), and
(2) complement activation.
formation of spherocytes
If internalization is only partial, the RBC membrane is
removed, resulting in the formation of spherocytes, which are
destroyed in the spleen.
Complement-mediated immune adherence involves the
interaction of C3b and C4b with receptors on the macrophage;
ACQUIRED HEMOLYTIC ANEMIAS
ACQUIRED HEMOLYTIC ANEMIAS:Immunologic Causes of Hemolysis
Warm" antibodies
TREATMENT
mild degree of hemolysis usually do not require therapy
clinically significant hemolysis:prednisone, 1.0 mg/kg per day)
A rise in hemoglobin is frequently noted within 3 or 4 days and occurs in
most patients within 1 to 2 weeks
Prednisone is continued until the hemoglobin level has risen to normal
values, and thereafter it is tapered rapidly to about 20 mg/d, then slowly
over the course of several months
For chronic therapy with prednisone, alternate-day administration is
preferred
ACQUIRED HEMOLYTIC ANEMIAS
ACQUIRED HEMOLYTIC ANEMIAS:Immunologic Causes of Hemolysis
Warm" antibodies
TREATMENT
More than 75% initial significant in half these patients the disease
recurs, either during glucocorticoid tapering or after its cessation
Glucocorticoids have two modes of action:
an immediate effect due to inhibition of the clearance of IgG-coated
RBC by the mononuclear phagocyte system
and a later effect due to inhibition of antibody synthesis.
ACQUIRED HEMOLYTIC ANEMIAS:Immunologic
Causes of Hemolysis
Warm" antibodies
TREATMENT
immunosuppressive drugs A success rate of ~50%
Intravenous gamma globulin may cause rapid cessation of hemolysis
it is not nearly as effective in this disorder as in immune
thrombocytopenia.
blood transfusions( problem = selection approprat doner)
antibody in this disease is usually a "panagglutinin," reacting with
nearly
all normal donor cells, cross-matching is impossible
adsorb the panagglutinin present in the patient's serum with the
patient's
own RBC from which antibody has been previously eluted
Serum cleared of autoantibody can then be tested for the presence of
alloantibody to donor blood groups
ACQUIRED HEMOLYTIC ANEMIAS: warm antibody
TREATMENT:
ACQUIRED HEMOLYTIC ANEMIAS:Immunologic
Causes of Hemolysis
Warm" antibodies
PROGNOSIS:
In most patients, hemolysis is controlled
Fatalities occur among three rare subsets of patients:
(1) those with overwhelming hemolysis who die from anemia;
(2) those whose host defenses are impaired by glucocorticoids,
splenectomy, and/or immunosuppressive agents; and
(3) those with major thrombotic events coincident with active
hemolysis.
ACQUIRED HEMOLYTIC ANEMIAS:Immunologic
Causes of Hemolysis
Warm" antibodies
Immunohemolytic anemia secondary to drugs
two mechanisms of action:
(1) they induce a disorder identical in almost every respect
to warm-antibody immunohemolytic anemia (e.g., amethyldopa )
(2) they become associated as haptenes with the RBC
surface and induce the formation of an antibody
directed against the RBC-drug complex (e.g., penicillin,
quinidine).
ACQUIRED HEMOLYTIC ANEMIAS:Immunologic
Causes of Hemolysis
Warm" antibodies : druges
a-methyldopa therapy in doses of 2 g/d or higher
A positive direct Coombs test up to 10%
a-Methyldopa alters and makes immunogenic the protein(s) of the
Rh complex
the resulting antibodies cross-react with the normal Rh protein.
Thus the antibody does not react with the drug
and the indirect Coombs test is positive in almost all patients even
when the drug is not added to the test.
The RBC are coated with IgG but not C3
Hemolysis decreases over the course of several weeks after cessation
of drug therapy, although the direct Coombs test may remain
positive for more than 1 year
ACQUIRED HEMOLYTIC ANEMIAS:Immunologic
Causes of Hemolysis
Warm" antibodies : druges
In most other cases of drug-induced hemolysis, the
antibody is directed against the combination of the
drug and the membrane glycoprotein to which it is
attached.
he hemolytic reaction in vivo is dependent on the
presence of the drug and usually ceases shortly after
the drug has been discontinued
Penicillin and its congeners may cause this type of
reaction if the drug is given in very high doses (10
million units per day or more)
Complement is not usually fixed, and the hemolysis in
vivo is usually not severe.
Since the antibody is usually IgG, spherocytosis and
splenic destruction may occur
ACQUIRED HEMOLYTIC ANEMIAS:Immunologic
Causes of Hemolysis
Warm" antibodies : druges
Most other drugs (such as quinine, quinidine, sulfonamides,
sulfonureas, phenacetin, stibophen, and dipyrone) do not adhere
as tightly to their glycoproteins, and the drug-antibody
complexes are removed during the washing steps of the direct
and indirect Coombs reactions.
These antibodies (particularly IgM) are usually able to fix
complement, and these components remain on the RBC surface;
thus the direct Coombs test is positive with anti-C3 but not antiIgG. The antibody is detected in the indirect Coombs test only
when the drug is added to the incubation mixture
Hemolysis may be quite severe, sometimes resulting in signs of
intravascular hemolysis; resolution is usually prompt after the
drug is discontinued.
ACQUIRED HEMOLYTIC ANEMIAS:Immunologic
Causes of Hemolysis
Immune hemolysis due to cold-reactive antibodies :
Antibodies that react with polysaccharide antigens are usually IgM
and
react better at temperatures lower than 37°C
Uncommonly, the antibody is IgG (the Donath-Landsteiner
antibody of paroxysmal cold hemoglobinuria)
Cold agglutinins arise in two clinical settings:
(1) monoclonal antibodies, the product of lymphocytic neoplasia or
paraneoplasia, and (2) polyclonal antibodies in response to
infection.
In many elderly patients, the "neoplasm" is benign monoclonal
gammopathy that does not progress, and the paraprotein
remains its only manifestation
ACQUIRED HEMOLYTIC ANEMIAS:Immunologic
Causes of Hemolysis
Immune hemolysis due to cold-reactive antibodies
• Occasionally, cold agglutinins are found in patients with
nonlymphoid neoplasms.
•Transient cold agglutinins occur commonly in two infections:
Mycoplasma pneumoniae infection and infectious
mononucleosis. ]
•in both, the titer of antibody is usually too low to cause clinical
symptoms, but its presence is of diagnostic value
•other viral infections.
ACQUIRED HEMOLYTIC ANEMIAS:Immunologic
Causes of Hemolysis
Immune hemolysis due to cold-reactive antibodies
Cold agglutinins reacting more strongly with adult RBC than
fetal (cord) RBC are called anti-Ithese antibodies are seen
in benign lymphoproliferation (chronic cold agglutinin
monoclonal gammopathy) and in Mycoplasma infections
Those reacting more strongly with cord RBC cells are called antiI these antibodies are seen in aggressive lymphomas and in
infectious mononucleosis
the clinical manifestations elicited by the antibody on exposure to
cold two :
1. intravascular agglutination (acrocyanosis)
2. H emolysis
ACQUIRED HEMOLYTIC ANEMIAS:Immunologic
Causes of Hemolysis
Immune hemolysis due to cold-reactive antibodies
acrocyanosis:
Acrocyanosis is the marked purpling of the extremities, ears,
and nose when the blood becomes cold enough to agglutinate in
the veins; it clears on warming and does not have the vasospastic
characteristics of Raynaud's phenomenon
Patients may also have symptoms when swallowing cold food or
drinks.
Hemolysis
is usually not severe and is manifested by a mild reticulocytosis,
agglutination on the blood film, and agglutination during
analysis of the blood by particle analysis (giving rise to a falsely
high mean corpuscular volume). The degree of hemolysis
depends on several variables: next slid
ACQUIRED HEMOLYTIC ANEMIAS:Immunologic
Causes of Hemolysis
Immune hemolysis due to cold-reactive antibodies
Variable of hemolysis
1. Antibody titer. in symptomatic patients is above 1:2000 dilution of
serum and may range to as high as 1:50,000
2. Thermal amplitude of the antibody (the highest temperature at which
the antibody will react with the RBC)
For most antibodies, this is 23 to 30°C
3. Environmental temperature
The hemolysis that occurs is due primarily to the hemolytic action of
complement, since there are no functional Fc receptors for the IgM
antibody
the normal human RBC is remarkably resistant to the hemolytic action of
complement because of several defense mechanisms.
severe hemolysis with hemoglobinuria occurs only with massive
activation of the antibody, such as by sudden cooling
ACQUIRED HEMOLYTIC ANEMIAS:Immunologic
Causes of Hemolysis
Immune hemolysis due to cold-reactive antibodies
The activation of complement is always marked by the accumulation
of a degradation product of C3, C3dg, on the surface; this product is
what is detected with appropriate antisera in the direct Coombs test in
all patients with significant cold agglutinin diseas
The cutaneous manifestations and hemolysis are best treated by
maintaining the patient in a warm environment.
Splenectomy is usually not of value in this disorderGlucocorticoids
are of limited value
although patients with the panthermal variety of cold agglutinin
disease may respond
Chlorambucil and cyclophosphamide are commonly used to treat
patients who have hemolysis associated with monoclonal
gammopathy, but their efficacy is usually marginal
Successful treatment of the malignant neoplasm responsible for the
cold agglutinin often reduces the titer of antibody and the severity of
the hemolysis.
ACQUIRED HEMOLYTIC ANEMIAS:Immunologic
Causes of Hemolysis
Immune hemolysis due to cold-reactive antibodies
Paroxysmal cold hemoglobinuria (PCH)
Now a rare disorder
PCH was more frequent when tertiary syphilis was prevalent
now, most cases are either secondary to a viral infection or are
autoimmune.
PCH results from the formation of the Donath-Landsteiner
antibody, an IgG antibody that is directed against the P antigen
can induce complement-mediated lysis
Attacks are precipitated by exposure to cold and are associated with
hemoglobinemia and hemoglobinuria; chills and fever; back, leg,
and abdominal pain; headache; and malaise
Recovery from the acute episode is prompt, and between episodes
patients are usually asymptomatic.
When this syndrome accompanies acute viral infections (e.g.,
measles and mumps in children), it is self-limited but may be severe
ACQUIRED HEMOLYTIC ANEMIAS:Immunologic
Causes of Hemolysis
Immune hemolysis due to cold-reactive antibodies
Paroxysmal cold hemoglobinuria (PCH)
Although the direct Coombs test may show complement to
be present (seldom IgG), this test may be negative
The diagnosis is made by demonstrating cold-reacting IgG
antibodies either by lytic tests (when the titer is very high)
or by special antiglobulin tests
When PCH is secondary to syphilis, it responds to therapy
for syphilis.
Chronic autoimmune PCH may respond to prednisone or
cytotoxic therapy (azathioprine or cyclophosphamide) but
does not respond to splenectomy
Hemolysis due to Trauma in the Circulation
RBC fragments called schistocytes
in three clinical settings:
(1) External impact
(2) Macrovascular
(3) Microvascular
Changes in RBC and Platelets Induced by Intravascular Trauma
Etiology
Fragments
Hemolysis
Impact: march hemoglobinuria, etc.
0
+
Thrombocyto
penia
0
Aortic valve prosthesis
++++
++++
0
Mitral valve prosthesis
++
++
0
Calcific aortic stenoses
+
±
0
Vessel diseasea
+++
+
+
Thrombotic thrombocytopenic
purpura
Hemolytic-uremic syndrome
++++
++++
++++
++++
++++
++++
Adenocarcinoma
++++
++++
++++
Cardiac (turbulence):
±
Disseminated intravascular
++
++++
coagulation
a Malignant hypertension, eclampsia, renal graft rejection, hemangiomas,
immune disease (scleroderma).
Hemolysis due to Trauma in the Circulation
External impact
Hemoglobinemia and hemoglobinuria
 prolonged march or a prolonged run
hemolysis can be prevented by the insertion of a soft inner sole
in the runner's shoes
 may produce myoglobinuria
renal function is preserved
No specific therapy is required except to obtain better running
shoes.
•Hemolysis due to Trauma in the Circulation
•Macrovascular traumatic hemolysis
•10% of patients with artificial aortic valve prostheses.
•greater with valves having stellite rather than Silastic occluders,
greater with small valves as compared with larger valves, and
greater when valves are cloth-covered or when there is a
paravalvular leak
•Traumatic hemolysis is rare in recipients of porcine valves
•ostium primum or endocardial cushion defects with a prosthetic patch
•Mitral valve prostheses incidence is lower
• severe calcific aortic stenosis
• aortofemoral bypass
•CLINICAL MANIFESTATIONS
•Anemia :50 to 70 g/L reticulocytosis
fragmented RBC
depressed haptoglobin elevated serum LDH
hemoglobinemia
hemoglobinuria
iron dif.
Anemia
The direct Coombs test may rarely become positive.
•Hemolysis due to Trauma in the Circulation
•Macrovascular traumatic hemolysis
•PATHOGENESIS
•(1) the shear stress
•(2) direct mechanical trauma
•3) the deposition of fibrin
•TREATMENT
•Iron deficiency
•Limitation in physical activity
•any paravalvular leak must be repaired or the prosthetic valve replaced.
Hemolysis due to Trauma in the Circulation
Microvascular traumatic hemolysis
fibrin or platelet microthrombi are deposited in arteriolar
sites
fibrin or platelet microthrombi are deposited in arteriolar sites
malignant hypertension, eclampsia, renal allograft rejection,
disseminated cancer, hemangiomas, or disseminated intravascular
coagulation (DIC)
The degree of hemolysis induced by this family of disorders is
usually quite mild
Throbocytopenia may be
Hemolysis due to Trauma in the Circulation
Microvascular traumatic hemolysis Thrombotic thrombocytopenia purpura (TTP)
Arteriolar lesions in various organs that contain platelet thrombi
Primarily young adults and more often women.
CLINICAL MANIFESTATIONS
intravascular hemolysis, thrombocytopenia, diffuse and nonfocal neurologic findings,
decreased renal function, and fever
The neurologic and renal symptoms are usually seen only when the platelet count is
markedly diminished (<20 to 30 ´ 103/uL)
Thrombocytopenia often parallels anemia
Fever is not reliably present
TTP may be acute in onset, but its course spans days to weeks in most
patients and occasionally continues for months
Neurologic symptoms
develop in >90% of patients whose disease terminates in death
mental status such as confusion, delirium, or altered states of
consciousness may occur. Focal findings include seizures, hemiparesis,
aphasia, and visual field defects. These neurologic symptoms may
fluctuate and terminate in coma
Hemolysis due to Trauma in the Circulation
Microvascular traumatic hemolysis Thrombotic thrombocytopenia purpura (TTP)
CLINICAL MANIFESTATIONS
myocardial blood vessels
The severity of the disorder can be estimated from the degree of anemia and
thrombocytopenia and the serum LDH level
The severity of the disorder can be estimated from the degree of anemia and
thrombocytopenia and the serum LDH level
If the coagulation tests indicate a major consumption of clotting factors, the
diagnosis of TTP is doubtful
A positive antinuclear antibody (ANA) determination is obtained in approximately
20% of patients.
Hemolysis due to Trauma in the Circulation
Microvascular traumatic hemolysis Thrombotic thrombocytopenia
purpura (TTP)
DIAGNOSIS:
Although they are not usually required for diagnosis, biopsies of skin
and muscle, gingiva, lymph node, or bone marrow may show the
typical arteriolar abnormalities.
The combination of hemolytic anemia with fragmented RBC,
thrombocytopenia, normal coagulation tests, fever, neurologic
disorders, and renal dysfunction is virtually pathognomonic of TTP