THE HEMOLYTIC DISORDFRS:
GENERAL CONSIDERATIONS
Hemolytic anemias are anemias that result from an increased rate of red cell
destruction. The term hemolytic anemia, or better still hemolytic disorders, is limited
to those conditions in which the rate of red cell destruction is accelerated and the
ability of the bone marrow to respond to the stimulus of anemia is unimpaired. Under
maximal stimulation, the normal marrow is capable of undergoing hyperplasia until
its production rate is increased about six-to eight-fold. With optimal marrow
compensation, it is theoretically possible for the survival of red cells in the circulation
to decrease from the normal 120 days to as little as 15 to 20 days without anemia
developing. Such an increase in both destruction and production of erythrocytes can
produce a compensated hemolytic state without anemia being present usually known
as compensated hemolytic disease. On the other hand, when red cell survival becomes
so short that anemia develops in spite of a vigorous erythropoietic response, the term
hemolytic anemia is appropriate.
Classification
1. Clinical forms----acute and chronic
2. Site of hemolysis---intravascular and extravascular
3. Pathogenetic classification---inherited and acquired
Since the intravascular hemolytic disorders are accompanied by unique manifestations,
such as hemoglobinemia, hemoglobinuria, and hemosiderinuzia, the classification is
easily made and often serves to limit the diagnostic possibilities.
Hemolytic anemias characterized by predominantly intravascular red cell destruction:
1. Paroxysmal nocturnal hemoglobinuria
2. Disorders associated with erythrocyte fragmentation
3. Certain immunohemolytic anemias
a. Transfusion reactions resulting from ABO isoantibodies
b. paroxysmal cold hemoglobinuria
c. Some instances of idiopathic autoimmune hemolytic anemia
4. Those associated with certain infections. Black water fever in faloiparum malaria.
5. Those caused by certain chemical agents
a. Introvenous administration of distilled water
b. Snake and spider venoms
c. Arsine poisoning
d. Acute drug reactions in association with glucose-6-phosphate dehydrogenase
deficiency
6. Thermal injury. Since most hemolytic diseases are characterized by extravascular
red cell destruction, detection of this mode of hemolysis still leaves one with a large
number of diagnostic possibilities, Hemolytic disorders also may be divided into
inherited and acquired varieties. Excessive destruction of erythrocytes may occur
either because of an intrinsic defect in the cell itself or because of the action of
extrinsic agents on normally constructed cells. As a general rule, the intrinsic defects
are inherited and the extrinsic ones are acquired.
Hemolytic Disorders
I. Inherited hemolytic disorders .
A. Defects in the erythrocyte membrane
B. Deficiency of erythrocyte glycolytic enzymes
C. Defects in globin structure and synthesis
II. Acquired hemolytic anemias
A. Immunohemolytic anemias
1. Transfusion of incompatible blood
2. Hemolytic disease of the newborn
3. Autoimmune hemolytic anemia due to warm-reactive antibodies
a. ldiopathic
b. "Secondary"
(1). Virus and mycoplasma infections
(2). Lymphosarcoma, chronic lymphocytic leukemia
(3). Other malignant diseases
(4). Immune-deficiency states
(5). Systemic lupus erythematosus and other “autoimmune” disorders
C. Drug-induced
B. Traumatic and microangiopathic hemolytic anemias
1. Prosthetic valves and other cardiac abnormalities
2. Hemolytic-uremic syndrome
3. Thrombotic thrombocytopenic purpura
4. Disseminated intravascular coagulation
5. Associated with immunologic phenomena (graft rejection, immune complex
disease, etc.)
C. Chemical, physical and biologic factors
1. drugs and chemicals----Aniline, Sulfonamides, Copper
2. Burns
3. infectious agents----malaria, toxoplasmosis
4. biologic toxin----Venoms
D. Hypersplenism
Pathogenesis:
The increased rate of red cell destruction may happen at intravascular or
extravascular spaces. Extravascular hemolysis is the red cell destruction within the
macrophage cell at spleen and liver. Intravascular hemolysis happens at the site within
the circulation and the hemoglobin is released to the plasma directly.
Extravascular hemolysis:
1. The spleen is capable of tapping and destroying and removing abnormal red blood
cells which have IgG or complement at the cell membrane.
2. The abnormality of cell membrane, or the existence of Heinz body within the red
cell will decrease the physical deformation of the red cell. Those red cells can not pass
through the microcirculation of the spleen, and will be destroyed by the macrophage
cell.
Intravascular hemolysis:
1.During the red cells are destroyed, hemoglobin is released into the plasma, and
combined with heptoglobin become a large molecular substance, which can not filter
through the kidney. The level of plasma heptoglobin is then increased during
intravascular hemolysis.
2.The hemoglobin is capable to degradation and produce heme. Heme can combine
with hemopexin, so plasma hemopexin is decreased during massive hemolysis.
3.lf the hemoglobin is exhausted during hemolysis, the free hemoglobin (M.W.66000)
can pass through the kidney (Hemoglobinuria). The iron of the hemoglobin(Ferritin
and hemosiderin) are deposited at the epithelial cell of renal tubule. The epithelial cell
can excrete it in urine. and it is called hemosideinuria what the Rous test is positive.
Extravascular hemolysis
↓
Mono-macrophage system
↓
Biliverdin
↓
Bilirubin
↓
(Liver)
↓
(intestine)
↓
Urobilinogen (stool)
↓(plasma)
(kidney)
↓
(plasma)
↓
Urine
↓
Urobilinogen
Intravascular hemolysis
Plasma free hemoglobin
Heptoglobin-hemoglobin (heptoglobin↓)
Hemopexin-heme
(hemopexin ↓)
Methemoalbumin
(kidney)
(Urine)
hemosiderin (Rous test +)
methemoglobin
hemoglobin (occult blood +)
Clinical Manifestations
The clinical manifestations of hemolytic anemia depend upon the red cell destroy
speed, degree and site.
Acute hemolysis
Chronic hemolysis
(intravascular)
(extravascular)
Onset
quickly
slowly
Fever
high
low or no
Aching
back renal area
no
Splenmegaly
no
yes
Jaundice
slight
frequent
Hemoglobinuria
+
Hemosiderinuria
+(chronic)
Renal failure
+
Gallstone
+
Laboratory Manifestation is and Diagnosis:
Laboratory findings in hemolytic anemia can be divided into three groups:
(1).those related to the increase in erythrocyte destruction.
(2).those related to the compensatory increase in the rate of erythropoiesis, and
(3).those found only in particular varieties of hemolytic anemia and therefore useful
in differential diagnosis.
The diagnosis of hemolytic anemia can be divided into two steps:
1 .Is it a case of hemolytic anemia?
2.What kind of hemolytic anemia is it?
Is it a case of hemolytic anemia ?
1.Laboratory findings of accelerated red cell destruction
(1).Erythrocyte survival----erythrocyte life span is decreased
(2).Catabolism of heme is increased----bilirubin production rate is increased. Serum
unconjugated bilirubin and urobilinogen excretion rates are increased
(3).Serum lactate dehydrogonase activity is increased.
(4).Signs of intravascular hemolysis
----hemoglobinemia
----absence of heptoglobin
----hemoglobinuria
----hemosiderinuria
----methemalbuminemia
----reduced serum hemopexin
2.Laboratory findings of accelerated erythropoiesis
(1).Blood
----reticulocytosis
----sometimes leukocytosis and thrombocytosis, but when crises of hemolysis is
happened, both leukocyte and platelet will decrease.
(2).Bone marrow----erythroid hyperplasia
(3).Ferrokinetic
----increase plasma iron turnover
----increase erythrocyte iron turnover
What kind of hemolytic anemia is it?
(l).Those with coombs positive hemolytic anemia----AIHA, Idiopathic
Secondary---SLE, lymph proliferative disorders
(2).Those with coombs negative and specific morphologic abnormalities red cell
----spherocyte (spherocytosis)
----elliptocyte (elliptocytosis)
----Target cell (thalassemia)
----helmet cell (machanical hemolysis)
----sickle cell (after specific test)----(sickle cell anemia)
(3).Those with non-specific morphologic abnormalities and a negative reaction to
coombs test
----Ham’s test, sucrose test (PNH)
----Isopropanol test or heat denaturation test (unstable hemoglobin disease)
---Methemoglobin deoxidation test, ascorbate
ZHONGLu