hemolysis is missed topic

1. DR BIKAL LAMICHHANE
INTERNAL MEDICINE
NAMS
APPROACH TO
INTRACORPUSCULAR
HEMOLYTIC ANEMIA

2. HEMOLYTIC ANEMIA (HA)
 Anemia as a result of increased destruction of red
cells which results from overconsumption of red
cells from the peripheral blood, whereas the
supply of cells from the bone marrow is normal or
is usually increased.

3. GENERAL CLINICAL AND
LABORATORY FEATURES
 Signs and symptoms arise directly from
hemolysis :
 Jaundice,
 Splenomegaly,
 Hepatomegaly,
 Skeletal changes

4.  Laboratory features related to (i) hemolysis (ii) the
erythropoietic response of the bone marrow.
 Extravascular hemolysis produces an increase in
unconjugated bilirubin and aspartate
aminotransferase (AST) in the serum and
urobilinogen in urine and stool.
 Intravascular hemolysis: hemoglobinuria with
hemosiderinuria,free hemoglobin, lactate
dehydrogenase (LDH) is increased,haptoglobin is
reduced, and the serum bilirubin may be normal or
mildly elevated.

5.  The main sign of the erythropoietic response by the
bone marrow :increased number of reticulocytes
associated with an increased mean corpuscular
volume (MCV) .
 On the blood smear,presence of
macrocytes,polychromasia, and sometimes
nucleated red cells.

6. Features of Hemolytic Disorder

7. Classification of Hemolytic Anemias
HAs may be :
 Inherited or acquired
 Acute or chronic
 Mild to very severe
 Site of hemolysis may be predominantly
intravascular or extravascular.
 Due to intracorpuscular causes or
extracorpuscular causes

8. Classification of Hemolytic Anemias

9. Intracorpuscular hemolytic
anemia
 In the red cell with the loss of mitochondria there is no
backup to anaerobic glycolysis, which is the only provider
of adenosine triphosphate (ATP). Also, the capacity of
making protein has been lost with the loss of ribosomes.
This places the cell’s limited metabolic apparatus at risk,
because if any protein component deteriorates, it cannot
be replaced.
 Any metabolic failure leads to structural damage to the
membrane or to failure of the cation pump.
 The life span of the red cell is reduced, which is the
definition of a hemolytic disorder.
 If the rate of red cell destruction exceeds the capacity of
the bone marrow to produce more red cells, the
hemolytic disorder will manifest as HA.

10. Abnormalities of the Membrane-
Cytoskeleton Complex
 The membrane-cytoskeleton complex has three
functions: It is an envelope for the red cell
cytoplasm, it maintains the normal red cells shape, it
provides highly specific cross-membrane transport of
electrolytes and of metabolites such as glucose.
 In the membrane-cytoskeleton complex the
individual components are so intimately integrated
with each other that an abnormality of almost any of
them will be disturbing or disruptive, causing
structural or functional failure, which results
ultimately in hemolysis.

11. RBC MEMBRANE

12. HEREDITARY
SPHEROCYTOSIS
 Relatively common
 Genetically determined HA
 Estimated frequency of at least 1 in 5000.
 Numerous spherocytes in the peripheral blood
 Presence of osmotic fragility main diagnostic test
.
 Genetically heterogeneous (can arise from a
variety of mutations in one of several genes)
 Inheritance autosomal dominant (some
autosomal recessive)

13.  Broad spectrum of clinical severity.
 Severe cases may present in infancy with severe
anemia, whereas mild cases may present in young adults
or even later in life.
 The main clinical findings: jaundice,enlarged
spleen,gallstones
 Normocytic, with MCHC >34
 Laboratory investigations (required): osmotic fragility,acid
glycerol lysis test, the eosin-5′-maleimide (EMA)–binding
test, and SDS-gel electrophoresis of membrane proteins

14. HEREDITARY ELLIPTOCYTOSIS:
Clinical features similar to HS
Disorders of Cation Transport :
 increased intracellular sodium in red cells, with
concomitant loss of potassium
 Cells overhydrated (stomatocytosis)
 Cells are dehydrated( xerocytosis).

15. Enzyme Abnormalities

16. .

18. Glucose 6-Phosphate
Dehydrogenase (G6PD) Deficiency
 G6PD only source of NADPH, which directly and
via glutathione (GSH) defends against oxidative
stress.
 HA due to interaction between an
intracorpuscular cause and an extracorpuscular
cause
 confers a relative resistance against Plasmodium
falciparum malaria.

19. Clinical Manifestations :
 The majority of people with G6PD deficiency remain clinically
asymptomatic throughout their lifetime.
 All of them have an increased risk of developing neonatal
jaundice (NNJ) and a risk of developing acute HA (AHA) when
challenged by a number of oxidative agents.
 NNJ can be very severe in some G6PD-deficient babies,
especially in association with prematurity, infection, and/or
environmental factors (such as naphthalene-camphor balls,
which may be used in babies’ bedding and clothing)
 If inadequately managed, NNJ associated with G6PD
deficiency can produce kernicterus and permanent neurologic
damage.

20.  AHA can develop as a result of three types of
triggers: (1) fava beans, (2) infections, and (3) drugs
.
 Typically, a hemolytic attack starts with malaise,
weakness, and abdominal or lumbar pain.
 After an interval of several hours to 2–3 days, the
patient develops jaundice and often dark urine.

21.  The anemia is moderate to extremely severe, usually
normocytic and normochromic, and is associated with
hemoglobinemia, hemoglobinuria, high LDH, and low or
absent plasma haptoglobin.
 Anisocytosis, polychromasia, and spherocytes; bizarre
poikilocytes, with red cells that have unevenly distributed
hemoglobin (“hemighosts”) and red cells that appear to
have had parts of them bitten away (“bite cells” or “blister
cells”)
 Most serious threat from AHA in adults is acute renal
failure which in absence of comorbidity, has full recovery.

22. Drugs with Risk of Hemolysis in
Persons with G6PD Deficiency

23.  Laboratory Diagnosis :
 Confirmed by semi-quantitative methods or
screening tests,
 Diagnostic test is usually needed when the patient
has had a hemolytic attack
 DNA testing

24. Paroxysmal Nocturnal Hemoglobinuria (PNH):
 PNH is an acquired chronic HA characterized by
persistent intravascular hemolysis with occasional or
frequent recurrent exacerbations.
 In addition to (i) hemolysis, there may be (ii)
pancytopenia and (iii) a distinct tendency to venous
thrombosis. (triad )
 Rare disease~5 per million . PNH has about the same
frequency in men and women.

25.  CLINICAL FEATURES:
 “passed blood instead of urine”
 Anemia with neutropenia, thrombocytopenia, or both, thus
signaling an element of bone marrow failure.
 Recurrent attacks of severe abdominal pain related to
thrombosis in abdominal veins.
 When thrombosis affects the hepatic vein it may produce
acute hepatomegaly and ascites, i.e., a full-fledged Budd-
Chiari syndrome, which, in the absence of liver disease, ought
to raise the suspicion of PNH.
 Hemorrhage secondary to severe thrombocytopenia.
 May terminate in acute myeloid leukemia.

26.  LABORATORY INVESTIGATIONS AND
DIAGNOSIS:
 Anemia (mild to moderate to very severe).
 Usually normo-macrocytic, with unremarkable red
cell morphology. If the MCV is high, it is usually
largely accounted for by reticulocytosis, which may
be quite marked (up to 20%, or up to 400,000/μL).
The anemia may become microcytic if the patient is
allowed to become iron-deficient as a result of
chronic iron loss through hemoglobinuria.

27.  Unconjugated bilirubin is mildly or moderately
elevated; LDH is typically markedly elevated
(values in the thousands are common); and
haptoglobin is usually undetectable.
 Hemoglobinuria may be overt.
 The bone marrow is usually cellular, with marked
to massive erythroid hyperplasia.
 Marrow may become hypocellular or even frankly
aplastic.

28.  Definitive diagnosis of PNH :
 The sucrose hemolysis test (unreliable);
 acidified serum (Ham) test is highly reliable .
 The gold standard today is flow cytometry

29. HEMOGLOBINOPATHIES

30. Sickle Hemoglobinopathies
 The sickle cell syndromes are caused by a mutation in the
β-globin gene that changes the sixth amino acid from
glutamic acid to valine.
 Premature RBC destruction (hemolytic anemia) in the liver
and spleen.
 Clog small capillaries and venules, causing tissue
ischemia, acute pain, and gradual end-organ damage.
 Prominent manifestations include episodes of ischemic
pain (i.e., painful crises) and ischemic malfunction or frank
infarction in the spleen, central nervous system, bones,
joints, liver, kidneys, and lungs.

31.  Hemolytic anemia, with hematocrits from 15 to 30%, and significant
reticulocytosis.
 Granulocytosis.
Diagnosis :
 hemolytic anemia, abnormal RBC morphology, and intermittent episodes of
ischemic pain.
 Diagnosis is confirmed by :hemoglobin electrophoresis, mass spectroscopy,
and the sickling tests
 Genotyping of family members and potential parental partners is critical for
genetic counseling
 Factors associated with increased morbidity and reduced survival include
more than three crises requiring hospitalization per year, chronic
neutrophilia, a history of splenic sequestration or hand-foot syndrome, and
second episodes of acute chest syndrome.
 Patients with a history of cerebrovascular accidents are at higher risk for
repeated episodes and require partial exchange transfusion and especially
close monitoring using Doppler carotid flow measurements.

32. Clinical features of Sickle
Hemoglobinopathies

33. THALASSEMIA SYNDROMES
 The thalassemia syndromes are inherited disorders of α-
or β-globin biosynthesis.
CLINICAL MANIFESTATIONS :
 Hypochromia and microcytosis .
 In β thalassemia trait, this is the only abnormality seen.
 Anemia is minimal.
 Erythroid hyperplasia
 Masses of extramedullary erythropoietic tissue in the liver
and spleen.

34.  Massive bone marrow expansion ,“chipmunk” facies( due to
maxillary marrow hyperplasia and frontal bossing).
 Thinning and pathologic fracture of long bones and vertebrae
and profound growth retardation.
 Hemolytic anemia causes hepatosplenomegaly, leg ulcers,
gallstones, and high-output congestive heart failure.
 The conscription of caloric resources to support erythropoiesis
leads to susceptibility to infection, endocrine dysfunction,
death during the first decade of life.
 Chronic transfusions with RBCs causes iron overload, (often
fatal by age 30 years).

35.  Patients with β thalassemia major require intensive
transfusion support to survive.
 Patients with β thalassemia intermedia have a
somewhat milder phenotype and can survive without
transfusion.
 b thalassemia minor and b thalassemia trait describe
asymptomatic heterozygotes for β thalassemia.

36. DIAGNOSIS OF
THALASSEMIAS
 Severe anemia accompanied by the characteristic
signs of massive ineffective erythropoiesis:
hepatosplenomegaly, profound microcytosis, blood
smear , and elevated levels of HbF, HbA2, or both.
 Many patients require chronic hypertransfusion
therapy designed to maintain a hematocrit of at least
27–30% so that erythropoiesis is suppressed.

37.  β Thalassemia minor (i.e., thalassemia trait)
:usually presents as profound microcytosis and
hypochromia with target cells, but only minimal or
mild anemia.
 The mean corpuscular volume is rarely >75 fL; the
hematocrit is rarely <30–33%.
 Hemoglobin analysis classically reveals an elevated
HbA2 (3.5–7.5%)

38.  α thalassemia : trait may exhibit mild hypochromia
and microcytosis usually without anemia.
 Affected individuals usually require only genetic
counseling.

39. REFERENCES
 HARRISON’S PRINCIPLES OF INTERNAL
MEDICINE -20TH EDITION
 DAVIDSON’S PRINCIPLE AND PRACTICE OF
MEDICINE -23RD EDITION

40. THANK YOU