Hemolytic anemia is caused by the abnormal breakdown of red blood cells. It can be due to defects in the red blood cell membrane structure or permeability that cause cells to break down prematurely, or due to enzymatic defects that compromise the cell's energy production. The most common membrane defect is hereditary spherocytosis, while glucose-6-phosphate dehydrogenase deficiency is the most common enzymatic defect. Signs and symptoms of hemolysis include jaundice, gallstones, splenomegaly, and fatigue. Laboratory findings provide evidence of increased red blood cell breakdown and bone marrow compensation.
This Presentation of Hemolytic Anemia try to cover important Hemato-pathological aspects of Red cell membrane disorders ( Hereditary Spherocytosis, others ) , Enzymopathies ( G6PD deficieny, others ) and Hemoglobinopathies ( Thallasemia, SCA) and their differentiation. References includes Robbins pathology, Wintrobes atlas and text, and others
Haemolysis indicates that there is shortening of the normal red cell lifespan of 120 days. There are many causes.
To compensate, the bone marrow may increase its output of red cells six- to eightfold by increasing the proportion of red cells produced, expanding the volume of active marrow, and releasing reticulocytes prematurely. Anaemia occurs only if the rate of destruction exceeds this increased production rate.
This Presentation of Hemolytic Anemia try to cover important Hemato-pathological aspects of Red cell membrane disorders ( Hereditary Spherocytosis, others ) , Enzymopathies ( G6PD deficieny, others ) and Hemoglobinopathies ( Thallasemia, SCA) and their differentiation. References includes Robbins pathology, Wintrobes atlas and text, and others
Haemolysis indicates that there is shortening of the normal red cell lifespan of 120 days. There are many causes.
To compensate, the bone marrow may increase its output of red cells six- to eightfold by increasing the proportion of red cells produced, expanding the volume of active marrow, and releasing reticulocytes prematurely. Anaemia occurs only if the rate of destruction exceeds this increased production rate.
In this presentation I've tried to summarize classification of hemolytic anemia and in depth review of rbc membrane disorders like hereditary spherocytosis, hereditary elliptocytosis, enzymopathies of hemolytic anemia like g6pd disorder, pyruvate kinase disorders, hemoglobinopathies related to hemolytic anemia like thalassemia, sickle cell anemia and especially pathophysiology and mechanism of hemolysis either extravascular or intravascular. Hope it helps you understand the entity better.
Hemolytic anemia occurs when the bone marrow is unable to increase production to make up for the premature destruction of red blood cells and the abnormal breakdown of red blood cells either in the blood vessels (intravascular hemolysis) or elsewhere in the body (extravascular). It has numerous possible causes, ranging from relatively harmless to life-threatening. The general classification of hemolytic anemia is either inherited or acquired. Treatment depends on the cause and nature of the breakdown.Symptoms of hemolytic anemia are similar to other forms of anemia (fatigue and shortness of breath), but in addition the breakdown of red cells leads to jaundice and increases the risk of particular long-term complications such as gallstones and pulmonary hypertension.
In this presentation I've tried to summarize classification of hemolytic anemia and in depth review of rbc membrane disorders like hereditary spherocytosis, hereditary elliptocytosis, enzymopathies of hemolytic anemia like g6pd disorder, pyruvate kinase disorders, hemoglobinopathies related to hemolytic anemia like thalassemia, sickle cell anemia and especially pathophysiology and mechanism of hemolysis either extravascular or intravascular. Hope it helps you understand the entity better.
Hemolytic anemia occurs when the bone marrow is unable to increase production to make up for the premature destruction of red blood cells and the abnormal breakdown of red blood cells either in the blood vessels (intravascular hemolysis) or elsewhere in the body (extravascular). It has numerous possible causes, ranging from relatively harmless to life-threatening. The general classification of hemolytic anemia is either inherited or acquired. Treatment depends on the cause and nature of the breakdown.Symptoms of hemolytic anemia are similar to other forms of anemia (fatigue and shortness of breath), but in addition the breakdown of red cells leads to jaundice and increases the risk of particular long-term complications such as gallstones and pulmonary hypertension.
HEMOLYTIC ANEMIA
Hemo: Referring to blood cells
Poiesis: “The development or production of”
The word Hemopoiesis refers to the production & development of all the blood cells:
Erythrocytes: Erythropoiesis
Leucocytes: Leucopoiesis
Thrombocytes: Thrombopoiesis.
Begins in the 20th week of life in the fetal liver & spleen, continues in the bone marrow till young adulthood & beyond!
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Hemolytic anemias share the following features:
A shortened red cell life span below the normal 120 days
Elevated erythropoietin levels and a compensatory increase in erythropoiesis
Accumulation of hemoglobin degradation products that are created as part of the process of red cell hemolysis
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
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1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
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Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
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5th edition of the Diagnostic and Statistical Manual of Mental Disorders
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disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
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the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
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Anti-ulcer drugs are medications used to prevent and treat ulcers in the stomach and upper part of the small intestine (duodenal ulcers). These ulcers are often caused by an imbalance between stomach acid and the mucosal lining, which protects the stomach lining.
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Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
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It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
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It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
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Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
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3. Hemolytic Anemia
- Introduction to Hemolytic Anemia :
- Definition
- Evidence of Hemolysis
- Signs & Symptoms , Lab Findings
- Classifications & differential diagnosis
- Hemolysis due to Membrane Defect ( Structure , Permeability )
- Hemolysis due to Enzyme Defect
- What is New In Hemolytic Anemia ?
4. Hemolytic Anemia
- Is a form of anemia due to hemolysis, the abnormal
breakdown of red blood cells (RBCs), either in the blood
vessels (intravascular hemolysis) or elsewhere in the human
body (extravascular) .
- Increased red cell destruction (and increased erythropoiesis)
- Cells are being produced at the same rate as they are
hemolyzed; this can develop into anemia if :
- Erythrocyte destruction accelerates beyond the
compensatory capacity of the marrow
-The B.M suddenly stops producing erythrocytes
5. Hemolytic Anemia
Sites of destruction
- Intravascular hemolysis: (within blood vessels)
Caused by :
-Activation of complement on erythrocyte membrane
- Physical or mechanical trauma
- Toxic substances
* Hemoglobinemia (free Hb in plasma)
* Hemoglobinuria (Hb in urine)
* Hemosiderinuria( hemosiderin granules in urine)
* Methemoglobinemia
6. Hemolytic Anemia
Sites of destruction
-Extravascular hemolysis :
- Erythrocytes removed by tissue phagocytes
- More common than intravascular .
- increase bilirubin , urobilinogen .
- Decrease haptoglobin .
- Spleen(slightly damaged RBC),liver( extensively damaged)
- Antibodies against RBCs (immune mediated)
10. Hemolytic Anemia
Signs & Symptoms
• Jaundice
Accumulation of Bilirubin
• Gallstones / red urine
Increased excretion of bilirubin into the biliary tract
• Splenomegaly
Accumulation of damaged RBCs
• Pulmonary hypertension
Increased pressure over the pulmonary artery
• Pallor , fatigue , cardiac symptoms
General Signs of Anemia
11.
12. Hemolytic Anemia
- Testing and Special Approaches :
- Reticulocyte Count :
Young Cells , Contain RNA .
Stained by Supravital Stain , 0.5-2% .
RPI = (%Retics /RMT )*(Hct/45)
1 --> 45
1.5 --> 35
2 --> 25
2.5 --> 15
RPI > 2 – 2.5 , indicate a hemolytic state .
- COOMBS ( DAT ) :
Detection of Auto Antibody
Next Lec.
14. Hemolytic Anemia
Lab Findings
Increased erythrocyte destructionIncreased BM production of
erythrocytes
Anemia
Spherocytes,schistocytes,poikilocytes
+ve DAT
Decreased haptoglobin
Decreased glycosylated Hb
Increased urobilinogen
Increased bilirubin
Hemoglobinemia,hemoglobinuria,he
mosiderinuria,methmoglobinemia
( intravascular hemolysis)
Reticulocytosis
Leukocytosis
Nucleated erythrocytes in P.B
Polychromasia of erythrocytes
Normoblastic erythroid hyperplasia
in the B.M
15. Hemolytic Anemia
Complications :
- Hemolytic crisis : due to accelerated hemolysis.
- Aplastic crisis : due to maturation arrest and associated
with megaloblastic changes
- Pigmented gallstones : Increased hemolysis of red blood
cells leads to increased bilirubin levels, because bilirubin is a
breakdown product of heme.
The high levels of bilirubin must be excreted into the bile by
the liver, which may cause the formation of a pigmented
gallstone, which is composed of calcium bilirubinate.
Since these stones contain high levels of calcium carbonates
and phosphate, they are visible on x-ray.
16. - Abnormally low hemoglobin A1C levels : the life span of
the red blood cells is decreased, providing less time for
the non-enzymatic glycosylation of hemoglobin. Thus,
even with high overall blood sugar, the A1C will be lower
than expected.
- Leg ulcer.
- Folate deficiency : caused by increased bone marrow
requirement.
Hemolytic Anemia
Complications :
17. Hemolytic Anemia
Differential diagnosis
Presence of Hemolysis
Increase RBC Production
Increase RBC destruction
COOMBS ( DAT )
+ve -ve
IHA PB Smear
RBC Morphology
Lab Investigation
( LDH , Bili , Retics ..)
Definitive Diagnosis
18. Hemolytic Anemia
Classifications
- Also it can classify into :
INTRACORPUSCULAR HEMOLYSIS
-Membrane Abnormalities
-Enzyme defects
EXTRACORPUSCULAR HEMOLYSIS
-Nonimmune
-Immune
- Generally , Hemolytic Anemia Classify depends on the
causes of Defect into :
- Hereditary
- Acquired
19.
20. Hemolytic Anemia
Membrane Defects
- The membrane protein and lipid interactions associated
with abnormal erythrocyte membranes can be divided
into two categories:
1- Vertical interactions :
interactions between the skeletal lattice on the cytoplasmic side and
the integral proteins and lipids.
Any defect cause uncoupling of the lipid bilayer from the skeletal
lattice, selective loss of portions of the lipid bilayer, decrease in the
surface area to volume .
22. Hemolytic Anemia
2- Horizontal interactions :
Parallel to the plane of the membrane and provide mechanical stability
to the membrane .
any defect lead to disruption of the skeletal lattice and membrane
destabilization which lead to cell fragmentation and formation of
poikilocytes .
Membrane Defects
23. Hemolytic Anemia
Hereditary spherocytosis
- Autosomal-dominant, most common disorder of the red
cell membrane (1:2000).
- Deficiency of spectrin , combined deficiency of spectrin and
ankyrin , mutations of ( ankyrin , α or β-spectrin , protein
4.2,band 3)
- Influx of Na+ 10 times the normal rate
- Increased cytoplasmic viscosity
Gene Locus
ANK1 8p11.2
SPTB 14q22-q23
SPTA 1q21
SLC4A1 17q21-q22
EPB42 15q15
27. Hemolytic Anemia
Normal or decreasedHb
> 8%Retics
60-87 flMCV
normalMCH
> 36g/dlMCHC
Normoblastic erythroid hyperplasia,
increased iron storage
BM
increasedOsmotic fragility
increasedIndirect bilirubin
increasedLD
decreasedhaptoglobin
RBCs small and lack the central pallorPB Smear
Laboratory findings
28. Hemolytic Anemia
Hereditary elliptocytosis
- Autosomal dominant
- Defect in the horizontal membran protein
interaction:
*Decreased association of spectrin dimers to form tetramers
*Defect in band 4.1
*Abnormalities in glycophorin C, abnormal anion
transport(band 3) with increased affinity to ankyrin
-The cells are abnormally permeable to Na+
- For Diagnosis : >25% of PB smear --> Elliptocyte
31. Hemolytic Anemia
Hereditary Pyropoikilocytosis
- Autosomal recessive , closely related to HE
- Presents in infancy as severe HA with extreme poikilocytosis
- HPP cell membranes fragment when heated to 45-46 C°
- Two defects :
1. Related to a deficiency in α-spectrin
2. The presence of mutant spectrin that prevents association
of heterodimers to tetradimers
34. Hemolytic Anemia
Hereditary Stomatocytosis Syndromes
- Autosomal dominant HA ,erythrocytes exhibit
abnormalities in Na+ and K+ permeability.
- Osmosis leads to the red blood cell having a
constant tendency to swell and burst.
- In the hereditary stomatocytosis, the passive leak
is increased and the cell becomes swamped with
salt and water.
35. Hemolytic Anemia
Hereditary Stomatocytosis Syndromes
OHS :
the RBC membrane is abnormally permeable to Na+ , K+ (
the net gain of Na+ > the net loss of K+) ,
the capacity of cation pump is exceeded
Water enters the cell ------> Stomatocyte
DHS :
The net loss of intracellular K+ exceeds the passive Na+ influx
decreased water and cation content ----> Xerocyte
* Variants :
40. Hemolytic Anemia
Abnormal lipid composition
Acanthocytosis
- Acquired or inherited abnormalities of the membrane lipids
- Liver disease, abetalipoproteinemia
- lipid of the membrane exchange with plasma lipids
- Acquiring excess lipids cause abnormal shapes.
- Sequestered in spleen
41. Hemolytic Anemia
Spur cell anemia
- Acquired hemolytic condition associated with severe
hepatocellular disease
Increased cholesterol and phospholipid leads to :
1- Decreased membrane fluidity and deformability
2- Membrane fragments are lost during splenic passage( spur cells)
*Moderate to severe normocytic normochromic anemia
Hb 5-10 g/dL
Reticulocyte 5-15%
Acanthocytes 20-80%
Increased bilirubin, liver enzymes.
45. Hemolytic Anemia
Rare forms
- Lecithin-cholesterol acyl transferase deficiency
- Autosomal recessive affects metabolism of HDL
- LACT catalyzes the formation of cholesterol esters from
cholesterol.
- Low HDL & LDL, high VLDL & lipoprotein X
- Mild HA, target cells
Other Forms :
- McLeod phenotype with Kx & K antigen deficiency,
Acanthocytosis with band 3 abnormalities
46. Hemolytic Anemia
Enzyme deficiencies
- RBCs require constant energy to maintain biconcave
disc shape and hemoglobin in reduced form.
- Without adequate energy, red cells lyse and/or
deform.
- Energy from glucose is derived from metabolism
- An inherited deficiency in one of the erythrocyte
enzymes can compromise the integrity of the cell
membrane or Hb and cause hemolysis.
51. Hemolytic Anemia
Hexose monophosphate shunt
Maintain adequate conc. Of
GSH
Hb in the reduced state
The most common enzyme
deficiency is G6PD
Heinz bodies
52. Hemolytic Anemia
G6PD deficiency
- The most common erythrocyte enzyme disorder
- G6PD deficient cells are more resistant to malarial parasites
and/or more readily phagocytosed .
- Sex linked carried by gene on the X chromosome.
- Heterozygote females have two population of cells ( deficient
& normal)
- The majority of people have no clinical expression of the
deficiency unless they have neonatal jaundice, exposed to
oxidative drugs, or have severe infections .
53. Hemolytic Anemia
Pathophysiology
The generation of NADPH,GSH is impaired
and cellular oxidants accumulate
erythrocyte injury
Hb is oxidized to metHb (heinz bodies)
increased cell permeability to cations
osmotic fragility, cell rigidity
bite and blister cells, spherocytes
58. Hemolytic Anemia
Females with G6PD deficiency
- Females heterozygotes for G6PD deficiency contain two
populations of cells ( normal & with G6PD deficiency)
- All cells in affected males are G6PD deficient
- Females may have no clinical expression or may be affected as
severely as males
- Case reports of homozygous-deficient females
59. Hemolytic Anemia
- Favism : the sudden severe hemolytic episode
that develops in some G6PD deficient individuals
after ingestion of fava beans
Signs :
- malaise, nausia, vomiting, abdominal pain,
tremor, fever.
- Hemoglobinurea, jaundice
- Severe favism affects children between the ages
of 2-5 years
60. Hemolytic Anemia
Methemoglobin Reductase pathway
- Maintains iron in the ferrous (Fe++) state.
- In the absence of the enzyme (methemoglobin
reductase), the oxygen carrying ferrous ion (Fe2+) of the
heme group of the hemoglobin molecule is oxidized to
the ferric state (Fe3+).
- Methemoglobin accumulates and it cannot carry oxygen
- Hypoxia occurs due to the decreased oxygen-binding
capacity of Methemoglobin, as well as the increased
oxygen-binding affinity of other subunits in the same
hemoglobin molecule which prevents them from
releasing oxygen at normal tissue oxygen levels.
62. Hemolytic Anemia
Pyruvate kinase deficiency
- One of The most common enzyme deficiency in glycolytic
pathway.
- Autosomal recessive , > 180 different mutations in the PK
gene (PKLR gene on chromosome 1q21”RBC”)
- Clinically significant HA are associated with the homozygous
or double heterozygosity for two mutant enzymes .
*Variation in clinical phenotype is related to the genotype and
interaction with physiological and environmental factors :
- ineffective erythropoiesis , splenic function, epigenetic
modifications, polymorphism of other enzymes
- Acquired PK deficiency is seen in some leukemias &
myelodysplastic disorders
- Single heterozygotes are asymptomatic
63. Hemolytic Anemia
Pyruvate kinase deficiency
Pathophysiology
Energy producing reaction is prevented
failure of cation pumps
potassium loss, calcium
& sodium gain
dehydration(echinocytes)
sequestration in splenic cord
and phagocytosis
66. Hemolytic Anemia
Other enzyme deficiencies in the glycolytic
pathway :
- Phosphoglyceratekinase deficiency:
sex linked, HA and mental retardation in males
females have milder form
- Phosphofructokinase deficiency:
indicated when subunits of the PFK enzyme
are found in various tissues. Appear as
myopathy or HA or both
- Triosephosphate isomerase deficiency:
severe abnormalities in RBCs ,severe hemolysis,
death in infancy, abnormalities in striated muscle &
CNS
67. Hemolytic Anemia
Other enzyme deficiencies in the glycolytic
pathway :
- Glucose phosphate isomerase deficiency :
cause hemolytic anemia, all mutants are unstable,show
partial response to splenectomy
- Hexokinase deficiency:
two types : 1.associated with HA that responds to
splenectomy
2.associted with HA & other abnormalities
The deficiency in this enzyme interferes with the
production of 2,3-BPG, patients tolerate anemia poorly.
68. Hemolytic Anemia
What is New In Hemolytic Anemia ?
خير كل!
- The most recent and new research's , concentrate on the
Autoimmune type of hemolytic anemia.
- A lot of aspects in Autoimmunity still unknown .
- Most of hereditary Hemolytic Anemia is well defined .
