Flashcards in CH5 - Red Blood Cell Disorders Deck (284)
What is Anemia?
Reduction in circulating red blood cell (RBC) mass
What does anemia present with?
signs and symptoms of hypoxia; 1. Weakness, fatigue, and dyspnea 2. Pale conjunctiva and skin 3. Headache and lightheadedness 4. Angina, especially with preexisting coronary artery disease
How is RBC mass measured?
Hemoglobin (Hb), hematocrit (Hct), and RBC count are used as surrogates for RBC mass, which is difficult to measure
Anemia is defined as what (in terms of Hb)?
Hb<12.5 g/dL in females (normal Hb is 13.5-17.5 g/dL in males and 12.5-16.0 g/dl. in females)
What is the basis for anemia classification?
Based on mean corpuscular volume (MCV), anemia can be classified as microcytic (MCV 100)
What does the MCV give you an indication of in anemia?
size of the red blood cell
Microcytic anemias are due to
decreased production of hemoglobin.
RBC progenitor cells in the bone marrow are?
large and normally divide multiple times to produce smaller mature cells (MCV = 80-100)
Microcytosis is due to?
an "extra" division which occurs to maintain hemoglobin concentration.
Hemoglobin is made of
heme and globin:
heme is composed of?
iron and protoporphyrin
A decrease in what components leads to microcytic anemia?
iron, protoporphyrin and globin
Microcytic anemias include
(1) iron deficiency anemia, (2) anemia of chronic disease, (3) sideroblastic anemia, and (4) thalassemia.
Iron deficiency anemia is due to?
decreased levels of iron -> dec heme -> dec hemoglobin —» microcytic anemia
What is the most common type of anemia?
iron deficiency anemia
What is the most common nutritional deficiency in the world?
Lack of iron, affecting roughly 1/3 of world's population
Iron is consumed in what forms?
heme (meat-derived) and non-heme (vegetable-derived) forms
Absorption of iron occurs in the?
duodenum, Enterocytes have heme and non-heme (DMT1) transporters; the heme form is more readily absorbed
How do enterocytes transport iron?
across the cell membrane into blood via ferroportin
How does transferrin transports iron?
in the blood and delivers it to liver and bone marrow macrophages for storage.
Stored intracellular iron is bound to what?
ferritin, which prevents iron from forming free radicals via the Fenton reaction
Laboratory measurements of iron status
1) serum iron 2)TIBC 3) % saturation 4) Serum ferritin
What does the serum iron measure?
Serum iron is a measure of iron in the blood
What does total iron-binding capacity (TIBC) measure?
transferrin molecules in the blood
What does % saturation of iron measure?
percentage of transferrin molecules that are bound by iron (normal is 33%)
What does serum ferritin measure?
reflects iron stores in macrophages and the liver
What is iron deficiency is usually caused by?
dietary lack or blood loss
What is iron deficiency is usually caused by in infants?
breast-feeding (human milk is low in iron)
What is iron deficiency is usually caused by in children?
What is iron deficiency is usually caused by in adults?
(20-50 years old)—peptic ulcer disease in males and menorrhagia or pregnancy in females
What is iron deficiency is usually caused by in elderly?
colon polyps/carcinoma in the Western world; hookworm (Ancylostoma duodenale and Nieator americanus) in the developing world
What are some other causes for iron deficiency?
malnutrition, malabsorption, and gastrectomy (acid aids iron absorption by maintaining the Fe2+ state, which is more readily absorbed
What are the stages of iron deficiency?
1. Storage iron is depleted— decreased serum ferritin; increased TIBC (transferrin) 2. Serum iron is depleted— dec serum iron; dec % saturation 3. Normocytic anemia—Bone marrow makes fewer, but normal-sized, RBCs 4. Microcytic, hypochromic anemia—Bone marrow makes smaller and fewer RBC's
The initial stage of iron deficiency results in what type of anemia?
normocytic anemia b/c the bone marrow's initial response is to make as many normal RBC's as possible
what are the clinical features of iron deficiency
anemia, koilonychia, and pica.
Laboratory findings for iron deficiency include?
microcytic, hypochromic RBCs with increased red cell distribution width increased RDW, 2. decreased ferritin; inc TIBC; dec serum iron; dec % saturation 3. inc Free erythrocyte protoporphyrin (FEP
What is FEP?
free erythrocyte protoporphoryin - decreased Fe means less protoporphorin is bound producing heme.
Why do you have increased RDW in iron deficiency?
initial response of bone marrow is to produce as many normal RBC's as possible, after the anemia progresses it produces small RBC's - varying sizes means increased RDW
What is RDW?
red blood cell distribution width, measures the spectrum of size of the RBC's
What does a low RDW mean?
all of the red blood cells have the same size
What does a high RDW mean?
RBC's have diffent sizes
What is the treatment for iron deficiency anemia?
involves supplemental iron (ferrous sulfate) - always ask why is the pt iron deficient
How does the size of the RBC and compare to a lymphocyte on a blood smear?
nucleus of the lymphocyte should represent the size of the RBC
What is Plummer-Vinson syndrome?
it is iron deficiency anemia with esophageal web and atrophic glossitis; presents with anemia, dysphagia, and beefy-red tongue
What is an esophogeal web?
some of the mucosa of the esophagous outfolds potentially creating a partial obstruction in the esophagus
What is anemia of chronic disease
Anemia associated with chronic inflammation (e.g., endocarditis or autoimmune conditions) or cancer;
What is the most common type of anemia in hospitalized patients?
anemia of chronic disease
How is hepcidin related to chronic disease?
chronic disease results in production of acute phase reactants from the liver including hepcidin.
What does hepcidin do?
sequesters iron in storage sites by (1) limiting iron transfer from macrophages to erythroid precursors and (2) suppressing erythropoietin (EPO) production; aim is to prevent bacteria from accessing iron, which is necessary for their survival.
How is anemia of chronic disease related to micrcytic anemia?
decreased availablity of iron —> decreased heme -> decreased hemoglobin -> microcytic anemia
What are the laboratory findings for anemia of chronic disease?
inc ferritin, dec TIBC, dec serum iron, dec % saturation, inc FEP
In anemia of chronic disease why is there increased ferritin?
in anemia of chronic disease there is an inability to use storage iron - storage iron builds up meaning ferritin goes up
Why is there a decrease in serum iron in anemia of chronic disease?
if the bone marrow cannot use the iron in the macrophages it will use the iron from the serum also decreasing % satuation
Why is there increased FEP in anemia of chronic disease?
decreased iron availability leads to free protoporphorin since Hb is composed of HEME and PROTOPORPHORIN
Is anemia of chronic classified as normocytic or microcytic?
in the early phase of anemia of chronic disease the pt first develops a normocytic anemia, as it becomes more severe the pt can go on to develop microcytic anemia
What is the treatment of anemia of chronic disease?
Treatment involves addressing the underlying cause, exogenous EPO is useful in a subset of patients, especially those with cancer.
What is sideoblastic anemia due to?
Anemia due to defective protoporphyrin synthesis
How does sideroblastic anemia lead to microcytic anemia?
decreased protoporphyrin -> dec hemoglobin -> microcytic anemia
Where are the reactions of the protoporphorin synthesis occuring?
in the progenitor cells of the red blood cells in the erythroblast
What is the first step in the production of protoporphorin
1. Aminolevulinic acid synthetase (ALAS) converts succinyl CoA to aminolevulinic acid (ALA) using vitamin B6 as a cofactor (rate-limiting step).
What is the rate limiting step in the synthesis of protoporphorin?
SCoA -> ALA via ALAS with B6 as a cofactor
What happens after the rate limiting step in the synthesis of protoporphorin?
Aminolevulinic acid dehydrogenase (ALAD) converts ALA to porphobilinogen (Additional reactions convert porphobilinogen to protoporphyrin)
In the synthesis of protoporphorin what happens in the final reaction?
Ferrochelatase attaches protoporphyrin to iron to make heme (occurs in the mitochondria).
How is heme formed?
Iron is transferred to erythroid precursors and enters the mitochondria to form heme.
What happens if protoporphyrin is deficient?
iron remains trapped in mitochondria
What is seen when iron gets trapped in the mitochondria?
iron-laden mitochondria form a ring around the nucleus of erythroid precursors; these cells are called ringed sideroblasts (hence, the term sideroblastic anemia).
Where does sideroblastic anemia get its name?
The ring around the nucleus of erythroid precursors of iron laden mitochondria is called ringed sideroblasts
Is sideroblastic anemia congenital or acquired?
can be either congenital or acquired
Describe the congenital form of sideroblastic anemia?
most commonly involves ALAS (rate-limiting enzyme)
What are the acquired causes of sideroblastic anemia?
Alcoholism, Lead poisoning, Vitamin B6 deficiency
How can alcoholism lead to sideroblastic anemia?
How does lead poisoning lead to sideroblastic anemia?
inhibits ALAD and ferrochelatase
How does Vitamin B6 deficiency lead to sideroblastic anemia? This is most commonly seen as a side effect of what treatment?
required cofactor for ALAS; most commonly seen as a side effect of isoniazid treatment for tuberculosis
In sideroblastic anemia why is there increased ferritin?
build up of iron in the erythroid precursor which dies and leaks iron -> consumed by bone marrow macrophages -> high stores of Fe (increased ferritin)
What are the laboratory findings for sideroblastic anemia?
inc ferritin, dec TIBC, inc serum iron, and inc % saturation
Why is there increased percent saturation in sideroblastic anemia?
its an iron overloaded state and results in leakage of iron into serum also increasing the percent saturation
How are hemachromatosis patients similar to sideroblastic anemia patients?
both are iron overloaded states - similar lab values
What is thalassemia?
Anemia due to decreased synthesis of the globin chains of hemoglobin
How is thalassemia related to microcytic anemia?
dec globin -> dec hemoglobin —> microcytic anemia
what is a characteristic of the carriers of thalasemia?
it is an inherited mutation; carriers are protected against Plasmodium falciparum malaria.
How is thalassemia divided?
into alpha and beta thalassemia based on decreased production of alpha or beta globin chains
Regarding microcytic anemia what are the normal lab findings?
Ferritin- normal, TIBC- 300pg/dL, Serum Iron- 100pg/dL, % Saturation- 33%
Regarding microcytic anemia what are the lab values for Iron Deficiency Anemia?
Ferritin- Low, TIBC- High, Serum Iron- Low, % Saturation- Low
Regarding microcytic anemia what are the lab values for Anemia of Chronic Disease?
Ferritin- High, TIBC- Low, Serum Iron- Low, % Saturation- Low
Regarding microcytic anemia what are the lab values for sideroblastic anemia?
Ferritin- High, TIBC- Low, Serum Iron- High, % Saturation- High
Regarding microcytic anemia what are the lab values for pregnancy and oral contraceptives?
TIBC- High, % Saturation- Low
What are the normal types of hemoglobin?
HbF (alpha and gamma), HbA (alpha and beta), and HbA2 (alpha and sigma)
What is alpha-Thalassemia usually due to?
gene deletion; normally, 4 alpha genes are present on chromosome 16.
In alpha thalassemia what are the symptoms when one gene is deleted?
In alpha thalassemia what are the symptoms when two genes are deleted?
mild anemia with increased RBC count; cis deletion is associated with an increased risk of severe thalassemia in offspring.
In alpha thalassemia what are the symptoms when cis deletion occurs?
it is when both deletions occur on the same chromosome; seen in Asians
In alpha thalassemia what are the symptoms when trans deletion occurs?
it is when one deletion occurs on each chromosome; seen in Africans, including African Americans
Which is worse cis or trans deletion in alpha thalassemia?
Cis because it is associated with an increased risk of severe thalassemia in offspring
In alpha thalassemia what are the symptoms when three genes are deleted?
severe anemia; beta chains form tetramers (HbH) that damage RBCs; HbH is seen on electrophoresis.
In alpha thalassemia what are the symptoms when four genes are deleted?
lethal in utero (hydrops fetalis); gamma chains form tetramers (Hb Barts) that damage RBCs; Hb Barts is seen on electrophoresis.
What is Hb Barts?
it is a tetramer of gamma chains
What is the difference between beta and alpha thalassemia?
alpha is due to gene deletions and beta is due to gene mutations
Beta-Thalassemia is usually due what?
to gene mutations (point mutations in promoter or splicing sites); seen in individuals of African and Mediterranean descent
Where are beta genes present?
Two beta genes are present on chromosome 11; mutations result in absent (ß0) or diminished (ß+) production of the ß-globin chain
What is the difference between ß0/ß+?
ß0 is the complete inability to produce beta chain, ß+ is decreased production of beta chain
(ß/ß+ - one normal beta and one decreased production of beta) is the mildest form of disease and is usually asymptomatic with an increased RBC count.
In ß-thalassemia minor, what is seen on blood smear?
microcytic, hypochromic RBCs and target cells are seen on blood smear
In ß-thalassemia minor, what is seen on hemoglobin electrophoresis?
It shows slightly decreased HbA with increased HbA2 (5%, normal 2.5%) and HbF (2%, normal 1%)
(ß0/ß0) is the most severe form of disease and
How does ß-Thalassemia major present?
with severe anemia a few months after birth; high HbF (a2y2) at birth is temporarily protective
In ß-Thalassemia major, why is there ineffective erythropoiesis and extravascular hemolysis?
alpha tetramers aggregate and damage RBCs, (removal of circulating RBCs by the spleen).
What is ineffective erythropoesis in ß-Thalassemia major?
damage to the red blood cells as they are being generated by alpha dimers
What is extravascular hemolysis in ß-Thalassemia major?
removal of circulating RBCs by the spleen
Why do the patients with ß-Thalassemia major develop massive erythroid hyperplasia?
due to the anemia that develops
Why is there expansion of hematopoiesis into the skull in ß-Thalassemia major?
There is severe anemia resulting in erythropoietin increase from the kidney resulting in hyperplasia at the bone marrow
What does expansion of hematopoiesis in ß-Thalassemia major present as?
reactive bone formation leads to crewcut appearance on x-ray and facial bones chipmunk face
In ß-Thalassemia, what is seen in massive erythroid hyperplasia?
(1) expansion of hematopoeisis into marrow of the skull and facial bones (2) extra medullary hematopoiesis with hepatosplenomegaly, and (3) risk of aplastic crisis with parvovirus B19 infection of erythroid precursors.
In ß-Thalassemia what is often necessary?
chronic transfusions are often necessary; leads to risk for secondary hemochromatosis
In ß-Thalassemia, what does the blood smear show?
microcytic, hypochromic RBCs with target cells and nucleated red blood cells
In ß-Thalassemia, what does electrophoresis show?
little or no HbA with increased HbA2 and HbF
What is Macrocytic Anemia?
Anemia with MCV > 100 most commonly due to folate or vitamin B12 deficiency (megaloblastic anemia)
What are folate and vitamin B12 are necessary for?
synthesis of DNA precursors,
What does folate circulates in the serum as?
methyltetrahydrofolate (methyl THF);
What happens to methyl-THF?
removal of the methyl group allows for participation in the synthesis of DNA precursors.
What happens to the methyl group from methyl THF?
It is transferred to vitamin B12 (cobalamin),
What does Vitamin B12 do with the methyl it receives from methyl THF?
B12 then transfers the methyl to homocysteine, producing methionine.
Lack of folate or vitamin B12 does what?
impairs synthesis of DNA precursors,
What does impaired division and enlargement of RBC precursors lead to?
What does impaired division of granulocytic precursors lead to?
Where is megaloblastic change also seen?
in rapidly-dividing (e.g., intestinal) epithelial cells.
What are some other causes of macrocytic anemia (without megaloblastic change)?
alcoholism, liver disease, and drugs (e.g., 5-FU).
Where is dietary folate obtained?
from green vegetables and some fruits
Where is dietary folate absorbed?
in the jejunum
How fast does folate deficiency develop?
within months, as body stores are minimal
What are some causes of folate deficiency?
1) poor diet. 2) increased demand 3) folate antagonists
What are some examples of poor diet leading to folate deficiency?
Seen in alcoholics and elderly
What are some examples of increased demand leading to folate deficiency?
pregnancy, cancer, and hemolytic anemia
What are the clinical and laboratory findings?
1. Macrocytic RBCs and hypersegmented neutrophils (> 5 lobes. Fig. 5.5) 2. Glossitis 3. decreased serum folate 4. increased serum homocysteine (increases risk for thrombosis) 5. Normal methylmalonic acid
What is dietary vitamin B12 complexed to?
What liberates Vitamin B12 that is complexed to animal derived protein?
salivary gland enzymes (e.g., amylase) liberate vitamin B12
After Vit B12 reacts with salivary gland enzymes what happens?
It is bound by R-binder (also from the salivary gland) and carried through the stomach.
What happens to Vit B12 after its bound to R binder?
Pancreatic proteases in the duodenum detach vitamin B12 from R-binder
After Vitamin B12 is detached from R binder, what happens?
It binds intrinsic factor (made by gastric parietal cells) in the small bowel;
Where is the intrinsic factor-vitamin B12 complex absorbed?
in the ileum
How common is vitamin B12 deficiency?
it is less common than folate deficiency and takes years to develop due to large hepatic stores of vitamin B12
Why does it take years for Vitamin B12 deficiency to develop?
Due to large hepatic stores of Vitamin B12
What is the most common cause of vitamin B12 deficiency?
What is pernicious anemia?
autoimmune destruction of parietal cells (body of stomach) leads to intrinsic factor deficiency
What are some other causes of vitamin B12 deficiency?
include pancreatic insufficiency and damage to the terminal ileum (e.g., Crohn disease or Diphyllobothrium latum - fish tapeworm); dietary deficiency is rare, except in vegans.
What are the clinical and laboratory findings for Vitamin B12 deficiency?
1. Macrocytic RBCs with hypersegmented neutrophils, 2. Glossitis, 3. Subacute combined degeneration of the spinal cord 4. decreased serum vitamin B12. 5. increased serum homocysteine 6. increased methylmalonic acid
How does vitamin B12 relate to spinal cord degeneration?
Vitamin B12 is a cofactor for the conversion of methylmalonic acid to succinyl CoA (important in fatty acid metabolism) – build up of methylmalonic acid which impairs spinal myelinization
How does Vitamin B12 deficiency relate to spinal cord degeneration?
Vit B deficiency results in increased levels of methylmalonic acid, which impairs spinal cord myelinization,
What does damage to the spinal cord due to Vitamin B12 deficiency result in?
poor proprioception and vibratory sensation (posterior column) and spastic paresis (lateral corticospinal tract)
How is Vitamin B12 deficiency similar to folate deficiency?
Increased serum homocysteine which is similar to folate deficiency and increases the risk for thrombosis and there is increased methylmalonic acid (unlike folate deficiency)
What is normocytic anemia?
Anemia with normal-sized RBCs (MCV = 80-100 um3)
What is normocytic anemia due to?
increased peripheral destruction or underproduction
How do you distinguish between the two etiologies of normocytic anemia?
What are reticulocytes?
Young RBCs released from the bone marrow,
How are reticulocytes identified?
They appear on blood smear as larger cells with bluish cytoplasm (due lo residual RNA)
What is the normal reticulocyte count (RC)?
What is the RBC lifespan?
it is 120 days;
What is the turnover of RBC’s?
each day roughly 1-2% of RBCs are removed from circulation and replaced by reticulocytes.
How does a properly functioning marrow respond to anemia?
by increasing the RC to >3%.
Is RC reliable in anemia?
RC is falsely elevated in anemia
Why is RC falsely elevated in anemia?
It is measured as a percentage of total RBCs; decrease in total RBCs falsely elevates percentage of reticulocytes.
How is RC corrected?
By multiplying reticulocyte count by Hct/45.
What does a corrected RC count > 3% indicate?
good marrow response and suggests peripheral destruction.
What does a corrected RC count < 3% indicate?
poor marrow response and suggests underproduction.
What is peripheral vascular destruction divided into?
Divided into extravascular and intravascular hemolysis;
What does peripheral vascular destruction result in?
both result in anemia with a good marrow response.
Extravascular hemolysis involves what?
RBC destruction by the reticuloendothelial system (macrophages of the spleen, liver, and lymph nodes).
What is the role of macrophages in extravascular hemolysis?
consume RBCs and break down hemoglobin
What do macrophages break down globin into?
globin is broken down into amino acids.
What is heme broken down into?
iron and protoporphyrin; iron is recycled.
In the reticuloendothelial system what is protoporphyrin broken down into?
unconjugated biliruhin, which is bound to serum albumin and delivered to the liver for conjugation and excretion into bile.
What does the clinical and laboratory findings include?
Anemia with splenomegaly, jaundice due to unconjugated bilirubin, and increased risk for bilirubin gallstones
When would marrow hyperplasia occur with extravascular hemolysis?
Occurs with corrected reticulocyte count > 3%
What does intravascular hemolysis involve?
The destruction of RBCs within vessels.
What are the clinical and laboratory findings for intravascular hemolysis?
1) Hemoglobinemia. 2) Hemoglobinuria 3) Hemosiderinuria 4) Decreased serum haptoglobin
Why is there hemosiderinuria in intravascular hemolysis?
Renal tubular cells pick up some of the hemoglobin that is filtered into the urine and break it down into iron, which accumulates as hemosiderin; tubular cells are eventually shed resulting in hemosiderinuria.
What are the normocytic anemias with predominant extravascular hemolysis?
1) hereditary spherocytosis 2) Sickle cell anemia 3) Hemoglobin C
What is hereditary spherocytosis?
Inherited defect of RBC cytoskeleton-membrane tethering proteins
What does hereditary spherocytosis most commonly involve?
spectrin, ankyrin, or band 3.1
What is seen in hereditary shperocytosis?
membrane blebs are formed and lost over time
In hereditary spherocytosis what happens due to loss of the membrane?
It renders cells round (spherocytes) instead of disc-shaped.
How does hereditary spherocytosis lead to anemia?
Spherocytes are less able to maneuver through splenic sinusoids and are consumed by splenic macrophages, resulting in anemia.
What do the clinical and laboratory findings for hereditary spherocytosis include?
1) Spherocytes with loss of central pallor, 2) increased RDW and increased mean corpuscular hemoglobin concentration (MCHC) 3) Splenomegaly, jaundice with unconjugated bilirubin, and increased risk for bilirubin gallstones (extravascular hemolysis) 4) Increased risk for aplastic crisis with parvovirus B19 infection of erythroid
How is hereditary spherocytosis diagnosed?
by osmotic fragility test, which reveals increased spherocyte fragility in hypotonic solution
What is the treatment for hereditary spherocytosis?
splenectomy; anemia resolves, but spherocytes persist and Howell Tolly bodies emerge on blood smear
What are Howell Tolly bodies?
fragments of nuclear material in RBCs – appears on blood smear
What is sickle cell anemia?
Autosomal recessive mutation in beta chain of hemoglobin; a single amino acid change replaces normal glutamic acid (hydrophilic) with valine (hydrophobic).
Who carries the gene for sickle cell anemia?
it is carried by 10% of individuals of African descent, likely due to protective role against falciparum malaria.
When does sickle cell disease arise?
When two abnormal beta genes are present; results in >90% HbS in RBCs
What causes the formation of the sickle cell structure?
HbS polymerizes when deoxygenated; polymers aggregate into needle-like structures, resulting in sickle cells
When is there increased risk of sickling?
hypoxemia, dehydration, and acidosis.
Is sickle cell seen at birth?
HbF protects against sickling; high HbF at birth is protective for the first few months of life.
What is the treatment for sickle cell anemia?
hydroxyurea increases levels of HbF
In sickle cell anemia, what happens to cells as it passes through microcirculation?
The cells sickle and de-sickle while passing through the microcirculation, resulting in complications related to RBC membrane damage.
How does sickle cell anemia interact with the reticuloendothelial system?
intravascular hemolysis where the reticuloendothelial system removes RBCs with damaged membranes, leading to anemia, jaundice with unconjugated hyperbilirubinemia, and increased risk for bilirubin gallstones.
How does sickle cell anemia lead to decreased haptoglobin and target cells on blood smear?
Intravascular hemolysis where RBCs with damaged membranes dehydrate, leading to hemolysis with decreased haptoglobin and target cells on blood smear
Massive erythroid hyperplasia ensues in sickle cell anemia resulting in what?
1) Expansion of hematopoiesis into the skull ('crewcut' appearance on x-ray) and facial bones ('chipmunk fades'). 2) Extramedullar hematopoiesis with hepatomegaly 3) Risk of aplastic crisis with parvovirus B19 infection of erythroid precursors
What does irreversible sickling lead to?
complications of vaso-occlusion
What are the complications of vasso-occlusion resulting from irreversible sickling?
1) Dactylitis 2) autosplenectomy 3) acute chest syndrome 4) Pain crisis 5) Renal papillary necrosis
What is dactylitis?
swollen hands and feet due to vaso-occlusive infarcts in bones; common presenting sign in infants
What is autosplenectomy, and what are the consequences?
shrunken, fibrotic spleen. Consequences include: 1) Increased risk of infection with encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae (most common cause of death in children); affected children should be vaccinated by 5 years of age. 2) Increased risk of Salmonella paratyphi osteomyelitis 3) Howell-Jolly bodies on blood smear
What is the most common cause of death in children sickle cell patients?
What is acute chest syndrome?
vaso-occlusion in pulmonary microcirculation
What does acute chest syndrome present with?
Presents with chest pain, shortness of breath, and lung infiltrates
Acute chest syndrome is often precipitated by?
Often precipitated by pneumonia
What is the most common cause of death in adult sickle cell patients?
Acute chest syndrome
Renal papillary necrosis results in what?
gross hematuria and proteinuria
What is the sickle cell trait?
It is the presence of one mutated and one normal beta chain;
What does presence of the sickle cell trait results in?
<50% HbS in RBCs (HbA is slightly more efficiently produced than HbS)
How does the sickle cell trait present?
Generally asymptomatic with no anemia; RBCs with < 50%, HbS do not sickle in vivo except in the renal medulla.
When would sickling occur in the sickle cell trait?
Extreme hypoxia and hypertonicity of the medulla cause sickling,
In the sickling trait what happens?
microinfarctions leading to microscopic hematuria and, eventually, decreased ability to concentrate urine,
What are the laboratory findings for the sickle cell trait?
1) Blood smear shows no sickle cells and target cells (unlike sickle cell disease) 2) Metabisulfite screen causes cells with any amount of HbS to sickle; positive in both disease and trait 3) Hb electrophoresis confirms the presence and amount of HbS.
What does Hb electrophoresis show in sickle cell disease?
90% HbS, 8% HbF, 2% HbA2 (no HbA)
What does Hb electrophoresis show in sickle cell trait?
55% HbA, 43% HbS, 2% HbA2
What is hemoglobin C?
Autosomal recessive mulalion in beta chain of hemoglobin
What amino acid is affected in hemoglobin C?
Normal glutamic acid is replaced by lysine
How common is Hemoglobin C?
It is less common than sickle cell disease
What does hemoglobin C present with?
presents with mild anemia due to extravascular hemolysis
In Hemoglobin C what is seen on blood smear?
Characteristic HbC crystals are seen in RBCs on blood smear
What are the normocytic anemias with predominant intravascular hemolysis?
1) paroxysmal nocturnal hemoglobinuria (PNH) 2) G6PD deficiency 3) Immune Hemolytic anema (INH) 4) Microangiopathic hemolytic anemia 5) Malaria
What is paroxysmal nocturnal hemoglobinuria?
Acquired defect in myeloid stem cells resulting in absent glycosylphosphatidylinositol (GPI); renders cells susceptible to destruction by complement
What is the relationship between blood cells and complement?
Blood cells coexist with complement.
What is DAF?
Decay accelerating factor (DAF) is on the surface of blood cells and protects against complement-mediated damage by inhibiting C3 convertase.
How is DAF secured to the cell membrane?
By GPI (an anchoring protein)
What does the absence of GPI on the RBC membrane leads to?
absence of DAF, rendering cells susceptible to complement-mediated damage.
How is intravascular hemolysis related to paroxysmal nocturnal hemoglobinuria?
Intravascular hemolysis occurs episodically, often at night during sleep,
What develops in paroxysmal nocturnal hemoglobinuria?
1. Mild respiratory acidosis develops with shallow breathing during sleep and activates complement.
In paroxysmal nocturnal hemoglobinuria what is lysed?
RBCs, WBCs, and platelets are lysed
What test is used to screen for paroxysmal nocturnal hemoglobinuria?
What is a confirmatory test for paroxysmal nocturnal hemoglobinuria?
Acidified serum test or flow cytometry to detect the lack of CD55 (DAF) on blood cells
What is the main cause of death in paroxysmal nocturnal hemoglobinuria?
It is thrombosis of the hepatic, portal, or cerebral veins.
In paroxysmal nocturnal hemoglobinuria what induces thrombosis?
Destroyed platelets release cytoplasmic contents into circulation, inducing thrombosis.
In paroxysmal nocturnal hemoglobinuria what are the complications?
iron deficiency anemia which is due to chronic loss of hemoglobin in the urine) and acute myeloid leukemia (AML), which develops in 10% of patients.
What is G6PD deficiency?
X-linked recessive disorder resulting in reduced half-life of G6PD; renders cells susceptible to oxidative stress
How does G6PD deficiency lead to intravascular hemolysis?
decreased G6PD ? decreased NADPH ? reduced glutathione ? oxidative injury by H202 ? intravascular hemolysis
What is the relationship between G6PD and RBCs?
RBCs are normally exposed to oxidant stresses particularly H2O2.
What neutralizes H2O2?
Glutathione (an antioxidant) neutralizes H2O2, but becomes oxidized in the process.
What is needed to regenerate glutathione?
NADPH, a by-product of G6PD, is needed to regenerate reduced glutathione.
How many variants are there for G6PD deficiency?
There are two major variants; African variant and Mediterranean variant
What is seen with the African variant of G6PD deficiency?
mildly reduced half-life of G6PD leading to mild intravascular hemolysis with oxidative stress
What is seen in the Mediterranean variant of G6PD deficiency?
markedly reduced half-life of G6PD leading to marked intravascular hemolysis with oxidative stress
Explain the carrier frequency for both variants of G6PD deficiency?
High carrier frequency in both populations is likely due to protective role against falciparum malaria.
What is the relationship between G6PD deficiency and Heinz bodies?
Oxidative stress precipitates Hb as Heinz bodies
What are some causes of oxidative stress?
infections, drugs (e.g., primaquine, sulfa drugs, and dapsone), and fava beans.
What happens to Heinz bodies?
they are removed from RBCs by splenic macrophages, resulting in bite cells
Hb precipitating as Heinz bodies leads to what?
Predominantly leads to intravascular hemolysis
What does G6PD deficiency present with?
hemoglobinuria and back pain hours after exposure to oxidative stress
What is used to screen G6PD deficiency?
Heinz preparation is used to screen for disease
How can precipitated Hb be seen?
precipitated hemoglobin can only be seen with a special Heinz stain
What is used to confirm G6PD deficiency? When is it performed?
enzyme studies confirm deficiency (performed weeks after hemolytic episode resolves).
What is immune hemolytic anemia?
Antibody-mediated (IgG or IgM) destruction of RBCs
In IHA what does the IgG-mediated disease usually involve?
In IgG mediated IHA how does spherocyte formation result?
IgG binds RBCs in the relatively warm temperature of the central body (warm agglutinin); membrane of antibody-coated RBC is consumed by SPLENIC macrophages, resulting in spherocytes
What is the most common cause of IgG mediated IHA?
What is IgG mediated IHA associated with?
SLE (most common cause), CLL, and certain drugs (classically, penicillin and cephalosporins)
How do certain drugs relate to IgG mediated IHA?
Drug may attach to RBC membrane (e.g., penicillin) with subsequent binding of antibody to drug-membrane complex. 2). Drug may induce production of autoantibodies (e.g., u-methyldopa) that bind self antigens on RBCs
What does the treatment of IgG mediated IHA involve?
cessation of the offending drug, steroids, IVIG, and, if necessary, splenectomy.
What does IgM-mediared IHA disease usually involve?
What happens in IgM mediated IHA?
IgM binds RBCs and fixes complement in the relatively cold temperature of the extremities (cold agglutinin).
What is the IgM mediated IHA associated with?
Mycoplasma pneumoniae and infectious mononucleosis
What test is used to diagnose IHA?
Coombs test is used to diagnose IHA; testing can be direct or indirect.
What is the Direct Coombs test?
confirms the presence of antibody-coated RBCs. Anti-IgG is added to patient RBCs; agglutination occurs if RBCs are already coated with antibody.
What is the most important test for IHA?
Direct Coombs test
What is the indirect Coombs test?
it confirms the presence of antibodies in patient serum. Anti-IgG and test RBCs are mixed with the patient serum; agglutination occurs if serum antibodies are present.
What is microangiopathic hemolytic anemia?
Intravascular hemolysis that results from vascular pathology; RBCs are destroyed as they pass through the circulation.
What occurs with chronic hemolysis?
Iron deficiency anemia
Microangiopathic hemolytic anemia occurs with what?
Occurs with microthrombi (TTP-HUS, DIG, HELLP), prosthetic heart valves, and aortic stenosis; microthrombi produce schistocytes on blood smear
What is malaria?
Infection of RBCs and liver with Plasmodium, transmitted by the female Anopheles mosquito
How does malaria affect RBCs?
RBCs rupture as a part of the Plasmodium life cycle, resulting in intravascular hemolysis and cyclical fever.
What does P falciparum present with?
What does P vivax and P ovale present as?
fever every other day
What is the role of the spleen in malaria?
Spleen consumes some infected RBCs; results in mild extravascular hemolysis with splenomegaly
What is anemia due to underproduction?
Decreased production of RBCs by bone marrow; characterized by low corrected reticulocyte count
What are the etiologies for anemia due to underproduction?
1) Causes of microcytic and macrocytic anemia 2) Renal failure 3) Damage to bone marrow precursor cells (may result in anemia or pancytopenia)
What is pancytopenia?
Medical condition in which there is a reduction in the number of red and white blood cells, as well as platelets
How does renal failure lead to anemia due to underproduction?
Decreased production of EPO by peritubular interstitial cells
What is parvovirus B19?
Infects progenitor red cells and temporarily halts erythropoiesis; leads to significant anemia in the setting of preexisting marrow stress e.g. sickle cell anemia
What is aplastic anemia?
Damage to hematopoietic stem cells, resulting in pancytopenia (anemia, thrombocytopenia, and leukopenia) with low reticulocyte count
What are the etiologies for pancytopenia?
Etiologies include drugs or chemicals, viral infections, and autoimmune damage.
In aplastic anemia, what does biopsy reveal?
Reveals an empty, fatty marrow
What does treatment of aplastic anemia include?
Includes the cessation of any causative drugs and supportive care with transfusions and marrow-stimulating factors (e.g., erythropoietin, GM-CSE, and G-CSE).
Aside from cessation of causative drugs what may be helpful in the treatment of apalstic anemia?
Immunosuppression may be helpful as some idiopathic cases are due to abnormal T-cell activation with release of cytokines.
What may be helpful in the treatment of aplastic anemia as a last resort?
bone marrow transplantation as a last resort