Chapter 14: Anemias Flashcards
What is anemia defined as?
reduction of the total circulating red cell mass below normal limits
Acute blood loss
-loss of intravascular volume
-cardiovascular collapse, shock, and death
-EPO will stimulate committed erythroid progenitors in the marrow
-
Chronic blood loss
- rate of loss exceeds the regenerative capacity of the marrow or when iron reserves are depleted
- iron deficiency anemia appears
Hemolytic anemias
- shortened lifespan of RBC
- elevated EPO
- accumulation of Hbg degradation products
- within phagocytes=extravascular hemolysis
Hereditary spherocytosis
- inherited disorder cause by intrinsic defects in the red cell membrane skeleton that render the red cells spheroid, less deformable, and vulnerable to splenic sequestration and destruction
- northern europe
- Spectrin is a problem
Pathogenic mutations in HS
- Ankyrin
- band 3
- spectrin
- band 4.2
What helps HS
a splenectomy
-the spleen is an asshole and keeps eating all of the abnormally shaped cells
Clinical features of HS
osmotic lysis
- HS red cells have increased MCHC (mean cell hemoglobin concentration, due to dehydration caused by the loss of K+ and H20
- anemia, splenomegaly, and jaundice*
What will cause an aplastic crisis in HS patients?
Parvovirus B19 infection
-they don’t have the reserves to deal with this
Glucose-6-Phosphate Dehydrogenase deficiency
- red cells can’t protect themselves against oxidative injuries and leads to hemolysis
- G6PD reduces NADP to NADPH,
- We need that NADPH in order to use glutathione to neutralize H202
- recessive X-linked trait
Which G6PD deficiency variant is the most clinically significant?
the mediterranean variant
-they eat a lot of fava beans which can cause it
What are Heinz bodies?
-high levels of oxidants causes cross-linking of reactive sulfhydryl groups on globin chains, which become denatured and form membrane-bound precipitates… that’s what they are
Sickle cell disease
- point mutation in B-globin that promotes the polymerization of deoxygenated hemoglobin
- red cell distortion, hemolytic anemia, microvascular obstruction, and ischemic tissue damage
- Glu to Val mutation
- HbS
What does Hbs protect against?
falciparum malaria
Why do infants not become symptomatic for sickle cell disease until 5-6 months?
HbF inhibits the polymerization of HbS even more than HbA
What is HbC variant of sickle cell disease
Val to LySINE (Seeeeeeeen=C)
-
What facitilitates sickling?
a higher Mean cell hemoglobin concentration (MCHC)
- decrease in intracellular pH
- transit time of red cells through microvascular beds
What is a wierd way that sickle cell patients can have a milder form of the disease?
if they also have an alpha thalassemia
-no Hemoglobin can get made… so it doesn’t matter if it’s screwed up or not
Why do ppl with sickle cell disease get microvascular occlusions?
- free hbg released from lysed sickle red cells can bind and inactivate NO
- NO is a potent vasodilator and inhibitor of platelet aggregation
- thrombosis
What are howell-jolly bodies?
small nuclear remnants
- seen in sickle cell disease
- also in asplenia
What morphologic changes are seen in sickle cell?
- new bone formation (crewcut and cheekbones)
- increased breakdown of Hgb leads to pigment gallstones… hyperbilirubinemia (unconjugated)
- autosplenectomy can happen (shrinkage
Clinical features of sickle cell?
- commonly involve bones, lungs, liver, brain, spleen, and PENIS
- children get the hand-foot syndrome or dactylitis of the bones of the hands or feet or both
What is acute chest syndrome
dangerous type of vaso occlusive crisis involving the lungs
- fever, cough, chest pain, and pulm infiltrates
- inflammation causes slow blood flow
What is priapism
-with sickle cell disease, 45% of males have hypoxic damage and erectile dysfunction
What 2 factors contribute to stroke in Sickle cell disease?
- adhesion of sickle red cells to arterial vascular endothelium
- vasoconstriction caused by the depletion of NO by free hemoglobin
Where do aplastic crises with sickle cell disease stem from
Parvovirus B19 infection of red cell progenitors
-transient cessation of erythropoiesis
What are we at risk for infection with if we have sickle cell disease (because of the altered splenic function)
Pneumococcus pneumonia
Haemophilus influenzae
meningitis
What can we use to diagnose sickle cell disease?
metabisulfite
- an oxygen consuming reagent
- if there is any HbS at all, it will sickle when we apply this
B thalassemias
caused by mutations that diminish the synthesis of B globin chains
- chromsoome 11
- mutations that diminish synthesis of B-globin chains
What kind of mutations are the most common cause of B null thalassemia?
chain terminator mutations
What is HbA,
2 alpha globulins and 2 Beta
What is the main result of B thalassemia?
diminished survival of RBCs and their precursors
-ineffective erythropoiesis
What is another serious comlication of ineffective erythropoiesis?
excessive absorption of dietary iron
- ineffective erythropoiesis suppresses hepcidin, a critival negative regulator of iron absorption
- iron accumulation
- secondary hemochromatosis
Where is B thalassemia major most common?
Mediterranean countries
What does the anemia manifest in infants?
6-9 months after birth
-because of the HbF with is 2 alpha 2 gamma.. there’s no B globin needed at that time
What kind of cells will we find in B thalassemia?
Target cells
-elevated reticulocyte count
Morphology of B-thalassemia Major?
- target cells
- crewcut and chipmunk facies
- phagocyte hyperplasia and extramedullary hematopoiesis…. enlargement of spleen
B-Thalassemia Minor
heterozygous carriers of a B+ or B null allele
- basophilic stippling and target cells
- much more common than major
- asymptomatic
- has implications for genetic counseling
- HbA2 is diagnostically helpful (alpha2 and delta 2)
alpha thalassemia
- inherited DELETIONS that result in reduced or absent synthesis of alpha-globin chains
- gamma tetramers=Barts…. that happens in newborns
- B4 tetramers are HbH
Alpha thalassemia trait
- there’s 4 genes for this
- 2 of them are (-) trait
- if on the same chromosome, watch out for genetic purposes (especially in asians)
Hemoglobin H disease
- caused by deletion of 3 alpha globin genes
- most common in Asian populations because of that weird chromosome thing they do
- HbH has high affinity for oxygen… useless for O2 delivery
- moderately severe anemia resembling B-thalassemia intermedia
Hydrops Fetalis
most severe form of alpha thalassemia
- deletion of all 4 genes
- Barts
- high affinity for oxygen, so baby doesnt get any
- other squiggly letter forms up with excess B to be functionall
Paraxysmal nocturnal hemoglobinuria (PNH)
results from acquired mutation sin the phosphatidylinositol glycan complementation group A gene (PIGA)
- essential for the synthesis of certain membrane-associated complement regulatory proteins
- the only hemolytic anemia caused by an acquired genetic defect
- GPI linked propteins are deficient because of inactive PIGA
- basically, red cells become more susceptible to lysis by complement (intravascular hemolysis)
What 3 GPI-linked proteins that regulate complement activity are deficient in PNH?
- decay accelerating factor (DAF)=CD55
- membrane inhibitor of reactive lysis (MIRL)= CD59 (most important): inhibitor of C3 convertase… prevents spontaneous activation of the alternative complement pathway
- C8 binding protein
What happens in PNH?
- we sleep
- shallow breaths
- decrease in pH increases activity of complement
- hemosiderinuria
- eventually leads to iron deficiency
leading cause of death in PNH?
thrombosis
What is the only cure for PNH?
stem cell transplantation
Immunohemolytic anemias
caused by antibodies that bind to red cells, leading to their premature destruction
direct coombs tests
sees if the patients red cells has Ig or complement on them
Indirect coombs test
patients serum is tested for its ability to agglutinate commercially available red cells bearing particular defined antigens
Warm antibody type
most common form of immunohemolytic anemai
- IgG class
- that binds Fc receptors… partial phagocytosis
- leads to spherocytes
- moderate splenomegaly due to hyperplasia of splenic phagocytes is usually seen
Cold agglutinin typ
- IgM antibodies
- bind RBCs avidly at low temperatures
- happens in fingers and toes
- transient interaction with IgM is good enough to deposit sublytic C3b… good opsonin
- removal of RBCs by phagocytes in spleen and liver and bone marrow
- Raynaud phenomenon
Cold hemolysin type
IgGs that bind to P blood group antigen on the red cell surface in cool, peripheral regions of the body
-children following viral infections
hemolytic anemia resuting from trauma to red cells
- cardiac valve prostheses and microangiopathic disorders
- microvascular lesion that results in luminal narrowing… often due to the deposition of fibrin and platelets
- schistocytes, helmet cells, triangle cells
name the hemolytic anemias
-hereditary spherocytosis
-G6PD deficiency
-sickle cell disease
-thalassemias
-PNH
Immunohemolytic anemia
-hemolytic anemia from trauma
name the anemias of diminished erythropoiesis
- megaloblastic anemias
- anemia of folate deficiency
- iron deficiency anemia
- anemia of chronic disease
- aplastic anemia
- pure red cell aplasia
- marrow failure
Megaloblastic anemias
- impairment of DNA synthesis
- leads to ineffective hematopoiesis and distinctive morphologic changes, including abnormally large erythroid precursors and red cells
- Pernicious anemia= B12 deficiency
- Folate deficiency
Morphology with megaloblastic anemias
nuclear hypersegmentations
- big ass cells (>100)
- giant metamyelocytes and band forms
Pernicious anemia
- B12 deficiency
- autoimmune gastritis
- impairs production of intrinsic factor (secreted by parietal cells of the fundic mucosa) which is required for B12 uptake from the gut (ileum)
- B12 will take methyl group from THF (makes Thymidine) and give methyl group to homocystein to make methionine
- this doesn’t get better with folate administration
- B12 is also good for methymalonic acid to succinyl CoA
What kind of antibodies will we likely see in pernicious anemia?
Type 3: 85-90%…. they get the alpha nd B subunits of the gastric proton pump
-leads to chronic atrophic gastritis
What other organism can compete with us for B12 and can induce a deficiency state?
raw fish tapeworms… diphyllobothrium latum
Morphology of pernicious anemia
fundic gland atrophy
- intestinalization
- atrophic glossitis
- demyelination fot eh dorsal and lateral spinal tracts
- spastic paraparesis and sensory ataxia
- severe paresthesias in the lower limbs
clinical lab values for pernicious anemia
- leukopenia with ypersegmented granulocytes
- low serum B12 (duh)
- elevated levels of homocystein and methylmalonic acid
How is diagnosis of pernicious anemia confirmed?
by an outpouring of reticulocytes and a rise in hematocrit levels begginning about 5 days after parenteral administration of vitamin B12
What are people who have pernicious anemia at risk for?
gastric carcinoma
Anemia of folate deficiency
- look a hell of a lot like B12 deficiency!
- BUT THERE’S NO NEURO CHANGES
- suppressed synth of DNA is the immediate cause of megaloblastosis
- we are entirely dependent on diet for folic acid
- absorbed in proximal jejunum
What drug inhibits dihydrofolate reductase and lead to a deficiency of FH4?
methotrexate
How can the diagnosis of folate deficiency be made?
low folate in serum or red cells
- the methylmalonate concentrations are normal
- so neruo changes do not occur
- remember that in B12 deficiency, folate will not prevent those neuro deficits
Iron deficiency anemia
- most common nurtitional disorder in the world
- inadequate hemoglobin synthesis
- transferrin binds it up in the plasma 1/3 saturation
- Ferritin binds it up in cells
- absorbed int he proximal duodenum
What regulates iron absorption?
hepcidin
- released by liver in response to increases in intrahepatic iron levels
- binds ferroportin and causes it to be endocytosed and degraded
- then, not as much iron is absorbed
- ineffective erythropoiesis suppresses hepatic hepcidin production
What are the 4 main causes of iron deficiency?
- dietary lack
- impaired absorption
- increased requirement
- chronic blood loss
what kind of anemia does iron deficiency produce?
hypochromic microcytic anemia
morphology of iron deficiency anema
dissappearance of stainable iron from macrophages in the bone marrow
- microcytic and hypochromic cells
- poikilocytosis: small elongated red cells (pencil cells)
Clinical features of iron deficiency anemia
Plummer vinson syndrome: glossitis, esophageal web, microcytic hypochromic anemia
- serum iron and ferritin are low,
- total plasma iron binding capacity (TIBC) is high
What are the stages of iron deficiency
- storage iron is depleted- ferritin is low and TIBC is high
- serum iron is depleted- serum iron is low and the is low % saturation (>33%)
- normocytic anemia: bone marrow makes fewer, but normal-sized, RBCs
- microcytic, hypochromic anemia: bone marrow makes smaller and fewer RBCs
Anemia of Chronic Disease
Impaired red cell production associated with chronic diseases that produce systtemic inflammation
- most common cause of anemia among hospitalized patients
- IL-6 stimulates increase in hepcidin…. ferroportin is gone,,,, no iron… damn
- reduction in EPO some some godforsaken reason… maybe to fend off certain types of infection… like bacteria
- “iron sequestration in the setting of inflammation”
Aplastic Anemia
syndrome of chronic primary hematopoietic failure and attendant pancytopenia
- most common cause is chemo drugs that cause marrow suppression
- chloramphenicol and gold salts
- most cases are idiopathic
- hypocellular bone marrow… there’s just fat there and fibrous stroma
- dry tap on bone marrow
Clinical features of aplastic anemia
- Splenomegaly is characteristically absent*
- red cells are slightly macrocytic and normochromic
- reticulocytopenia is the rule
Pure Red cell aplasia
a primary marrow disorder in which only erythroid progenitors are suppressed
- Parvovirus B19 preferentially infects and destroys red cell progenitors
- this could lead to an aplastic crisis in anyone who has a moderate to severe hemolytic anemia
- if someone is immunosuppressed, an ineffective immune response can let the infection persist… leading to chronic red cell aplasia and a moderate to severe anemia
Myelophthisic anemia
a form of marrow failure in which space-occupying lesions replace normal marrow elements
- the commonest cause is metastatic cancer
- teardrop-shaped cells… believed to be deformed because of their tortuous escape from the fibrotic bone marrow
Chronic renal failure
whatever its cause, it is almost invariably associated with an anemia that tends to be roughly proportional to the severity of the uremia
-the dominant cause of anemia in renal failure is the diminished synthesis of EPO by the damaged kidneys, which leads to inadequate red cell production
hepatocellular liver disease
erythroid progenitors are preferentially affected
-macrocytic due to lipid abnormalities with liver failure…. cuase RBC membranes to acquire phopholipid and cholesterol
Endocrine disorders
hypothyroidism
-may be associated with a mild normochromic, normocytic anemia
