Anemia Flashcards
Healthy Erythron
12-15 g/dL
Normal structure
Circulate for 120 days
Kidneys respond to RBC need with erythropoeitin
RBC precursors normal with enough iron and vitamin cofactors
Senescent RBCs cleared by spleen
Normal RBCs
Pliable, elastic, anucleate
Membrane is selectively permeable
Large SA to V ration permites RBC to squeeze through capillaries and resume shape
Normal RBC cytoplasm content
Hemoglobin A for transport of oxygen to tissues
RBC membrane structure
Phospholipid bilayer and cholesterol Internal spectrin cytoskeleton Transmembrane proteins Glycopeptides and glycolipids (outer) GPI-linked proteins (outer) Absorbed plasma substances (outer)
Interactions of RBC membrane determine
Shape, metabolism, trasnport, and survival
Definition of anemia
Reduction in RBC mass, numbers, or hemoglobin concentration with corresponding decrease in oxygen carrying capacity of the blood
Compensatory mechs to anemia
Circulatory - increase HR, dilation of arterioles to increase tissue perfusion
Biochem - increase 2,3-DPG in RBCs…decreases hemoglobin affinity to increase delivery to tissues
Bone marrow - hyperplasia due to increase in erythropoetin…increase in reticulocytes
When compensation fails (clinical features of anemia)
Pallor Weakness Malaise Headaches Dyspnea (on exertion at firt)
Later consequences of anemia with resulting hypoxia
Angina pectoris and heart failure
Fatty change in liver
Compensatory bone marrow hyperplasia
How do we classify anemia?
By RBC morphology
RBC morphology (size, color, appearance)
Size - normocytic, microcytic, macrocytic
Color - normochromic, hypochromic
Appearance - spherocytes, target cells, schistocytes, cytoplasmic inclusions
Color reflects
Degree of hemoglobinization
Hypochromic microcytic anemia
Could be due to iron deficiency
Small red cells contain narrow rim of peripheral hemoglobin
Megaloblastic anemia
Enlarged oval RBCs
Spherocyte
Membrane loss…loss of SA relative to volume
Loss of central pallor
Typical of extravascular hemolysis
Not all affected
Target cell
Membrane excess…def of cytoplasm
Cause might be thalassemias (reduces Intracell Hb but not membrane surface area)
Schistocytes
RBCs mechanically fractured in circulation
Cytoplasmic inclusions
Could see precipitate of denatured globin in supravital staining
Think G6PD deficiency
Bite cells will be produced as macrophages pluck out
Reticulocytes
Larger size with blue tint
Percentage reflects both demand and effective of erythropoiesis
If large, increases MCV
Polychromasia
Many reticulocytes
Mechs of anemias
Blood loss
Impaired RBC production (nutrient def or marrow disorder)
Increased RBC destruction (hemolytic anemias)
Acute blood loss symptoms depend on
Rate of hemorrhage and site of bleeding (int vs ext)
Severe blood loss can
Lead to cardiovascular collapse, shock, and death
Acute blood loss compensatory
Shift of fluid from extraascular space ot cirulcation—–leads to hemodilution and decreased hematocrit…**hemocrit and hemoglobin values may not reflect magnitude of blood loss because this takes some time
Acute blood loss and renal
Renal hypoxia increases production of EPO…leads to increased reticulocytes in peripheral blood
As blood loss increase (urine, mental status, other vitals)
Pulse increases BP decreases RR increases Urine output decrease CNS goes first to anxious and confused, then lethargic
Chronic blood loss and examples
Rate of loss exceeds regen capacity
Iron reserves depleted so iron deficiency anemia
(colon cancer, hookworm, chronic menorrhagia)
Disorders of stem cell proliferation or differentiation
Aplastic anemia
Pure red cell aplasia
Anemia due to renal failure
Anemia due to liver dz and endocrine disorders (mild)
Aplastic anemia with mechs
Bone marrow aplasia and pancytopenia
Suppression of stem cell activity by activated T cells or intrinsic clonal stem cell abnormalities
Few reticulocytes and no splenomegaly…hyocellular marrow with mostly fat cells (dry tap)
Pathophys of aplastic anemia and tx
Damaged stem cells produce
1) profeny expressing neo-antigens that avoke AI response
2) Cloncal pop with reduced prolif capacity
BOTH lead to marrow aplasia
immune suppression and BM trasnplant
PRCA
Aplasia of marrow RBC precursors
Reduced reticulocytes and marrow BC precursors
Other marrow lineages normal and present
Associated with thymomas, AI dz and parvovirus B-19
Anemia due to renal failure
EPO def
Normocytic and normochromic
Due to reduced production of EPO by kidney likely iwht decrease in renal mass
RBC survivial may be shortened
Myelophthisic anemias
Space occupying lesions reducing hematopoetic capcity may include metastases, fibrosis and granulomas
Infiltrating nonhematopoeitic cells can cause varying degrees of anemia
Could be due to toxins or infection
Defects in hemoglobin synthesis
Iron def
Sideroblastic anemias
Key steps in synthesis of heme take place in
Mitochondria of RBC precursors
Sideroblastic anemias
Ringed sideroblasts…formed by abnormal deposition of iron in mitochondria of RBC precurosrs
Common pathological process is through to be disordered heme synthesis
Globin synthesis disorders
Hemoglobinopathies (qualitative)
Thalassemias (quantitative)
Iron def casues
Dietary lack
Increased requirements
Chronic blood loss
Impaired absorption
Total iron stores normally…trasnport, functional, storage
4 grams…intake 10-20 mg
Trnasport - transferrin (33% bound to iron)
Functional - hemoglobin, myoglobin, enzymes
Storage - ferritin (not in circulation), hemoseridin
Iron regulating organ, metabolism
Duodenum (absorbed in both heme and non-heme forms)
Controlled by rate of absorption (once absorbed, very little iron excreted)
In iron deficiency
Serum iron decreases and iron binding capcity increases….ferritin SHOULD be low in iron def and high in excess but could be misleadingly increased if inflammation
Iron regulation
On luminal side, heme iron is absorbed by heme transporter…non-heme iron is reduced to ferrous form by stomach acid or cytochrome B before absorption…once entering cytoplasm, stored in ferritin…iron that is not absorbed into plasma is lost into fecal stream when enterocyte shed….fraction enters plasma via ferroportin-hephaestin complex which oxidizes back to ferric form for attachment o transferrin in portal blood…when iron nromal and erythropoeisis at steady state, absorption into plasma is minimal
When body iron needs to increase,
More iron reaches plasma…HFE protein in gut cells plays role
Iron cycle
Plasma iron bound to transferrin is transported to marrow and transferred to RBC which incorporate it into hemoglobin…RBCs circulate for 120 ays befroe ingested my macros of RES…macros extract iron from hemoglobin and return it to plasma
Iron def anemia
Microcytic, hypochromic anemia
Low serum iron and ferritin
High total iron binding capcity…surplus transferrin carrying capacity relative ot iron concentratyion
Visible marrow ion stores absent
Signs and symptoms of iron-def anemia
Pallor Irritable Fatigue Tachycard Sore or swollen tongue Koilonychia Alopecia Craving for clay or ice Plummer-Vision syndrome - hypochromic microcytic anemia, esophageal web, glossitis
Anemia of chronic dz
Can be normochromic, normocytic or hypochromic, microcytic Low serum iron AND low iron binding capcity because transferrin concentration decreases in inflammation (distinguishes from iron-def) Low erythropoeitin (due to IL-1 and TNF)
Why is serum iron low in anemia of chronic dz
Increased activity of hepcidin in inflam sites…this degrades ferroportin activity and decreases iron absorption
Types of megaloblastic anemias
B12 def or malabsorption
Folate def
Pernicious anemia
Folate def anemia
B-12 and folate needed for
Thymidine synthesis for DNA synthesis
Cobalamin def
Inhibits metab of folate into form needed to serve as cofactor for thymidine stnehsis
Def of B-12 or folate patho
Inhibits conversion of homocysteine into methionine, allowing homocysteine to accumulate in serum
B-12 other cofactor
MMA to succinate…B-12 def allows MMA to accumulate
How can you tell difference between folate and B-12 def
FOlate - only homocysteine elevate
B-12 - both MMA and homocysteine
Neurologic consequences of B-12 def
Most B-12 def due to
Impaired absorption
Folate vs. B-12 def prevalence
Folate more common
Megaloblastic anemias morphology, peripheral blood, and bone marrow
Morphology- due tp DNA derangement, erythroid precursors are large
Per blood - pancytopenia, anisocytosis, macrocytosis, ovalocytosis, low reticulocyte count, large hypersegmeneted neutrophils
Bone marrow - hypercellularity, megaloblastic cells and ineffevtive erythropoeisis
Megaloblastic marrow shows
Delayed nuclear maturation due to impaired DNA synthesis
B-12 absorption depends on
Adeuqate diet
Acid-pepsin in stomach - releases B-12 from protein
Gastric secretion of IF
Pancreatic proteases - liberate from R factor
Ileum with functioning B12-IF receptors
Once absorbed in the ileum B-12
Bound to transcobalamin 2 and released to plasma
B12 population
Dietary lack from vegetarians
Increased requirements in pregnancy
Impaired absorption in white people over 50
B-12 malabsorption causes
Gastric - achlorhydria (gastric juices release B-12 from food)…gastrectomy, parasites, atrophic gastritis/AI pernicious anemia (IF absent)
Ileal - Ileal resection, diffuse intestinal dz, bacterial overgrowth, fish tapeworm
Pathogen of pernicious anemia
AI destruction of gastric mucosa…loss of parietal cells and chronic inflammatory infiltrate
3 types of ABs - Block binding of B12 to IF
Block binding of B12/IF complex to ileal
AB against gastric proton pump
Associated with other AI disorders (thyroiditis)
Morphology of pernicious anemia
Bone marrow and peripheral blood changes…GI tract - atrophic glossitsm chronic gastritis with intestinal metaplasia (increased cancer risk)
Pernicous anemia due to B12 symtpoms and tx
Spinal cord myelin degeneration producing spastic paraparesis, sensory ataxia and parethesias (subacute combined degneeration)
Folate tx can reverse megaloblastic changes but NOT tx neurological symptoms
Must use IV B-12 to tx nervous system
Schilling test for B-12
Give B-12 orally and easure in 24 hour urine…If over 7% is excreted, then normal
If part 1 low, give B-12 with IF…if increases (greater than 9%, then demonstrates IF missing and diagnoses PA)
Folate def anemia
Similar to B12 without neurological alterations
Tx with folate
Clinical features of hemolytic anemias
Abnormal RBC destruction inside or outside spleen
Shortened RBC lifespan
Increased EPO levels and increased compensatory EPO
Accumulation of hemoglobin catabolism products (bilirubin)
Classification of hemolytic anemias
Intrinsic RBC abnormalities (hereditary or acqwuired)
Extrinsic causes of RBC destruction
Hemolysis may take place inside the circulation (intravascular) or outside (spleen, extravascular)
intrinsic RBC abnormalities
Cytoskeleton disorders (spherocytosis, elliptocytosis)
Disorders of lipid synthesis (increased membrane lectin)
Glycolytic enzyme disorders (pk def, hexokinase def.)
Hexose monophosphate shunt enzyme disorders (G6PD or glutathione synthetase def)
Thalassemias and hemoglobinopathies
Only acquired intrinsic RBC idsorder
PNH
Extrinsic RBC abnormalities
Auto/alloantibodies
Allo - transfusion rxns or hemolytic dz of fetus and newborn
Immune mediated hemolysis may or may not
Involve complement and MAC…dictates whetehr intravascular, extravascular or both
Mechanical trauma to RBCs
Microangiopathic hemolytic anemias - produce schistocytes…could also be from IV fluids, chem injry and infections like malaria
Intravascaulr hemolysis manifestation
Hemoglobinemia
Hemoglobinuria
Jaundice
Decrease serum haptoglobin…haptoglobin binds free hemoglobin and felps prevent urinary excretion
Extravascaulr hemolysis
Mostly in spleen
Jaundice
RBCs phagocytosed by splenic macrophages
Increased normoblasts, reticulocytes, and spehrocytes
Hereditary spehrocytosis
Intrinsic cytoskeleton defect - spheroid RBCs, fragile, porrly deformable, vulnerable to splenic sequestration
Mutations to ankyrin, band 3, band 4.2, spectrin
Auto dominant
Hereditary spherocytosis morphological
Spherocytes increase Reticulocytosis Marrow hyperplasia Splenomegaly Cholelithiasis
HS clinical
20-30% asymptomatic
Others have aplastic crisis or hemolytic crisis
Splenectomy resolves symptoms but RBC abnormality remains
Osmotic fragilty test
Suspend Pt RBCs for 24 hours…spherocytes will tolerate saline less well and burst sooner
G6PD def general
Enzyme dysfunction in hexose monphosphate shunt of glutathione metab…decreases RBC ability to withstand injury
Oxidizes G6P and reduces NADP
G6PD def
Intra and extra hemoylsis associated with certain drugs
Sensitive to fava beans
X-linked rec
2 variatns
G6PD lab
Normochromic normocytic anemia with reticulocytosis
Elevated bilirubin
Hemoglobinuria
Peripheral blood of G6Pd shows
Heinz bodies (denatured precipitated globin chains)…form on oxidant exposure and can cause intravascular hemolysis…can be plucked out by splenic macrophages and produce bite cells
PNH
Rare intrinsic defect
Mutation in PIGA which is needed for synthesis of GPI
Stem cell clone are prone to lysis because without GPI linakge, important GPI proteins which regulate complement on RBC membranes are missing (DAF, MIRL, C8 binding protein)
PNH clinical
Usually intravascular hemolysis leading to iron def via urinary hemoglobin loss
Tendency to thrombosis and AML
AIHAs
Caused by autoantibodies with specificities for RBC antigens which promote intra and extra vascular hemolysis
Can be IgG or IgM
DAT
Can test for AIHAs
Try to detect IgG on RBCs using AHG
AIHA classification
Temperature at which AB reacts most strongly…IgG reacts best at higher temps
Warm AI HA
37 C Most comon Can be pirmary or secondary IgG causing mostly extravascular hemolysis with partial RBC phagocystis producing spherocytes in peripheral blood Splenectomy and immunosuppressants
CAS
IgM
Can be extra ro intra
Clinically cyanosis of areas exposed to cold and Raynaud phenomenon
PCH
Intermittent massive intravascular hemolysis with hemoglobinuria following cold expossure
May accompany infections
IgG binds to RBCs at cold temps and fixes complement which lyses them at warming temp
Drug induced immune hemolysis mechs
Cross reacting autoABs Haptens (antigenic) Immune complexes (bind to RBCs) Membrane modification T cell acitivty suppresssion
Microangiopathic hemolytic anemias
Due to mechanical trauma
Hallamrk is schistocyte in peripheral blood
Common cause of splenomegaly
Portal hypertension
Splenic pathology in sickle cells dz
Spleen sequesters large portion of RBCs…can lead to vascular occlusion…most function asplenically
Splenic enlargement infections
Mono, malaria, hepatic schistosomiasis
Splenic infarction
Thromboembolism of splenic artery or branches
Sickle cell, atheromatous, infective endocarditis
Rapid splenic enlargment
LUQ pain, fever, N/V
