Red Blood Cell Disorders Flashcards
Anemia-> definition and classifications
- reduction in circulating RBC mass
- measured by <b>Hb, Hct & RBC count</b>
Hb <b> in males (N= 13.5-17.5) & <b> in females (N= 12.5-16)</b></b>
*based on MCV (um^3)–> <b>Microcytic (100)</b></b></b>
Microcytic Anemia Overview
- decreased production of Hb
- extra division of RBC progenitor cells to maintain Hb concentration
*<b>iron deficiency anemia, anemia of chronic disease, sideroblasic anemia & thalassemia</b>
What is Hb & how does heme get into the system?
Hb–> 4 hemes–> each made up of protophorphyrin ring–> Fe in center–> binds oxygen
- <b>Ferroportin</b>- transports heme from duodeum to blood
- <b>Transferrin</b>- transports iron in blood to liver & marrow macrophages for storage
- <b>Ferritin</b>: binds intracellular iron preventing the formation of free radicals
Iron Deficiency Anemia–> causes, stages, clinical features, labs, treatment
- <b>dietary lack</b> (malabsorption, malnutrition, gastrectomy) <b>or blood loss</b> (ulcer, menorrhagia, pregnancy, colon polyps/carcinoma, hookworm)
- stages: depletion of storage iron (low ferritin, high TIBC)–> depletion of serum iron (low % saturation)–> normocytic anemia–> microcytic, hypochromic anemia
- Clinical Features: anemia, koilonychia, pica
<b>-labs: microcytic, hypochromic RBCs, high RDW (red cell distribution width), low ferritin, serum iron & % saturation, high TIBC & free erythrocyte protoporphyrin (FEP)</b>
-treatment: ferrous sulfate (iron supplement)
lab tests
- serum iron: iron in blood
- TIBC: measures transferrin
- % saturation: % of transferrin molecules bound by iron
- serrum ferritin: reflects stores in macrophages and liver
Plummer-Vinson Syndrome
-iron-deficiency anemia with <b>esophageal web and atrophic glossitis</b> presenting as anemia, dysphagia and beefy-red tongue
Anemia of Chronic Disease–> cause, Hepcidin’s role, labs
-from chronic inflammation leading to production of acute phase reactants from liver (i.e. hepcidin)
<i>Hepcidin sequesters iron sites by limiting iron transfer from macrophages to erythroid precursoes & suppressing EPO prduction to prevent bacteria from accessing iron (which they need for survival)</i>
-<b>labs: high ferritin & free erythrocyte protoporphyrin, low TIBC, serum iron & % saturation</b>
Sideroblastic Anemia
- <b>congential or acquired defect in protoporphyrin synthesis</b> causing iron to remain trapped in mitochondria
- *<b>forms a ring around nucleus of erythroid precursors (ringed sideroblasts)</b>
- congenital–> ALAS (rate-limiting enzyme)
- acquired–> alcoholism (damages mitochondria which makes protoporphrin), lead poisoning (inhibits ALAD and ferrochelatase), VB6 deficiency (required cofactor for ALAS)
<b>-labs: high ferritin, serum iron & % saturation, low TIBC</b></b>
Important relationships between labs
indirect: ferritin and TIBC
direct: serum iron and % saturation
Protoporphyrin synthesis
Succinyl CoA –(ALAS & Vitamin B6 cofactor)–> ALA
ALA –(ALAD)–> Porphobilinogen
Porphobilinogen —-> Protoporphyrin
Protoporphyrin + Fe –(Ferrochelatase)–> Heme
<b>**first reaction is rate-limiting</b>
<i>**final reaction occurs in mitochondria</i>
Thalassemia Overview
- inherited mutation causing decreased synthesis of a or B globin chains <b>(normal Hb: HbF (a2y2), HbA (a2B2), HbA2 (a2d2))</b>
- carriers are protected against <b>Plasmodium falciparum malaria</b>
a Thalassemia
-gene deletion:
1= asymptomatic 2= mild anemia with increased RBC count (cis- severe and in Asians, trans- Africans) 3= severe anemia <b>(B chains form tetramers HbH that damage RBCs)</b> 4= hydrops fetalis; <b>(y chains form tetramers HbBarts that damage RBCs)</b>
B Thalassemia
- gene mutations (African or Mediterranean descent):
- chrmosome 11 which has two B genes
<b>Minor</b>: mild, asymptomatic, increased RBC count, microcytic hypochromic RBCs & target cells; decreased HbA and increased HbA2 & HbF
<b>Major</b>: severe, high HbF is temporarily protective, unpaired a chains precipitate and damage RBC membrane (ineffective erythropoiesis & extravascular hemolysis), <b>massive erythroid hyperplasia</b> (expansion of hematopoiesis into skull and facial bones, extramedullary hematopoiesis with hepatosplenomegaly and risk of aplastic crisis with parvovirus B19 infecton of erythroid precursors); microcutic, hypochromic RBCs with target cells and nucleated RBCs; no HbA
Macrocytic Anemia Overview
-commonly due to folate or VB12 deficiency (megaloblastic anemia) which impairs DNA precursor synthesis
- <b>Megaloblastic anemia</b>- from impaired division & RBC enlargement
- <b>Hypersegmented neutrophils</b>- from impaired division of granulocytic precursors
Folate deficiency (Macrocytic Anemia)
- folate is absorbed in the <b>jejunum</b>
- <i>minimal body stores</i>
- causes: poor diet, increased demand (pregnancy, cancer, hemolytic anemia), & folate antagonists
-<b>labs: macrocytic RBCs & hypersegmented neutrophils, glossitis, low serum folate, high serum homocysteine (not converted to methionine), normal methylmalonic acid</b>
Vitamin B12 deficiency (Macrocytic Anemia)
- takes years to develop due to <i>large hepatic stores</i>
- most commonly caused by <b>pernicious anemia</b> (autoimmune destruction of parietal cells); or pancreatic insufficiency and damage to terminal ileum
<b>-labs: macrocytic RBCs & hypersegmented neutrophils, glossitis, <i>spinal cord degeneration</i>, low serum VB12, high serum homocysteine & <i>methylmalonic acid</i></b>
<i>VB12 is a cofactor for conversion of methylmalonic acid to succinyl CoA. With a deficiency, methlmalonic acid accumulates and impairs spinal cord myelination leading to poorproprioception and vibratory sensation and spastic paresis</i></b>
Normal Vitamin B12 movement throughout the body
- VB12 is liberated from animal proteins by salivary gland enzymes and carried to stomach by R-binder
- pancreatic proteins detach VB12 from R-binder
- VB12 binds intrinsic factor (from parietal cells) which is absorbed in the ileum
Normocytic Anemia Overview
- normal-sized RBCs
- <b>increased peripheral destruction or underproduction</b> distinguished by reticulocyte count
Reticulocytes
- young RBCs= large, blueish cytoplasm (residual RNA)
- Normally 1-2% which replaces RBCs that die after 120 days but increases to 3% in response to anemia
<b>**RC is falsely elevated in anemia since is it measured as a percentage of total RBCs
**corrected by: Rc x Hct/45</b>
Peripheral RBC Destruction (Hemolysis)
-extravascular or intravascular resulting in anemia with good marrow response
<b>Extravascular</b>: (hereditary spherocytosis, sickle cell anemia) RBC destruction by reticuloendothelial system (macrophages consume them); anemia with splenomegaly, jaundice, risk for bilirubin gallstones, marrow hyperplasia with corrected RC >3%
<b>Intravascular</b>: (PNH, G6PD, IHA, microangiopathic hemolytic anemia, malaria) RBC destruction within vessels; hemoglobinemia, hemoglobinuria, hemosiderinuria, decreased serum haptoglobin
- <i>haptoglobin usually binds Hb to reprocess in spleen</i>
- hemosiderinuria: shedding of tubular cells after an accumulation of hemosiderin (Hb broken down into iron)</i>
How do macrophages break down Hb?
globin–> amino acids
heme–> iron (recycled) & protoporphyrin
protoporphyrin–> unconjugated bilirubin (bound to albumin & delivered to liver for conjugation & excretion into bile)
Hereditary Spherocytosis–> cause, labs, diagnosis, treatment
- defect of RBC cytoskeleton-membrane tethering proteins (ankyrin, spectin, band 3)
- formation of blebs and spherocytes (round cells)
<b>-spherocytes are less able to get through splenic sinusoids and thus are consumed by macrophages</b>
-<b>labs: spherocytes with loss of central pallor, high RDW & MCHC, splenomegaly, jaundice, risk of gallstones, aplastic crisis with parvovirus B19 infection of erythroid precursors</b>
<i>diagnosed with osmotic fragility test & treated with splenectomy (treats anemia but results in spherocytes and Howell-Jolly bodies</i>
Sickle Cell Anemia–> trait and disease
-mutation of B chain (glu–>val) but driven by hypoxemia, dehydration & acidosis
<b>Sickle Cell Disease–> 2 abnormal B genes</b>
-<b>deoxygenated HbS polymerizes–> aggregate into needle-like structures</b>
-sickle and de-sickle causing RBC membrane damage and <b>complications of vaso-occlusion</b>: dactylitis (edema), autosplenectomy (leading to increased risk of infection by encapsulated organisms), acute chest syndrome, pain crisis, renal papillary necrosis (hematuria & proteinuria)
<b>Sickle Cell Trait–> 1 abnormal B gene</b>
- asymptomatic with no anemia
- renal medulla- sickling with hypoxia and hypertonicity
Hemoglobin C
- AR mutation in B chain (glu–>lys)
- <b>mild anemia due to extravascular hemolysis</b>
- HbC crystals</b>
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Cause: acquired defect in myeloid stem cells–> absent GPI–> cells susceptible to destruction by complement
<i>GPI secures DAF to the membrane
DAF inhibits C3 convertase (protecting against complement-mediated damage)</i>
Clinical features: episodic intravascular hemolysis (thus hemoglobinemia & hemoglobinuria; hemosiderinuria) during sleep since complement is activated by respiratory acidosis–> platelet fragments can induce thromosis
<b>test: sucrose test for screening, acidified serum test of flow cytometry to detect lack of CD55 (DAF) on blood cells is confirmatory test</b>
Complications: iron deficiency anemia & AML
Glucose-6-Phosphate Dehydrogenase Deficiency (G6PD)
-reduced G6PD half life increasing susceptibility to oxidative stress
<b>low G6PD–> low NADPH–> low reduced glutatione–> oxidative injury by H2O2 (causing Hb precipitation as Heinz bodies which become bite cells when removed by macrophages)–> intravascular hemolysis</b>
-African (mild) & Mediterranean (severe) variants: protective role against <b>falciparum malaria</b>
Immune Hemolytic Anemia (IHA)
-Ab mediated (IgG or IgM) destruction of RBCs
<b>IgG-mediated</b>: extravascular hemolysis; associated with SLE, CLL and certain drugs
<b>IgM</b>: intravascular hemolysis; RBCs inactivate complement but residual C3b serves as an opsonin for spenic macrophages resulting in spherocytes and <b>associated with Mycoplasma pneumoniae and infectious mononucleosis</b>
- Coombs tests diagnoses IHA (direct or indirect)
- <b>direct</b>: agglutination occurs if RBCs are already coated with IgG or complement when anti-IgG-complement is added
- <b>indirect</b>: agglutination occurs if serum Ab are present when anti-IgG and test RBCs are added
Microangiopathic Hemolytic Anemia
- vascular pathology causing destruction of RBCs (intravascular hemolysis)
- occurs with microthrombi: TPP-HUS, DIC, HELLP, prosthetic heart valves & aortic stenosis <b>producing schistocytes on blood smear</b>
Malaria
- infection of RBCs and liver with Plasmodium (transmitted by female Anopheles mosquito)
- <b>RBCs rupture; intravascular hemolysis and cyclical fever</b>
- P. falciparum- daily fever
- P. vivax & P. ovale- fever every other day
-<i>mile extravascular hemolysis with splenomegaly since spleen consumes some RBCs</i>
Anemia due to under production Overview
- decreased RBC production by marrow
- low corrected RC
- <b>etiologies: causes of microcytic & macrocytic anemia (low RC), renal failure (low EPO), damage to bone marrow precursors (progenitor cells do not develop properly)</b>
Parvovirus B19
- infection of progenitor red cells halting erythropoiesis–> significant anemia in setting of preexisiting marrow stress
- infection is self-limited
Aplastic Anemia
- pancytopenia with low RC due to damage to hematopoietic stem cells
- due to: drugs, chemicals, viral infections, autoimmune damage
<b>biopsy</b>–> empty, fatty marrow
- treatment: marrow stimulating factors (erythropoietin, GM-CSF, G-CSF), transfusions, bone marrow transplantation
- <i>immunosuppression may be helpful as some idiopathic cases are due to abnormal T-cell activation with release of cytokines</i>
Myelophthisic Process
- replaces bone marrow
- hematopoiesis is impaired–> <b>pancytopenia</b>
