Heme Lecture 1 - RBCs Part 1B (Anemia)
Oral Iron Supplements (syllabus)
ferrous sulfate (325 mg tablets, each containing 60 mg of elemental iron) 3X daily preferably on empty stomach to avoid binding of iron to complexes in food
Anemia Of Chronic Inflammation ("Anemia of Chronic Disease")
i.e. infection, inflammatory diseases, malignancy; *block of iron reutilization (Iron stores normal or increased in marrow macs, but cannot be delivered to developing erythroid precursor cells)*; protective response designed to limit delivery of Fe to infectious agents - *Low reticulocyte* production - Due to impaired delivery of iron to erythron, decreased erythropoietin response to anemia, decreased bone marrow response to erythropoietin - *MCV low to normal* - *HIGH FERRITIN (total body Fe stores) distinguishes this disorder from iron deficiency*
Ferrokinetic Findings in Normal Effective Erythropoiesis
iron taken up by marrow cells is incorporated into circulating red cells
"Normal" hematocrit for a smoker with chronic obstructive pulmonary disease, a resident of an Andean village in Peru, or a patient with congenital heart disease
is higher than that of a normal individual living at sea level
Hypoproliferative Erythropoiesis
marrow iron uptake is diminished
Jaundice and/or Ichterus
may suggest hemolysis (increased rate of RBC destruction)
Hemoglobin (Hb) Normals
measured directly and expressed as grams of hemoglobin per deciliter of blood (g/dl) Adult Male: *13-18*g/dl Menstruating Female: *11.5-15.5*g/dl
Absolute Reticulocyte Count
% reticulocytes × number of RBCs × 100 *Normal*: 20,000 - 65,000/μl - this value is often provided by the lab on a reticulocyte count report
Differential Diagnosis (DDx) of Low Reticulocyte Count (<3)
*Decreased RBC Production* DDx Varies based on Normal, High, or Low MCV
Blood Values
*Hematocrit*: % of the blood volume occupied by RBCs *Hemoglobin*: measured directly and expressed as grams of hemoglobin per deciliter of blood (g/dl) *Red Cell Number*: Less commonly used - *Testosterone enhances erythropoiesis*, contributing to these minor discrepancies in the range of normal values in females and in males
Red Cell Indices
*MCV (mean corpuscular volume)*: Hct/red cell count per mm3 (in millions) X 10 (Actual average volume of each RBC) *MCHC (mean corpuscular Hb concentration)*: Hb/Hct X 100 *MCH (mean corpuscular Hb)*: Hb/red count/mm3 X 10 (mass)
Evaluation of Iron Status: Iron Depletion
*Marrow Iron Stores: +/-* *Ferritin: Slightly Low* TIBC: Normal Fe: Normal % Saturation (Fe/TIBC): Normal FEP: Normal Marrow Sideroblasts: + (normal) MCV: Normal Anemia: No
Evaluation of Iron Status: Iron Deficient Erythropoiesis
*Marrow Iron Stores: 0* *Ferritin: Low* *TIBC: Normal/Slightly High* *Fe: Slightly Low/Low* *% Saturation (Fe/TIBC): Low* *FEP: High* *Marrow Sideroblasts: 0* *MCV: Low* Anemia: No
Evaluation of Iron Status: Iron Deficiency Anemia
*Marrow Iron Stores: 0* *Ferritin: Very Low* *TIBC: High* *Fe: Low* *% Saturation (Fe/TIBC): Low* *FEP: High* *Marrow Sideroblasts: 0* *MCV: Low* *Anemia: Yes*
Anemia of Chronic Inflammation: Lab Values
*Normocytic or rarely Microcytic* - MCV not under 75 Serum iron: Low *TIBC: Low due to reduced transferrin!!* % Saturation: 10-20% (normal) Serum ferritin: >150 (normal to high) acute phase reactant, may increase in inflammation - Increased Iron stores in BM - Decreased Iron in RBC precursors - NO response to iron - Elevated hepcidin
Differential Diagnosis (DDx) of High Corrected Reticulocyte Count (>3)
*Peripheral Destriuction of RBCs or Blood Loss* 1.) Acute Blood Loss (5-10 days previously) 2.) Chronic Blood Loss (Iron Reserve still intact) 3.) Hemolysis RBC morphology on smear provides the most important clues to the Dx in this situation If reticulocyte count is very high (>10%), MCV can be elevated, as reticulocytes are large cells
If Hct Does not Rise with Iron Suplementation
1.) Investigate possibility of *persistent bleeding* 2.) Consider whether there's reason for *impaired GI absorption* (antacids, prior surgical removal of the duodenum or proximal jejunum, disorders which affect mucosal surfaces at these sites) 3.) Consider whether *other reasons* exist for the anemia, in addition to iron deficiency
Helpful Studies for Intravascular Hemolysis (High Reticulocyte Count due to Hemolysis)
1.) Peripheral blood smear 2.) Haptoglobin 3.) Indirect Bilirubin 4.) Plasma Hb 5.) Urine Hemosiderin
Etiologies of Normocytic Anemia include...
1.) Renal Failure 2.) Aplastic Anemia 3.) Endocrine Disorders (e.g. Hypo/Hperthyroidism) 4.) Pure Red Cell Aplasia 5.) Myelophthristic Process Marrow aspirate and biopsy is often indicated to distinguish these possibilities when renal and thyroid function tests are normal
When Iron is Given, what Response is Expected?
1.) Rise in reticulocyte count over 5-10 days 2.) Rise in Hb and Hct over 3-4wks - Hb should increase by at least 2g/dl over 3 weeks - Delay results from requirement for iron early in the differentiation stages of erythroid precursor cells
Etiologies of Macrocitic Anemia include...
1.) Vit B12 Deficiency 2.) Folate Deficiency 3.) Drugs that impair DNA Synthesis (Zidovudine, Cancer Chemo) 4.) Myelodysplasia
Helpful Studies in Macrocytic Anemia
1.) Vitamin B12 level Folate level 2.) Marrow aspirate (Wright- Giemsa and Prussian blue stains, and cytogenetics)
Case 1: 24 y/o woman; Fatigued, SOB w/exertion. Craves ice, has soreness of her tongue. - She has 2 children, aged 6 m and 2 y; the younger one is nursing. She has always had heavy menstrual periods. Physical exam: Pale. Heart rate 106. Hemoglobin 7.1 Hct 22 (anemia). MCV 75 (low). Retic count 0.9% (low). Iron 29 (low) TIBC 509 (high) Ferritin 3 (low) This patient has : 1.) Macrocytic anemia 2.) Microcytic, hypochromic anemia 3.) Normochromic, normocytic anemia 4.) No Anemia
2.) Microcytic, hypochromic anemia Pt is Iron Deficient
The treatment of anemia of chronic inflammation is 1.) Vitamin B12 injection. 2.) Iron supplements. 3.) Treat the underlying disease. 4.) Growth factors.
3.) Treat the underlying disease - and/or red cell transfusions
IV iron infusion (syllabus)
Associated w/anaphylaxis and thus requires careful monitoring of the patient - Iron should NOT be given intramuscularly because of the frequency of sterile abscesses, and the risk of sarcoma
RDW (Red Cell Distribution Width)
Automatic counters display histograms of RBC volume distribution curve and compute an RDW (red cell distribution width, or coefficient of variance in red cell size), using the assumption that the *distribution of cell size should fit a bell-shaped (Gaussian) curve* - Peripheral blood smear must be examined to interpret the RDW result
Peripheral Blood Smear
Blood smear on glass slide stained w/ Wright-Giemsa stain and examined w/ light microscopy *First*: Confirm Size of RBCs *Second*: assess hemoglobinization *Third*: Assess RBC morphology
Anemia with lack of CV symptoms (SOB, palpitations, lightheadedness with mild exertion) is indicative of...
Chronic or Gradual Onset Anemia Lack of these symptoms implies that the pt has had time to compensate for the anemia by increasing cardiac output - Alternatively, the presence of these symptoms suggests that the anemia is more acute or abrupt in onset (days-weeks) - Symptoms such as fatigue may develop slowly as a chronic anemia becomes more severe.
Red Cell Number Normals
Less commonly used Adult Male: *4.4-5.6 million*/μl Menstruating Female: *3.8-5.0 million*/μl
High EPO Effect on MCV
MCV can be mildly elevated (up to 110fl) if pt's Epo level is very high (e.g. pts w/ aplastic anemia or pure red cell aplasia who have extremely low Hct and healthy kidneys). Results in a change in the kinetics of erythroid differentiation, leading to *fewer cell divisions during red cell maturation, and thus larger cells*
Low Reticulocyte Count (<3): High MCV (Macrocytic)
Macrocytic Generally due to an abnormality intrinsic to the red cell that interferes w/ nuclear maturation, such as a problem with DNA synthesis
Myelophthrisis
Marrow is replaced w/ metastatic tumor, extensive granuloma, or fibrosis Blood smear may show *tear drop shaped and nucleated RBCs*
Free erythrocyte protoporphyrin (FEP)
Measured in RBCs as zinc protoporphyrin (a precursor of the heme molecule) - If insufficient iron is available to make a heme-iron complex, this heme precursor protein accumulates and can be measured directly; study is inexpensive, quick, and can be done on small volumes of blood - Very *sensitive way to screen large populations (esp children) for the presence of iron deficiency*
Anemia (Definition)
Syllabus Definition: Adult Males: Hematocrit <38% Adult Females: Hct <36% Lecture Definition: *Decreased RBCs, Decreased Hgb, Decreased Hct*
Decreases or Absence of stainable Iron in Macrophages in the Marrow
When iron stores are depleted, there is a decrease or absence of stainable iron in macrophages in the marrow Assessed by a *Prussian blue stain of the marrow aspirate* - Iron stains as dark blue globs w/in the macs in the reticuloendothelial regions (spicules) of the aspirate
Complete blood count (CBC)
White blood count (WBC) Red blood count Hemoglobin Hematocrit MCV MCH MCHC RDW (won't need to know for this class!!) Platelet count
Evaluating Iron Status via Bone Marrow Aspirate
1.) Marrow aspirate stained w/ Prussian blue to evaluate for presence or absence of storage iron 2.) Using high power lens of the microscope, evaluate developing erythroid precursors for presence of iron granules in cytoplasm: - *Normal:, 20-30%* of developing erythroid cells contain 2-3 granules of stainable iron and are called *sideroblasts* - *Iron deficient erythropoiesis*: Sideroblasts are not seen Evaluation of sideroblasts also important for assessment of chronic inflammatory block in iron use, and in certain pathological states as myelodysplasia and lead toxicity
Iron Deficiency Anemia Peripheral Blood Smear
1.) Mild Anemia: Microcytipc hypochromic - increased central pallor - small cells 2.) Severe - pencil cells also develop
Helpful Studies for Extravascular Hemolysis (High Reticulocyte Count due to Blood Loss)
1.) Peripheral blood smear 2.) Ferritin 3.) Indirect Bilirubin 4.) Coomb's Test (Direct Antiglobulin Test) 5.) Osmotic Fragility
Sideroblastic Anemia
Blocking Heme Synthesis *Congenital*: Defects in heme synthesis [(e.g.-X-linked sideroblastic anemia (ALA synthase def), erythropoietic porphyria)] *Acquired:* (uncommon) Heme biosynthesis impaired by alcohol, drugs [e.g.-isoniazid interferes with pyridoxine (vitamin B6) metabolism], copper deficiency, lead poisoning
Iron Deficiency Anemia (Lecture) KNOW THIS INFO AND PIC!!!!!!!!
*MicrOcytic, HypOchromic* - Decreased Iron, Increased TIBC, Increased Transferrin - Decreased % saturation of transferrin with iron (Fe/TIBC) <10-15% in iron deficiency - Decreased Ferritin (iron storage protein) - Low to absent marrow iron stores
Low MCV (<80fl)
*Microcytic Anemia* Suggests a cytoplasmic maturation defect (abnormality in Hb synthesis) - RBCs appear *hypochromic* on blood smear
Hereditary Hemochromatosis: Cause
*Mutation HFE gene: C282Y, H63D* (KNOW) - Results in increased GI absorption of iron *Other mutations*: β2M, Tfr2, hepcidin Normally found in Caucasian/European pts - usually need to be homozygous
Myelodysplasia
*Neoplastic disorder of a hematopoietic stem cell* - Red cells, white cells, and platelets derived from this neoplastic clone have abnormal morphology, and may not function normally *Specific findings on marrow examination may include*: - Ringed sideroblasts - Excess blasts - Abnormal granulation in granulocytic cells - Pelger-Huet cells (bilobed neutrophils) - Abnormal cytogenetics
Normal vs High RDW
*Normal*: 14.5 ± 1.5 % *High*: - should suggest increased variation in the size of RBCs (termed *anisocytosis*) - also seen if there are 2 distinct populations of RBCs in circulation (e.g. reticulocytes and fragmented cells w/ certain types of hemolytic anemia, or microcytic and normal cells after an iron deficient patient receives a red cell transfusion) Peripheral blood smear must be examined to interpret the RDW result
Hereditary Hemochromatosis: Treatment
*Phlebotomy* - Clinical features of HH occur later in women than men, bc women are partially protected by menstrual iron loss Each unit of blood (500 ml) contains 200-250mg of iron - 1 unit of blood removed per week until ferritin is <20-25 ng/ml - After that, 2-4X/yr (lifelong) to maintain ferritin <100 ng/ml (or w/in the mid-range of normal)
FDA Approved Uses for Epo (ESAs - erythropoiesis stimulating agents)
- Chronic renal failure - AIDS - Cancer chemotherapy - Reduce transfusions in elective surgery BLACK BOX warning issued by FDA: risks of thrombosis and cancer progression
Diagnostic studies in Anemia "The Basics"
- Complete Blood Count - Blood smear - Reticulocyte Count - Iron Studies - Sometimes a bone marrow examination
Hematocrit (Hct) Normals
% of the blood volume occupied by RBCs Adult Male: 38-50% Menstruating Female: 26-45%
Corrected Reticulocyte Count
% reticulocytes × patient's Hct ÷ Normal Hct
Lymphocyte Nucleus Size
Microcytic: small size Normocytic: normal size Macrocytic: large
Petechiae
Suggests Platelet Deficiency
Etiologies of Extravascular Hemolysis (High Reticulocyte Count due to Blood Loss)
1.) Immunohemolytic anemia (IgG mediated) 2.) RBC membrane defects (i.e., hereditary spherocytosis) RBC enzyme defects (i.e., G6PD deficiency, pyruvate kinase deficiency, and hexokinase deficiency) 3.) Hemoglobin defects (i.e., HbS, HbC, or unstable hemoglobins) 4.) Hypersplenism
Etiologies of Intravascular Hemolysis (High Reticulocyte Count due to Hemolysis)
1.) Immunohemolytic anemia (IgM- mediated) including hemolytic transfusion reactions 2.) Fragmentation hemolysis (DIC, TTP, vasculitis, clostridium toxin, and mechanical and thermal injuries: prosthetic valve hemolysis, march hemoglobinuria, burns, electric shock) 3.) Paroxysmal Nocturnal Hemoglobinuria (PNH)
When Iron Deficiency is Severe Enough that Insufficient Iron is Available for Developing RBC Precursors
1.) Decrease in the % of transferrin that is saturated with iron (the ratio of serum iron to TIBC, termed transferrin saturation, becomes <15%) 2.) Free Erythrocyte Protoporphyrin (FEP) becomes elevated 3.) RBCs become microcytic --> MCV always decreases before the fall in Hct. Smaller RBCs are made as a physiologic compensation for low iron availability Changes in the FEP and MCV occur over weeks.
As the iron supply becomes limited, several physiologic responses occur prior to the onset of anemia, in an attempt to maintain red cell production despite this limited resource. What are they?
1.) Decreases or Absence of stainable Iron in Macrophages in the Marrow 2.) Low Serum Ferritin Level 3.) Elevation in Total Iron Binding Capacity (TIBC) of the Plasma
Reticulocyte Count
*Reticulocyte count is the % of RBCs w/ residual RNA* - During the *first 24-36hrs of circulation (after release from marrow)*, young RBCs contain residual ribosomal RNA which precipitates w/ dyes, such as new methylene blue, to form blue clumps or a reticulum *Normal: ~1%* (1/100 rbcs)
Hereditary Hemochromatosis: Clinical Features
*Transferrin saturation >50 -60%* Excess iron deposited in liver, heart, pancreas, pituitary, skin, joints --> leads to tisue damage *Symptoms/Signs*: "Bronze Diabetes" - Cirrhosis - Cardiomyopathy - Diabetes - Hypogonadism -Characteristic arthropathy most commonly affecting the 2nd and 3rd MCP joints (pain when shaking hands)
Role of Hepcidin in Anemia of Chronic Inflammation
- Inflammatory cytokines lead to increased hepcidin expression - Hepcidin binds to ferroportin, leading to internalization and destruction of ferroportin --> decreases cellular export of iron - Also reduces production of Transferrin --> *Decreased TIBC* (Hepcidin has a 'cidal effect on iron export protein ferroportin aka ferro-ex-portin')
Microcytic Anemia: 3 Types
- Iron deficiency - Anemia of chronic inflammation - Globin/Porphyrin defect
Iron balance
- Iron intake about 1mg/d absorbed - Iron loss 1mg/d sweat, shed skin, gi loss - Menstrual loss: additional 0.5-1 mg/d
Signs/Symptoms of Iron Deficiency Anemia
- Pallor - Pica (appetite for clay, paper, cornstarch) - Pagophagia (pica for ice) - Glossitis (tongue smooth and sore) - Angular stomatitis (ulcers in corners of mouth) - Koilonychia (spoon shaped brittle nails) - Shortness of breath with exertion - Palpitations
Etiologies of Microcytic (Low MCV) Anemia include...
1.) Defects in Heme Synthesis (iron deficiency, inflammatory block in iron re-utilization, and some sideroblastic anemias such as lead poisoning) 2.) Defects in Globin Synthesis (Thalassemia trait or disease) - Measurements of iron, total TIBC, and ferritin distinguish these entities - Hb electrophoresis and brilliant cresyl blue stain (BCB preparation) can be used to help diagnose β and α thalassemia trait, respectively
Workup for Anemic Patient with High MCV
1.) Drug history 2.) Vitamin B12 level 3.) Folate level If these are normal or noninformative, a marrow exam to determine if the specific morphologic and/or cytogenetic abnormalities that characterize myelodysplasia are present
Syllabus Notes on Epo
1.) EPO very effectively increases RBC production in anemia of chronic renal failure, but it is *less effective for other causes of anemia in which kidneys are normal and pt's EPO level is already high* 2.) For EPO to stimulate erythropoiesis, *Fe stores must be adequate* - 1 atom of Fe is incorporated into each porphyrin ring, to form heme. When iron supply is deficient, Epo therapy will not increase RBC production 3.) EPO treatment can exacerbate HTN in pts w/ renal failure; not understood why
Helpful Studies in Normocytic Anemia
1.) Epo level 2.) Marrow aspirate (with Wright-Giemsa stain) and marrow biopsy 3.) Thyroid Function Tests
Helpful Studies in Microcytic Anemia
1.) Fe, TIBC, % saturation Ferritin 2.) Marrow aspirate with Prussian blue (iron) stain 3.) Hemoglobin electrophoresis Reticulocyte stain
For the initial lab eval of anemia, required data include:
1.) *CBC*: Hct, WBC, and platelet count 2.) *Reticulocyte count* (a measure of newly formed RBCs) 3.) *MCV* (mean cell volume), a measure of the size of RBCs 4.) *Peripheral blood smear* (to allow a morphologic assessment of RBC shape)
Iron Deficiency Anemia: Causes
1.) *Inadequate diet*: e.g. infants fed milk alone for many months 2.) *Rapid growth*: infancy, adolescence - American adolescent females: 11% iron deficiency, 3% iron deficiency anemia 3.) Normal or excessive *menstrual blood loss* 4.) *Pregnancy* 5.) *Acute hemorrhage* 6.) *Malabsorption*: Gastrectomy, regional enteritis 7.) *GI blood loss*: varices, peptic ulcers, bowel tumors, diverticulitis, angiodysplasia - common in older pts, colonoscopies important 8.) *Premature birth*: fetus receives most of its iron during last trimester
Treatment of Iron Deficiency
1.) *Oral iron supplements* 2.) *IV iron infusion if unable to absorb oral iron or if can't compensate for iron loss* Therapy should be continued until ferritin reaches normal range (>100 μg/l); takes 3-4 months - Difficult to administer bc meds cause nausea and constipation - compliance is a problem - Anemia improves before iron stores are fully replete, so pt feels well and wants to discontinue therapy prematurely and must be encouraged to complete the full course
Anemia with Reduced Erythropoietin Response: Causes
1.) *Renal disease!!!!* (Kidney = major source of Epo production in adults) 2.) Inflammatory states - Acute and chronic infection - Collagen vascular diseases - AIDS - Malignancies 3.) Hypometabolic states - Protein deprivation - Endocrine defiency (e.g.-hypothyroidism)
Reticulocyte Count is Dynamic - How does it change in Blood Loss (e.g. from a GI bleed)?
1.) 1st 24hrs after blood loss: redistribution of the interstitial fluid into the circulation to compensate for volume loss and maintain BP --> *Hct falls* 2.) Kidney senses decreased O2 delivery, Epo increases, and stimulates CFU-E to mature to reticulocytes - takes 5-10 days --> *reticulocyte count increases ~1wk after acute blood loss* 3.) If blood loss continues, reticulocyte count remains elevated 4.) If blood loss is sufficient in duration or intensity to deplete Iron reserve, RBC production will decrease, the reticulocyte count will fall, and anemia will worsen ---> Blood loss can be associated w/ normal, high, or low reticulocyte index, and the *reticulocyte index accurately describes the physiology at a given point in time*
Anemia Work-Up: 2 Basic Q's
1.) Are red cells produced appropriately? 2.) Do red cells mature normally?
Name Symptoms Indicative of Anemia Caused by... 1.) Iron Deficiency 2.) Folate Deficiency 3.) B12 Deficiency 4.) Hereditary 5.) Racial/Ethnic Predisposition
1.) Black tarry stools suggest chronic blood loss resulting in iron deficiency 2.) Diet devoid of green, leafy veggies is a clue to folate deficiency 3.) Numbness or burning in hands or feet, altered balance, and a wide-based gait suggest VitB12 deficiency 4.) Family Hx of anemia can suggest hereditary cause 6.) Racial and ethnic background provides additional info; e.g. Sickle cell disease and G6PD deficiency should be considered in a black pt, and thalassemia syndromes in a pt from the Middle East, Mediterranean region, or Southeast Asia 7.) Hx of alcohol abuse, medication use, toxin exposure (benzene, lead, pesticides), or radiation exposure may provide other important data
Anemia of Chronic Inflammation: Symptoms
CV compensation occurs in pts w/ chronic anemia --> Pts may be relatively asymptomatic w/ Hct in the range of 25-30% - Symptoms of fatigue may be a consequence of the inflammatory disease, rather than the anemia
MCV
Calculated MCV = Hct/RBC Number - most automatic counters measure this value directly and very accurately *Normal mean value*: 90 fl (femtoliter or 10-15L) *Normal range*: 80-100 fl
Erythropoietin deficiency
Can be seen with creatinine values of ≥ 2 mg/dl (normal creatinine is 0.3 - 1.2 mg/dl) - as renal function declines, likelihood of anemia due to Epo deficiency increases - Hct in chronic renal failure may slowly fall to 15 - 20% = pts tend to be severely anemic - WBC and platelets usually normal - Pts w/ chronic renal failure may have slightly shortened RBC survival, and may also have blood loss due to dialysis or bleeding that may contribute to the development of anemia.
Hereditary Hemochromatosis: Screening
Controversial 1.) *Transferrin saturation (Fe/TIBC)*: Men >60%; Women >50% - will identify ~90% of pts w/ HH 2.) *Ferritin*: less reliable since a greater amount of Fe loading is needed to raise the ferritin, and chronic liver inflammation and the *presence of infection/inflammation* (inflammatory cytokines TNF and IL-1) will also raise the ferritin value 3.) PTs w/ elevated transferrin saturation should get *PCR test for C282Y and H63D* mutations in the HFE gene, if positive first degree relative should be tested either by genotype analysis or serum iron studies
Iron Deficiency vs Chronic Inflamation Anemia
Iron deficiency and anemia of chronic inflammation are similar in that *erythropoiesis is iron deficient* - In iron deficiency anemia, this is because of the total lack of iron. - In the anemia of chronic inflammation, iron stores are present, but iron is unavailable for the developing erythroid cells.
Are red cells produced appropriately?
Determined by *corrected reticulocyte count* - provides insight into the physiology of the anemia, but not necessarily the exact cause *Low (<2)*: anemia results, at least in part, from inability of marrow to make RBCs *High (>3)*: anemia results primarily from destruction (hemolysis) or loss of circulating RBCs - high reticulocyte count thus reflects an appropriate -marrow response.
Low Reticulocyte Count (<3): Do red cells mature normally?
Determined by MCV - normal MCV (normocytic) suggests that RBCs are intrinsically fine (hemoglobinization and membrane structure are intact), but that too few cells are made
Peripheral Blood Smear: RBC Morphology
Different morphologic features provide insights into the Dx - See Color Atlas to immediately before the syllabus index for different features
Evaluating Iron Status in a Patient
Fe, TIBC, and ferritin values are usually sufficient to evaluate the iron status in an individual pt - Occasionally, esp in acute inflammation, this evaluation may be problematic. In these circumstances, a marrow aspirate can be obtained
Ineffective Erythropoiesis
Ferrokinetic studies in diseases such as thalassemia or B12 deficiency, which show an *imbalance between the amount of iron that is endocytosed by marrow erythroblasts and the amount of iron incorporated into circulating erythrocytes* - Ineffective bone marrow shows an *excess of differentiating erythroid cells w/ low reticulocyte counts, implying that erythroid precursors die prior to exiting the marrow*
Infant Hematocrit
Fetal Hb (HbF) has a high O2 affinity (to permit fetal uptake of O2 from maternal circulation) so *Hct of an infant at birth is elevated (mean Hct = 50%)*
Iron Deficiency Anemia
Final state of iron deficiency; all of the above findings are present and the Hb and Hct have fallen below the normal range - As Hct decreases, the MCV further decreases and abnormal red cell morphology is readily apparent on the peripheral blood smear (microcytosis and hypochromia)
Molecular mechanism for HFE
HFE protein binds to β2M, associates w/transferrin receptor, modulates uptake or release of Fe
Artificially Low or High Hct
Hct is artificially low at times of expanded plasma volume (e.g. 3rd trimester of pregnancy) Hct is artifically high with dehydration (e.g. after running a marathon, in pts on diuretics, after severe vomiting)
Hypoxia and Hematocrit
Hypoxia --> kidney senses O2 need --> increased Epo produced --> Epo increases RBC production --> *new steady state is established (w/ an increased hematocrit)* Poor oxygenation (e.g. high altitude, low ambient pO2 or pulmonary disease resulting in low blood O2 Sat), inadequate cardiac output, abnormal function of Hb (e.g. inherited disorders in which Hb binds abnormally tightly to O2 and prevents appropriate release of O2 to tissues) all lead to *less effective renal O2 delivery and consequently an increased hematocrit* --> Thus, the "normal" hematocrit for a smoker w/ COPD, a resident of an Andean village in Peru, or a pt w/ congenital heart disease is higher than that of a normal individual living at sea level
Pallor
Nonspecific sign of anemia - Related to *severity* of anemia
Peripheral Blood Smear: RBC Size
Normal RBC = 8μm diameter, ~ the size of the nucleus of a small lymphocyte
Anemia with Reduced Erythropoietin Response (anemic with low Epo):
Normocytic, Normochromic anemia due to under production of RBCs in the bone marrow
Elevation in Total Iron Binding Capacity (TIBC) of the Plasma
Occurs when iron stores are depleted *Indirect measure of the transferrin level*
Low Serum Ferritin Level
Occurs when iron stores are depleted - Serum ferritin is an excellent predictor of ferritin in tissues, and thus *reflects total body iron stores* - However, this protein is an acute phase reactant, and therefore *increases at times of inflammation or altered metabolism (hyperthyroidism, hypothyroidism), and in the presence of some neoplasms*, and no longer accurately reflects body iron stores
Iron Overload
Primary: Hemachromatosis Secondary: Transfusions - % Iron Saturation can identify Iron overload
Anemia with Reduced Erythropoietin Response: Treatment (syllabus)
Pts w/ anemia of renal failure treat w/: 1.) EPO administered SubQ weekly or 3X/wk OR 2.) Darbepoietin (long-acting form) at a lower frequency Goal: to achieve a Hb sufficient to avoid RBC transfusion - higher mortality rate, and higher rate of thrombosis, when targeted Hb goes too high
Peripheral Blood Smear: Hemoglobinization
RBCs are biconcave discs, which is why they have a red stained rim and a pale interior If one draws a line across the diameter of a normal RBC, it should pass through 1/3 red, 1/3 white, then 1/3 red *Hypochromic cells* contain an increased central pale area --> suggests poor hemoglobinization
Hereditary Hemochromatosis
Results in *increased dietary Iron absorption due to suppressed hepcidin expression* - Normal adult has a total of ~3-4g of body iron; in HH, the iron loading can be 20-40g
Adjusting Reticulocyte Count
Reticulocyte count must be adjusted before clinically important info can be obtained. *Number of new RBCs made and released by marrow each day is of physiologic relevance, and not the % of reticulocytes* 1.) Must *correct the reticulocyte count for the hematocrit* --> Corrected reticulocyte count OR 2.) Can compute an *absolute reticulocyte count* directly
Normal Reticulocyte Count
~1% (1/100 rbcs)
