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Anemia
Blood Loss Acute Chronic
IN-creased destruction (HEMOLYTIC)
DE-creased production
Features of All Anemias
Pallor, where?
Tiredness
Weakness
Dyspnea, why?
Palpitations
Heart Failure (high output), why?
Blood Loss
Acute Trauma
Chronic Lesions of gastrointestinal tract, gynecologic
disturbances. The features of chronic blood loss anemia are the same as iron deficiency anemia, and is defined as a situation in which the production cannot keep up with the loss.
Hemolytic
Hereditary MEMBRANE disorders: e.g., spherocytosis ENZYME disorders: e.g., G6PD deficciency HGB disorders (hemoglobinopathies)
Acquired MEMBRANE disorders (PNH) ANTIBODY MEDIATED, transfusion or autoantibodies MECHANICAL TRAUMA INFECTIONS DRUGS, TOXINS HYPERSPLENISM
Impaired Production
Disturbance of proliferation and differentiation of stem cells: aplastic anemias, pure RBC aplasia, renal failure
Disturbance of proliferation and maturation of erythroblasts
Defective DNA synthesis: (Megaloblastic)
Defective heme synthesis: (Fe)
Deficient globin synthesis: (Thalassemias)
Modifiers
MCV, microcytosis, macrocytosis
MCHC, hypochromic
RDW, anisocytosis
Hemolytic Anemias
Life span LESS than 120 days
Marrow hyperplasia (M:E), EPO+
Increased catabolic products, e.g., bilirubin, serum HGB, hemosiderin
Hemolysis
INTRA-vascular (vessels)
EXTRA-vascular (spleen)
M:E Ratio normally 3:1
Sickle Cell Disease Classic hemoglobinopathy
Normal HGB is α2 β2: β-chain defects (Val->Glu)
Reduced hemoglobin “sickles” in homozygous
8% of American blacks are heterozygous
Clinical features of HGB-S disease
Severe anemia
Jaundice
PAIN (pain CRISIS)
Vaso-occlusive disease: EVEREWHERE, but clinically significant bone, spleen (autosplenectomy)
Infections: Pneumococcus, Hem. Influ., Salmonella osteomyelitis
THALASSEMIAS
A WIDE VARIETY of diseases involving GLOBIN synthesis, COMPLEX genetics
Alpha or beta chains deficient synthesis involved
Often termed MAJOR or MINOR, depending on severity, silent carriers and “traits” are seen
HEMOLYSIS is uniformly a feature, a microcytic anemia
A “crew cut” skull x-ray appearance may be seen
Paroxysmal Nocturnal Hemoglobinuria (PNH)
ACQUIRED, NOT INHERITED like all the previous hemolytic anemias were
ACQUIRED mutations in phosphatidylinositol glycan A (PIGA)
It is “P” and “N” only 25% of the time
GlycosylphosPhatidylInositol
Immunohemolytic Anemia
All of these have the presence of antibodies and/or compliment present on RBC surfaces
NOT all are AUTOimmune, some are caused by drugs
Coombs Test
DIRECT: Patient’s CELLS are tested for surface Ab’s
INDIRECT: Patient’s SERUM is tested for Ab’s.
Direct anti-globulin test
HEMOLYSIS/HEMOLYTIC ANEMIAS DUE TO RBC TRAUMA
Mechanical heart valves breaking RBC’s
MICROANGIOPATHIES:
TTP
Hemolytic Uremic Syndrome
NON-Hemolytic Anemias:i.e., DE-creased Production
“Megaloblastic” Anemias
B12 Deficiency (Pernicious Anemia)
Folate Deficiency
Iron Deficiency
Anemia of Chronic Disease
Aplastic Anemia
“Pure” Red Cell Aplasia
OTHER forms of Marrow Failure
MEGALOBLASTIC ANEMIAS
Differentiating megaloblasts (marrow) from macrocytes (peripheral smear, MCV>94)
Impaired DNA synthesis
For all practical purposes, also called the anemias of B12 and FOLATE deficiency
Often VERY hyperplastic/hypercellular marrow
Decreased intake
Inadequate diet, vegetarianism
Impaired absorption
Intrinsic factor deficiency
Pernicious anemia
Gastrectomy
Malabsorption states
Diffuse intestinal disease, e.g., lymphoma, systemic sclerosis
Ileal resection, ileitis
Competitive parasitic uptake
Fish tapeworm in
Fish tapeworm infestation
Bacterial overgrowth in blind loops and diverticula of bowel
Increased requirement
Pregnancy, hyperthyroidism, disseminated cancer
Vit-B12 Physiology
Oral ingestion
Combines with INTRINSIC FACTOR in the gastric mucosa
Absorbed in the terminal ileum
DEFECTS at ANY of these sites can produce a MEGALOBLASTIC anemia
Please remember that ALL megaloblastic anemias are also MACROCYTIC (MCV>94 or MCV~100), and that not only are the
RBC’s BIG and hyperplastic/hypercellular, but so are the neutrophils, and neutrophilic
precursors in the bone marrow too, and even more so, HYPERSEGMENTED!!!
PERNICIOUS ANEMIA
MEGALOBLASTIC anemia
LEUKOPENIA and HYPERSEGS
JAUNDICE
NEUROLOGIC posterolateral spinal tracts
ACHLORHYDRIA
Can’t absorb B12
LOW serum B12
Flunk Schilling test, i.e., can’t absorb B12, using a radioactive tracer
FOLATE DEFICIENCY MEGALOBLASTIC AMEMIAS
Decreased Intake: diet, etoh-ism, infancy
Impaired Absorption: intestinal disease
DRUGS: anticonvulsants, BCPs, CHEMO
Increased Loss: Hemodialysis
Increased Requirement: Pregnancy, infancy
Impaired Usage
APLASTIC ANEMIAS
ALMOST ALWAYS involve platelet and WBC suppression as well
Some are idiopathic, but MOST are related to drugs, radiation
FANCONI’s ANEMIA is the only one that is inherited, and NOT acquired
Act at STEM CELL level, except for “pure” red cell aplasia
APLASTIC ANEMIAS
APLASTIC ANEMIAS
CHLORAMPHENICOL
OTHER ANTIBIOTICS
CHEMO
INSECTICIDES
VIRUSES EBV HEPATITIS VZ
MYELOPHTHISIC ANEMIAS
Are anemias caused by metastatic tumor cells replacing the bone marrow extensively
Fe Deficiency Anemia
Due to increased loss or decreased ingestion, almost always, in USA, nowadays, increased loss is the reason
Microcytic (low MCV), Hypochromic (low MCHC)
THE ONLY WAY WE CAN LOSE IRON IS BY LOSING BLOOD, because FE is recycled!
Fe
Transferrin
Ferritin (GREAT test)
Hemosiderin
Gut lumen
Fe +++ Fe ++ Heme Fe
Enterocyte DMT1
FerritinFe++
Fe+++
MTP1
Plasma transferrin
Enterocyteprecursor
Hepcidin
Transferrin Receptor
HFE
Regulation of iron absorption
Gastrointestinal absorption1 mg/day
Storage ironLiver, RES1 gram
Functional ironBlood, marrow, myoglobin2 grams
Plasma transferrin2 mg
Daily physiologic loss1 mg
Clinical Fe-Defic-Anemia
Adult men: GI Blood Loss
PRE menopausal women: menorrhagia
POST menopausal women: GI Blood Loss
2 BEST lab tests:
Serum Ferritin
Prussian blue hemosiderin stain of marrow (also called an “iron” stain)
Marrow iron stores
1 - 3+ 0 - 1+ 0 0
Ferritin 50 - 200 <20 <15 0
TIBC 300 - 360 >360 >380 >400
Serum iron 50 - 150 50 - 150 <50 <30
Red cells normal normal normal microcytic, hypochromic
Iron stores
Erythron iron
Serum transferrin receptor
Storage iron = 107 mg
Storage iron = 335 mg
Storage iron = 1,102 mg
Serial measurement of sTfr during phlebotomy in 3 individuals
Goodnough, Skikne, Brugnara. Blood, 2000; 96: 823 - 833
Ratio of serum transferrin receptor to ferritin as a measure of total body iron
Cook, Flowers, Skikne. Blood 2003; 101: 3359 - 64
Kaltwasser, Gottschalk. Kidney Int. 1999; 55(suppl): S49 - S56
Serum ferritin and total body iron
Treatment of iron def anemia
Oral iron is the preferred initial treatment
Recommended daily dose is 150-200mg/day of elemental iron
325 mg of ferrous sulfate contains 65 mg of elemental iron
One table three times a day
Administer iron on an empty stomach with half a glass of OJ or 250mg ascorbic acid
Serum iron after oral iron in patients with iron deficiency
WH Crosby, Arch Int Med; circa 1970
20
40
60
80
1 2 3 4
Ser
um
iron
Hours
Safety of intravenous iron
Faich, Strobos. Am J Kidney Dis 1999: 33(3):464-70
Sodium ferric gluconate in sucrose (Ferrlecit)
Available in Europe > 30 years
2.7 x 106 doses/year in Germany + Italy in 1995
Iron dextran (Imferon until 1992, InFed since 1992)
3 x 106 doses/year in US in 1996
Safety of intravenous iron
Faich, Strobos. Am J Kidney Dis 1999: 33(3):464-70
Reported severe adverse reactions (1976 - 1996):
SFGS 3.3 severe allergic reactions/106 doses, no fatalities
ID 8.7 severe allergic reactions/106 doses, 31 fatalities
Safety of intravenous iron
Faich, Strobos. Am J Kidney Dis 1999: 33(3):464-70
Other theoretical risks:
iron overload
sepsis
acceleration of atherosclerosis
Recombinant human erythropoietin is approved only for treatment of anemia caused by renal failure or by cancer treatment and for certain hematologic malignancies.
Sodium ferric gluconate in sucrose is approved only for treatment of anemia in patients on hemodialysis and for patients who have had a severe reaction to iron dextran.
Medicare warning :(
Anemia of Chronic Disease*
CHRONIC INFECTIONS
CHRONIC IMMUNE DISORDERS
NEOPLASMS
LIVER, KIDNEY failure
* Please remember these patients may very very much look like iron deficiency anemia, BUT, they have ABUNDANT STAINABLE HEMOSIDERIN in the marrow!
Anemia of chronic disease
Typical lab findings:
Serum iron < 50
TIBC < 150
Normochromic or hypochromic red cells
Normal ferritin
Normal serum transferrin receptor
Anemia of chronic disease
Mechanisms:
blunted erythropoietin response
diminished response of erythroid precursors to erythropoietin
decreased delivery of iron from RES, increased intracellular ferritin in macrophages
decreased gastrointestinal iron absorption
Anemia of chronic disease
Mediators:
IL-1
IL-6
-interferon
TNF-
Anemia of chronic disease
Inflammation
Tissue necrosis
Infection
Neoplasia
Congestive heart failure
Acute myocardial infarction