Causes of Anemia: decreased Hb, decreased Hct, decreased RBCs, decreased O2 carrying capacity --> tissue hypoxia, cellular injury, and death
Causes of Anemia:
decreased Hb, decreased Hct, decreased RBCs, decreased O2 carrying capacity --> tissue hypoxia, cellular injury, and death
Decreased RBC production:
decreased erythropoiesis, decreased reticulocyte count
Inability to use iron
: ACI and IRIDA are characterized by inappropriate hepcidin levels leading to decrease absorption and retention of Fe.
Anemia of chronic disease
(inflammation): most common form of anemia among hospitalized and chronically ill patients. Usually mild to moderate anemia (Hb 8-11 g/dl). Normo/microcytic. Normal or low retic count.
chronic infection, connective tissue disorders (ex. Lupus), cancer and lymphoma, major trauma, ulcerative colitis, regional enteritis.
Inflammation stimulates IL-6 production, which in turn promotes hepatic hepcidin expression. Fe recycling becomes inefficient and iron is retained in macrophages (hence increase in ferritin levels). Transferrin saturation decreases and erythropoiesis becomes iron restricted.
Iron-resistant iron deficiency anemia
(IRIDA): Rare autosomal recessive disorder. Lifelong low serum iron and transferrin saturation. Impaired iron absorption and utilization that is unresponsive to oral iron. Mutations in gene for protein that helps decrease transcription of hepcidin.
Other causes of decreased RBC production
Aplastic anemia (note: PNH causes increased risk for aplastic anemia).
Folate and B12 deficiencies
serum B12 < 150, total serum homocysteine >15 umol/l or methylmalonic acid > 0.4 umol/l. If serum folate > 4 ng/ml then NOT folate deficiency.
morphology: macrocytic (megaloblastic), high MCV (<100), low reticulocyte count, hypersegmented neutrophils.
If you suspect B12 or folate deficiency, check for both!
Causes of B12 deficiency
low stomach acid due to antacid use, bacterial overgrowth and consumption of B12, pancreatic insufficiency resulting in lack of proteases to release B12 from binding protein, surgical factors.
autoimmune destruction of gastric parietal cells due to anti-IF antibodies (0.1% of general population, 1.9% of those 60+), anti-parietal cell antibodies. Often seen in association with other autoimmune diseases as well as with an increased risk of GI tract malignancy.
Causes of folate deficiency
alcoholism, cooking/food processing, depressed patients (not eating)
Celiac disease, IBD, short bowel syndrome
methotrexate, trimethoprim (Bactrim - often used for bladder infections).
pregnancy, lactation, chronic hemolysis, exfoliative dermatitis.
Iron deficiency anemia (IDA)
infancy and adolescence. Infants triple their weight in the first year of life and must accumulate ~100mg of iron during the first year to keep up with the hemoglobin production.
GI (malignancy, peptic ulcers, gastritis from NSAIDS or
, hookworm, Meckel's diverticuli, hemorrhoids, vascular malformations, menstrual (avg blood loss 30-40 ml, 15-20 mg Fe), childbirth, trauma, chronic hemoglobinuria (mechanical heart valve,
increased absorption of heme iron (15%) over non-heme iron, ascorbic acid (Vitamin C) facilitates ferrireduction. Decreased absorption due to plant iron (3%), tannins (tea, coffee), bran/fiber/Ca++, disrupted mucosa (IBD, Celiac disease, surgery), achlorhydria (gastrectomy, antacids, proton pump inhibitors).
(a) young children (1-5yo) due to excessive milk intake, prolonged bottle use, picky eaters, (b) teenage girls due to poor diet, worsened by rapid growth and menstrual blood loss, (c) socioeconomic status.
biochemical markers: decreased ferritin, decreased serum Fe, decreased transferrin saturation, increased TIBC, increased serum transferrin receptor, increased FEP. No iron in bone marrow aspirate.
morphology: microcytic, hypochromic RBCs (MCV < 80), occasional elliptocytes (pencil cells), high RDW.
Treatment: (1) correct deficiency and (2) address underlying problem/cause
Folate: oral folate of 400-1000 ug daily
B12: parenteral B12 - intense loading dose followed by monthly maintenance or oral B12 at 1-2 mg/day.
ACI: Erythropoietin, IV iron, RBC transfusion.
Reticulocyte count begins to rise in 3 to 4 days, peaking in 5 to 10 days. Hb rises following elevation in retics.
oral ferrous sulfate (3-6 mg/kg/day elemental Fe [200mg for adults], treat for 2 months beyond correction of anemia to replete stores, side effects include nausea, epigastric discomfort, constipation).
slow release iron (decrease GI side effects, more expensive, may release Fe below duodenum).
parenteral iron (IM, IV) which is useful in cases of poor adherence. This option has significant side effects and risk of anaphylaxis.
Signs and symptoms:
jaundice (due to release of bilirubin resulting from breakdown of Hb), splenomegaly, hemoglobinuria (especially with intravascular hemolysis), gallstone disease.
hemolysis is usually precipitated by an acute event that induces oxidant stress: (1) acute illness, e.g. infection, (2) exposure to certain drugs or chemicals, e.g. napthalene, sulfa antibiotics (also problematic w/ folate deficiency), (3) fava bean ingestion.
pallor, weakness, fatigue, headache, irritability, alopecia, dry/rough skin, restless leg syndrome, neurocognitive dysfunction, pagophagia, beeturia, blue sclerae, koilonychia (nails), angular stomatitis.
Fatigue, appetite loss, venous thrombosis
Neuropsychiatric (if untreated, irreversible): polyneuritis, ataxis/balace, combined sclerosis of spinal cord (specific to B12), neural tube defects (specific to folate) depression, blindness. Subacute combined degeneration affects brain, spinal cord, peripheral nerves -- optic neuropathy, memory loss, visual impairment, weakness, progressive sensory abnormalities, gait impairment.
oral/GI: diarrhea, cheilitis, glossitis (inflammation of the tongue)
Increased RBC destruction:
hemolysis, decreased RBC survival, increased erythropoiesis, marrow compensation, increased reticulocyte count
(1) Thrombotic thrombocytopenic purpura (TTP)
(3) Malignant hypertension
(4) Vasculitis (inflammation of blood vessels)
(5) Disseminated intravascular coagulation (DIC)
(2) Hemolytic uremic syndrome (HUS)
Immune hemolytic anemia
Autoimmune hemolytic anemia (AIHA)
(1) Idiopathic, (2) autoimmune disorders, (3) lymphoproliferative disorders.
IgG antibodies bind to antigens on the RBC (optimal binding occurs as 37 degrees Celsius. Ab-coated RBCs are cleared by Fc receptor-expressing macrophages in the spleen. Partial phagocytosis results in spherocytes.
Corticosteroids, splenectomy, treat underlying disorder (if present), other immunosuppressive agents.
IgM antibodies to antigens on the RBC. Optimal binding occurs below 37 degrees Celsius. The IgM Ab fix complement. Complement remains bound even after IgM leaves the RBC. Complement-coated RBCs are cleared by C3b receptor-expressing Kuppfer cells in the liver.
(1) Idiopathic, (2) infection especially with EBV, mycoplasma, (3) lympoproliferative disorders.
Avoidance of cold exposure, treat underlying disorder (if present), Rituximab (anti-CD20), plasma exchange as a temporizing measure.
: Direct antiglobulin test (Coombs). Patient's RBCs are washed and incubated with Coombs reagent (anti-human IgG or anti-human C3). Agglutination indicates a positive test.
Drug-induced immune hemolytic anemia
Beta-lactam Abx, NSAIDs, quinine/quinidine
Withdrawal of causative agent.
Alteration of antigen: Drug (e.g. methyldopa) induces an alteration in a
Neoantigen-mediated: drug (e.g. quinine) binds to a membrane antigen and induces it to change conformation, exposing a neoantigen.
Hapten-mediated: drug (e.g. penicillin) binds directly to the RBC membrane, where it serves as the target antigen.
(2) Hemolytic uremic syndrome (HUS)
(1) Thrombotic thrombocytopenic purpura (TTP)
3) malignant hypertension
(4) vasculitis (inflammation of blood vessels)
(5) disseminated intravascular coagulation (DIC)
Paroxysmal Nocturnal Hemoglobinuria (PNH)
RBC membranes contain glycosyl phosphatidylinositol (GPI) molecules, which anchor extracellular proteins to the RBC surface, such as CD55 and CD59 which limit complement activation of RBC surfaces. PNH is an acquired clonal disorder due to somatic mutations in
, which encodes an enzyme required for the synthesis of GPI. The result is intravascular hemolysis.
Iron and folate supplementation, blood transfusion, Eculizumab (C5 terminal complement inhibitor - increased risk for meningococcal infections). Also note increased risk of VTE.
Flow cytometry for CD55 and CD59 on neutrophils or monocytes (because RBCs without them will likely have already been destroyed)
RBC membrane injury caused by bacterial toxin. This is seen in Clostridial sepsis. A toxin produced by the bacterium (phospholipase C) destroys the RBC membrane, leading to brisk intravascular hemolysis.
Infestation of RBCs by parasites. Seen in malaria, Babesiosis - infested RBCs are removed by macrophages in the spleen.
Immune hemolysis due to antigen mimicry (mycoplasma pneumoniae, EBV, HSV).
Abnormal RBC membrane
Hereditary spherocytosis (HS)
: defect in one of several proteins that make up the RBC cytoskeleton (commonly spectrin). Abnormal RBCs have shortened lifespan. High reticulocyte count.
Morphology: spherocytes, normocytic, hyperchromic, high reticulocyte count (polychromasia).
RBC enzyme deficiency
: most common red cell enzymopathy, X-linked, mostly males affected. Two common variants - African American males G6PD A-, and Mediterranean/Asian ancestry G6PD B.
Diagnostics: biochemical assay, best tested several months after the acute event.
Treatment: avoidance of triggers; RBC transfusion as needed for acute episodes.
quantitative problem with hemoglobin synthesis due to abnormalities in synthesis of the global chains (alpha or beta).
: excess B chains resulting in HbH.
Silent carrier (-a/aa)
a thalassemia trait: -a/-a OR --/aa
HbH disease: --/-a
Hydrops fetalis: --/--
: excess alpha chains resulting in damaging precipitate --> profound anemia.
B thalassemia major (Cooley's anemia): Bo/Bo
B thalassemia intermedia:
Bo/B+, B+/B+. Occasionally nucleated RBCs.
B thalassemia minor (trait)*
: Bo/B, Hb > 10 g/dl, MCV 50-70, 5-7% HbA2.
: microcytic RBCs, low MCV (<70), hypochromic, presence of target cells, elevated reticulocytes, normal iron, increased HbA2 +/- HbF on hemoglobin electrophoresis.
Sickle Cell Disease:
mutation of glutamic acid to valine in the 6th position on the Hb beta chain. HbS molecules aggregate into needle-like structures when deoxygenated, resulting in anemia, RBC damage, and extravascular hemolysis.
Diagnosis: Normocytic, sickle cells, occasional target cells.
CBC, reticulocyte count, peripheral blood smear. Specific tests then based upon differential.
If decreased WBC count or platelet count, proceed with bone marrow evaluation.
If normal WBC/platelets: evaluate blood smear for size, color, and shape of RBCs. Classify by MCV - micro, normo, or macro.
decreased heme synth (IDA, sideroblastic anemia, severe lead poisoning, ACI) and decreased globin synthesis (thalassemia syndromes).
Pencil cells: check iron studies for IDA
Target cells: check for a thalassemia (decreased globin synthesis).
Check reticulocyte count
Low retics: marrow not active and the issue is probably a bone marrow disorder or decreased EPO.
High retics: marrow is healthy and compensating for hemolysis or bleeding
All hemolysis: increased LDH, bilirubin (unconjugated), retics; intravascular hemolysis: decreased haptoglobin, increased plasma Hb, hemoglobinuria
Sickle cell anemia
: B12, folate deficiencies
if MMA and homocysteine are both elevated then B12
If only homocytsteine elevated, then folate deficiency