Anemia

• • Definition: Anemia is a reduction in the oxygen-carrying capacity of blood, usually because of a reduction of the total circulating RBC mass to below-normal levels. The Hb <14 g/dL in men, and <12 mg/dL in women or Hct <40% in men, and <37% in women.

  • Classification: Anemia can be broadly classified into 3 etiologic categories:

    • Blood loss (acute or chronic)

    • Decreased RBC production

    • Increased RBC destruction (hemolysis)

  • Severe anemia may be well tolerated if it develops gradually, but generally Pts. with Hb <7 gm/dl have sx of tissue hypoxia.

    • fatigue, headache, dyspnea, malaise, dizziness, tinnitus, lightheadedness, angina, pallor, visual impairment, syncope, and tachycardia.

  • H & P: Determine if

    • acute, subacute or chornic

    • possible etiologies

    • risk factors

    • family history of anemia

    • drug exposure (ethanol), NSAID use

    • blood loss

      • FOBT (GI), gastritis, PUD (H. pylori), gastric ulcer disease, GIB,

      • C-scopy for diverticulosis

    • Disease of stomach and proximal small inestitine: H. pylori infection, achlorhydria, celiac disease, and bariatric surgery) often lead to impaired iron absorption.

    • Atrophic glossitis, angular cheliosis, koilonychia, brittle nails, reduced excercise tolerance, dyspnea on exertion, LAD, hepatosplenomegaly, jaundice, bone tenderness, neurologic sx

• Lab evaluation:

  • • Hb and Hct: check Pt vol status, since there is no marked change in acute blood loss.

    • RDW is a measure of increased variability in RBC size.

    • MCH describes the concentration of Hb in each cell an an elevated level is indicative of spherocytes or hemoglobinopathy.

    • CBC, CMP, retic count, peripheral blood smear morphology, iron, TIBC, ferritin, bilirubin, endoscopic or abdominal CT, SIEP, HbEP, haptoglobin, LDH, Coombs test, bone marrow biopsy.

    • Bone marrow Bx may be indicated in cases of normocytic anemia with a low reticulocyte without an identifiable cause or anemia associated with other cytopenias. The Bx may confirm myelophthisic process (i.e., presence of teardrop or fragmented cells, normoblasts, or immature WBCs or peripheral blood smear)

    • First check the absolute reticulocyte count and reivew the perpheral smear. RBC size, shape, orientation of cells in relation to each other, presence of any inclusions. Abnormal forms of RBCs: acathocytes, shistocytes, spherocytes, or teardrop cells, abnormal orientation such a Rouleaux formation.

• • Absolute retic count is number of reticulocytes present in 1 mm3 of blood.

    • Absolute reticulocyte count = % of retic x RBC count (mm3)

    • Increase of retic >100,000/mm3 means a hyperproliferative bone marrow associated with destruction of RBCs

  • Reticulocyte index:

    • Adjusts Reticulocyte Count for hematocrit

    • Reticulocyte Index reflects Bone Marrow activity

    • Known as "Poor man's Bone Marrow Aspirate

    • Calculation

      • RI = Reticulocyte % x (Pt's HCT / normal HCT)

  • Normal Reticulocyte Count: 0.5-1.5%

  • Normal Reticulocyte Index: 1-2%

  • Anemias can be categorized as follows:

    • Hypoproliferative anemia: underproduction of RBCs with few reticulocytes seen in perpheral smear. Retic index is <2

      • Subdivided in basis of MCV: Microcytic (<80), macrocytic (>96) , and normocytic (80 - 96)

    • Hyperproliferative anemia: increased production of RBCs. Retic count is elevated. Retic index >2

      • Two most common causes are bleeding and hemolysis

Classification of Hypoproliferative Anemia

Classification of Anemia According to Mechanism of Production

1. Blood loss

   1. • Acute: trauma

      • Chronic: lesion of the GIT, gynecological d/o

2. Increased Rate of Destruction of RBCs (Hemolytic Anemia)

   1. • Intrinsic (intracorpuscular) abnormalities of RBCs

        • Hereditary

          • D/o of RBC membrane cytoskeleton: e.g., hereditary spherocytosis, hereditary elliptocytosis

          • RBC enzyme deficiencies

            • Glycolytic enzymes: pyruvate kinase, hexokinase

            • Enzymes of the HMP shunt: G6PD, glutathione synthetase

          • Disorders of Hb synthesis

            • Deficient globin synthesis: thalassemia syndromes

            • Structural abnormal globin synthesis (hemoglobinopathies): sickle cell anemia, unstable Hb

        • Acquired

          • Membrane defect: PNH

      • Extrinsic (extracorpuscular) abnormalities

        • Antibody mediated

          • Isohemagglutinins: transfusion reactions, erythroblastosis fetalis (Rh disease of the newborn)

          • Autoantibodies: idiopathic (primary), drug-associated, SLE

        • Mechanical trauma to RBCs

          • Microangiopathic hemolytic anemias: TTP, DIC

        • Infections: malaria

3. Impaired RBC Production

   1. • Disturbance of proliferation and differentiation of stem cells: aplastic anemia, pure RBC aplasia, anemia of renal failure, anemia of endocrine d/o.

      • Disturbance of proliferation and maturation of erythroblasts

        • Defective DNA synthesis: deficiency or impaired utilization of vitamin B12 and folic acid (megaloblastic anemias)

        • Defective hemoglobin synthesis

          • Deficient heme synthesis: Iron deficiency

          • Deficient globin synthesis: Thalassemias

        • Unknown or multiple mechansims: sideroblastic anemia, anemia of chronic inflammation, myelophthisic anemia due to marrow infiltrations.

Blood loss anemia:

• • With acute blood loss mmediate threat is hypovolemic shock rather than anemia. It takes 2 - 3 days for the Hct to drop, as hemodilution begins at once, but take 2 - 3 days.

    • Anemia is Normocytic normochromic.

    • Marked reticulocytosis due to ▲ eyrthropoietin level → bone marrow response.

  • With chronic blood loss: Iron stores are gradually depleted.

Hemolytic anemias (increased rate of RBC destruction)

• • RBC have a life span of 12 days. RBC life span is decreased in hemolytic anemia.

  • There is a compensatory increase in erythropoiesis that results in reticulocytosis

  • Retention in the body of the products of RBC destruction including iron.

  • RBC regeneration keeps pace with the rate of hemolysis: erythroid hyperplasia in bone marrow and an increased retic count in the peripheral blood. If the anemia is severe extramedullary hematopoiesis may develop in the spleen, liver, and lymph nodes.

  • Intravscular hemolyis occurs when RBCs are subjected to mechanical trauma or biochemical or physical agents (complement fixation, exposure to clostridial toxins, or heat). Hemoblobinuria, hemosiderinuria, and hemoglobinemia. Heme pigment → bilirubin → unconjugated hyperbilirubinemia → Jaundice.

    • Massive intravascular hemolysis → ATN (sometimes). Sr. haptoblobin a protein that binds to free Hb is characteristically low.

  • Extravascular hemolysis, the more common mode of RBC destruction occurs in the phagocytic cells of the liver and spleen. The mononuclear phagocytes removes erythrocytes from the circulation whenever RBCs are injured or immunologically altered.

    • Not associated with hemoglobinemia and hemoglobinuria, but it may result in jaundice and if of long standing, in the formation of bilirubin-rich gallstones (so-called pigment stones). Sr. haptoglobin is always decreased.

  • Systemic hemosiderosis

Neurological complications of anemia:

• • Lightheadedness, HA, sickle cell anemia can cause strokes, seizures, or extramedullary hematopoiesis in the meninges that mimics seizures.

Anemia of CKD

Anemia of chronic renal insufficiency is mainly attributed to decreased endogenous production of Epo (erythropoietin), and may occur when creatinine clearance declines <50 mL/min. Iron deficiency may also contribute to the etiology.

Dx:

• • MCV is normal in 85% of cases.

  • Hct level is usually 20% - 30%.

  • Peripheral smear: RBCs are hypochromic, with occasional presence of echinocytes (burr cells).

  • If Pt. creatinine level >1.8 mg/dL, primary cause can be assumed to be Epo deficiency and/or iron deficiency, and an Epo level is not needed.

  • Iron deficiency should be check for in Pts undergoing HD due to chronic blood loss via ferritin and transferrin saturation.

  • Oral iron supplementation is not effective in CKD so that parenteral iron to maintain a ferritin level <500 ng/mL is recommended.

Tx:

• • Erythropoietin-stimulating agents (ESAs) including epoetin alfa and darbepoetin.

  • Therapy is initiated in predialysis patients who are symptomatic.

  • Objective benefits of reversing the anemia include exercise capacity, improved cognitive function, elimination of RBC transfusions, and reduction of iron overload. Subjective benefits include increased energy, enhanced appetite, better sleep patterns, and improved sexual activity.

  • Administration of ESAs can be IV (HD patients) or SC (predialysis or peritoneal dialysis patients). The target Hb should be 11 - 12 g/dL and should not exceed 13 g/dL. Hb and Hct is checked monthly while receiving ESA. Dose adjustment is made to maintain the target Hb.

  • Adverse reactions to ESAs: Targeting higher Hb levels and/or exposure to higher doses of ESAs is associated with a greater risk of cardiovascular complications and mortality. Higher Hct from ESAs increase risk of stroke, heart failure, and DVT.

  • Suboptimal responses to ESA therapy is common due to iron deficiency, inflammation, bleeding, infection, malignancy, malnutrition, and aluminum toxicity.

  • IV iron administration is standard therapy in many patients who receive ESA therapy. It also reduces the ESA dosage required to correct anemia.

  • Ferritin and transferrin saturation is tested at least monthly during initiation of ESA therapy. The goal of ferritin level is >200 ng/mL and a transferrin saturation of >20% in dialysis dependent patients. In predialyis or preritoneal dialysis patients a ferritin level of >100 ng/mL, and a transferrin saturation of >20% is maintained.

  • Iron therapy is of unlikely benefit if the ferritin level is >500 ng/mL.

  • Secondary hyperparathyroidism that causes bone marrow fibrosis and relative ESA resistance may also occur.

Erythropoietin Dosing

• • Chemo-Tx-induced anemia from nonmyeloid malignancy, multiple myeloma, lymphoma; anemia secondary to malignancy, or MDS:

    • Epo: 40,000 units/wk or 150 units/kg three times a week.

      • Increase dose after 48 wk up to 900 units/kg/wk or 60,000 units/wk; discontinue if Hct is >40%; resume when Hct <36% at 75% of previous dose.

    • Darbepoetin: 2.25 mcg/kg/wk or 100 mcg/wk or 200 mcg/2 wk or 500 mcg/3 wk.

      • Increase dose after 6 wk up to 4.5 mg/kg/wk or 150 mg/wk or 300 mg/2 wk; hold dose if Hct is >36%; then resume if Hct <36% at 75% of previous dose.

  • Anemia associated with renal failure:

    • Epo: 150 units/kg three times a week.

    • Darbepoetin: 0.45 mcg/kg/wk

  • Anemia associated with HIV infection:

    • Epo: 100-200 units/kg three times a week.

  • Anemia of chronic disease: 150-300 units/kg three times a week.

  • Anemia in patients unwilling or unable to receive RBCs; anemic patients undergoing major surgery: 600 units/kg/wk x 3 or 300 units/kg/d x 1-2 wk

Anemia of Chronic Disease

ACD develops in patients with long-standing inflammatory diseases, malignancy, autoimmune disorders, and chronic infection.

Etiology:

• • Multifactorial with defective iron mobilization during erythropoiesis, inflammatory cytokine-mediated suppression of erythropoiesis, and impaired Epo response to anemia all play a role.

  • ACD is also a common complication of therapy for the underlying disease (e.g., chemotherapy for malignancy, zidovudine for HIV infections).

Dx:

• • No lab test is Dxtic for anemia of chronic disease.

  • Normocytic, normochromic anemia is typical.

  • Iron studies may be similar to patients with iron deficiency and are difficult to interpret.

  • Serum transferrin receptor may help in distinguish iron-deficiency anemia for anemia of chronic disease (elevated in iron deficiency, normal in anemia of chronic disease).

  • Clinical responses to iron therapy can be seen in patients with ferritin levels of up to 100 ng/mL.

  • Bone marrow evaluation for storage iron may be necessary to rule out an absolute iron deficiency accompanying an ACD.

Tx:

• • Treat underlying disease and eliminate exacerbating factors such as nutritional deficiencies and marrow-suppressive drugs.

  • Erythropoiesis-stimulating agents (ESA) Tx is considered if the patient is transfusion dependent or has symptomatic anemia.

    • Epo doses are higher than those in anemia from CKD.

    • If no response is observe at dose of 900 units/kg/wk, further dose escalation is unlikely to be effective.

    • Risks of ESA include: HTN, cardiovascular and arterial and venous thromboembolic events.

    • Transfusion is considered for patients with Hct levels of <24% or if symptomatic.

Anemia associated with HIV infection

Anemia is the most common cytopenia in Pts with HIV. Progressive with progress of disease and decline in CD4 counts.

Etiology: chronic inflammatory process causes decrease in erythropoiesis.

Dx: CBC count. Normocytic, nomochromic anemia, although zidovudine and stavudine induce a macrocytic anemia. ▼ retic count. Dysplasia similar to MDS. BM exam rarely needed.

Tx: Epo improves Hct level in Pts with Epo level of <500 mU/mL.

Considerations:

• • MAC inf are frequently associated with severe infection. Dx is based on BM exam and culture.

  • Parvovirus B19 should be considered in HIV-infected Pts with transfusion-dependent anemia and low retic count. Lab studies to include Parvovirus B19 PCR from serum or BM.

  • Tx with IVIG 0.4 g/kg IV daily x 5-10 days results in erythropoietic recovery. Relpases occur between 2-6 months and can be readily managed with intermittent IVIG at an empiric maintenance dose of 0.4 g/kg IV x 1 day given every 4 wks.

Aplastic anemia is an aquired abnormality of the hematopoietic cells that usually presents with pancytopenia.

Etiology:

• • Most cases are idiopathic.

  • 20% are due to drug or chemical exposure.

  • 10% are due to viral illnesses (hepatitis, EBV, CMV).

  • Bone marrow failure may occur from immunologic destruction of hematopoietic stem cells.

Dx:

• • Pancytopenia

  • Fatigue, malaise, dyspnea, or thrombocytopenia (mucosal bleeding, bruising), although some patients present with fever and leukopenia.

Dxtic Criteria:

• • Severe aplastic anemia.

  • Bone marrow cellularity of <30% with normal cytogenetics.

  • Two of three peripheral blood criteria:

  • Absolute neutrophil count <500/mm³

  • Platelet count <20,000/mm³

  • Reticulocyte count <40,000/mm³.

  • No other hematologic disease

  • Moderate aplastic anemia is considered if patients do not fulfill criteria.

Labs: BM Bx is required for Dx. Morphology of BM is difficult to distinguish from hypocellular MDS and PNH.

Tx:

• • Suspected offending drug must be discontinued and exacerbating factors corrected.

  • Once diagnosed, further care should be provided in a center experienced with aplastic anemia.

  • Suppressive treatment with cyclosporine, glucocorticoids, and antithymocyte globulin should be considered in patients who do not undergo an SCT (stem cell transplant).

  • Stem cell transplant. Early referral to a center specialized in management of aplastic anemia is recommended. SCT from an HLA-identical sibling is generally recommended and has achieved a long-term rate of 60% to 70%.

  • Transfusion in aplastic anemia. Transfusions with RBCs should be kept to a minimum. Prophylactic platelet transfusions are generally recommended if the platelet count is below 10,000/mm3. Transfusion with blood products from family members should be avoided while SCT is being considered.

Anemias Associated with Increased Erythropoiesis

Definition: Anemias associated with increased erythropoiesis (▲ retic count) are caused by bleeding or destruction of RBCs (hemolysis), that may exceed the capacity of the BM to corrected the Hb. Bleeding is much more common than hemolysis.

Etiology:

• • Blood loss

  • Sites of blood loss is usually evident.

    • Suspect occult loss in GI tract, retroperitoneum, rectus sheath, thorax, and deep compartments of thigh depending on history (recent instrumentation, trauma, hip fracture, cogulopathy).

  • Hemolytic anemias are characterized by the predominant site of hemolysis.

    • IV hemolysis may present with fever, chills, tachycardia, and backache.

  • ABO-incompatible RBC transfusion

    • MAHA

    • TTP

      • DIC

      • Mechanical heart valve

      • Malignant HTN

      • Vasculitis

    • Cold autoimmune hemolytic anemia (cold agglutinin disease)

    • RBC infection (malaria, babesiosis)

  • Extravascular hemolysis is characterized by RBC destruction in the reticuloendothelial system, primarily the spleen.

    • Warm, autoimmune hemolytic anemia.

    • Hereditary spherocytosis.

Dx:

• • If presentation is <5 days, the only lab abnormality may be decreased Hb and Hct levels.

  • Elevated retic count response occurs in 3-5 days, which is indicative of appropriate erythropoietic response.

  • LDH and bilirubin are increased in most patients reflecting an increase in RBC turnover.

  • Serum haptoglobin is decreased with hemolysis due to clearance of intravascular Hb.

  • With severe hemolysis, free Hb can be measured in the plasma, and hemosiderin can also be detected in urine with more chronic hemolysis.

  • Examination of peripheral smear is an important clue to detect hemolysis and may help define the cause. IV hemolysis may reveal red cell fragmentation (schistocytes, helmet cells), whereas spherocytes indicated extravascular, immune-mediated hemolysis.

  • Polychromasia and nucleated RBCs can be seen with intense hemolysis and increased erythropoiesis.

  • Evaluation for hemolysis includes the direct Coombs test (DAT) for the presence of antibody associated to red cells; the indirect Coombs test indicates the presence of free antibody in the plasma.

Sickle Cell Disease

Iron-deficiency anemia:

• Common d/o worldwide

• US cases caused by menstrual blood loss and increased iron requirement in pregnancy, lactation.

• In the absence of menstrual bleeding, GI blood loss (check for occult malignancy)

• Disease of the stomach and proximal small intestine (H. pylori) infection, bariatric surgery often lead to decreased iron absorption. Celiac disease, post-gastrectomy (decreased Fe absorption). PNH is rare cases.

• H & P: Fatigue, malaise, pica, splenomegaly, restless leg syndrome, koilonychia, brittle nails, reduced excercise tolerance, dyspnea on exertion, and Plummer-Vinson syndrome (glossitis, dysphagia, and esophageal webs) are rare findings.

  • GIB (melena, , hematochezia, hematemesis), menstrual abnormalities - menorrhagia.

• Lab eval:

  • Fe and ferritin is down, TIBC is up.

  • If Fe/TIBC ratio is <20%, treat with ferrous sulfate 325 mg PO tid.

  • MCV usually normal in early iron def.

  • Hct <30% leads to anisocytosis, hypochromic microcytic cells appear (decreased MCV), platelets may be increased.

  • Dx requires documentation of low iron stores, measure indirectly with serum ferritin which is the best surrogate marker of iron stores. Ferritin is the primary storage form of iron in the liver and bone marrow.

  • If MCV low, check Sr. ferritin. If it is <10 ng/mL in women and <20 ng/mL in men is Dxtic of Fe-def.

    • Ferritin is an acute phase reactant so normal levels may be seen in inflammatory states, liver dz, or malignancy despite low iron stores.

  • Sr. Ferritin level >200 ng/mL generally rules out iron def but in patients on renal dialysis and who also have iron def can show ferritin levels >500 ng/mL.

  • High Sr. transferrin rcp levels in Fe-def.

  • Fe-def anemia: low Fe (<50 mcg/dl), low ferritin, low transferrin (Fe) sat. ▲ TIBC (>420 mcg/dl), ▲ transferrin, and ▲ platelet.

    • Transferrin increases linearly to approximately 400 mg/dL once patients are in negative iron balance so that transferrin saturation falls below 16% only when iron stores are exhausted.

  • Check for adenoca of GIT.

  • If serum ferritin is not dxtic:

    • Bone marrow aspirate should be stained for iron, and if absent is definitive for establishing iron def.

    • Therapeutic challenge with supplemental iron - to check if it is iron responsive.

• Tx: replete Fe stores with PO or parenteral iron. Normal dietary intake of iron meets only the daily losses.

  • After starting iron therapy, reticulocytes typically begin to rise 2 - 5 days after iron therapy, and Hb rises over 1 - 2 months.

  • Poor response to Tx?!:

    • non-compliance, poor absorption, continued blood loss, malignancy.

  • With adequate f/up a menstruating woman needs only a baseline Hb/Hct value that is repeated 2-4 months after the initiation of oral iron therapy.

  • Postmenopausal women and men need detailed evaluation, including investigation of potential RBC losses, commonly via GI tract (PUD, colon carcinoma) or, rarely, the urinary tract (PNH). First rule out iron deficiency before further evaluation.

  • Oral Tx: Ferrous sulfate, 325 mg (65 mg elemental iron) PO tid with meals.

    • Iron is best absorbed on empty stomach, and between 3 and 10 mg of elemental iron can be absorbed daily.

    • Do not give PPI and other acid-neutralizing meds, for it can result in impaired iron absorption. Give Vit C along with Fe as it helps maintain Fe in a reduced state.

    • Oral iron can induce a number of GI side effects, including epigastric distress, bloating, and constipation, as a result of noncompliance is a common problem. These side effects can be decreased by initially administering the drug with meals or once a day. Concomitant administration of a stool softner can also alleviate Sx.

    • Iron polysaccharide complex (Niferex) contains 150 mg of elemental iron, given bid, is as effective as other preparations at a similar cost and seems to have fewer GI side effects.

  • Parenteral iron therapy: Used in patients with poor absorption (inflammatory bowel disease, malabsorption), ongoing bleeding, intolerance to oral perparations.

    • Iron dextran (INFeD, Dexferrum). Check online dose calculator: www.globalrph.com/irondextran.htm

      • Iron dextran, 1000 - 2000 mg in 500 - 1000 mL of NS and run at 6 mg/min is used.

      • Anaphylaxis is a rare complication. Hence, test Iron dextran by administering 0.5 ml (25 mg) IV in 50 mL of normal saline is used as a test dose; given over 5 - 10 minutes. Epinephrine 1:1000, 1 mg ampule for sc administration, methylprednisone, diphenydramine should be available to treat anaphylaxis while during the infusion.

      • Delayed reactions to IV iron, such as arthralgia, myalgia, fever, pruritus, and lymphadenopathy may be seen within 3 days of therapy and usually resolve spontaneously or with NSAIDs.

    • Sodium ferric gluconate (Ferrlecit), 125 mg diluted in 100 mL normal saline IV x 1 hour or as a slow infusion over 10 minutes (12.5 mg/min). Repeat weekly but do not exceed greater than 250 mg/day, until circulating iron (normalize Hct).

    • Iron sucrose (Venofer), 100 - 200 mg IVP or upto 400 mg x 2.5 hr IV infusion, in normal saline, repeat 1 - 3 times/week.

    • Iron polysaccharide complex (Niferex), 150 mg of elemental iron, bid. Has fewer GI side effects.

    • They cannot be used to replenish the entire iron deficit with a single infusion.

  • RDW: anisocytosis. Value more in post-Tx. eg. if Pt. with low MCV does not exhibit increase in RDW after iron therapy, means not responding to iron therapy.

Thalassemias:

• Heterogenous group of inherited d/o where there is underproduction of either the alpha or beta-globin chains of the Hb. molecule.

• Sufficient normal Hb, comprised of 2 alpha and 2 beta chains, cannot be produced, resulting in microcytic anemia.

• Occurs in persons of Mediterranean, African, Middle Eastern, Indian, and Asian descent.

• Beta-thalassemia:

  • Reduced production of beta-globin chains with normal alpha-globin production.

  • Excess alpha-globin relative to beta-globin polymerizes to form insoluble tetramers in RBCs, resulting in damage to RBC membrane, ineffective erythropoiesis, and hemolytic anemia.

    • Beta-thalassemia minor (trait) occurs with 1 gene abnormality. Has variable amounts of beta-chain underproduction. ASx. Hb >10 g/dL, MCV <80 fL. Not transfusion dependent.

    • Beta-thalassemia intermedia. Both beta-globin genes are dysfunctional but present. Anemia is more sever Hb 7-10 g/dL; MCV: 65-75. +/- transfusion dependent.

    • Beta-thalassemia major (Cooley anemia) is caused by severe abnormalities of both genes and requires lifelong transfusion support. Hb: <7 g/dL; MCV: <70 fL.

• Alpha-thalassemia:

  • Reduced production or deletion of one or more of the four alpha-globin chains. Beta-globin gene excess. Beta-globin tetramers form. These are relatively soluble, and thus clinical severity is milder. It is seen more frequently in Asians.

  • Alpha-thalassemia-2 trait: 1 gene affected. Hb is normal, MCV is normal. Not transfusion dependent.

  • Alpha-thalassemia-1-trait: 2 genes affected. Hb >10 g/dL; MCV <80 fL. Not transfusion dependent.

  • Hemoglobin H: 3 genes affected. Hb 7-10 g/dL; MCV <70; +/- transfusion dependent.

    • Clinically significant, characterized by splenomegaly, chronic hemolytic anemia. Rarely requires blood transfusion or splenectomy. Oxidant drugs similar to G6PD should be avoided because increased hemolysis may occur.

    • Hydrops fetalis: All 4 alpha-globin genes affected. Incompatible with life.

  • Family hx of anemia, splenomegaly, bone abnormalities caused by expansion of bone marrow.

  • Microcytic, hypochromic cells with poikilocytosis, target cells, and nucleated RBCs may be present in peripheral smear. Hb analysis may aid in the diagnosis. In thalassemia trait RDW is normal, iron studies are normal.

• HbEP is Dxtic for beta-thalassemia showing an increased percentage of HbA2 and HbF.

• Silent carriers with a single alpha-chain loss have an essential normal electrophoresis. Dx is made by alpha-globin gene analysis. Alpha-thalassemia often has normal HbEP results and Dx is made by molecular biology testing.

• Mentzer's index: Microcytic anemia is seen in both iron deficiency and thalassemia. Mentzer's index differentiates the two:

  • Mentzer's index = MCV/RBC. >13 is Fe-def; <13 is thalassemia.

Tx:

• Those with thalassemia trait require no specific treatment.

• In more severe forms of the disease. PRBC transfusions to maintain Hb >9-10 g/dL are needed to prevent skeletal deformities that result from accelerated erythropoiesis.

• Transfusions in severe forms can result in tissue iron overload, which may cause CHF, hepatic dysfunction, glucose intolerance, and secondary hypogonadism. Supplementation iron must never be given. Iron chelation therapy delays or prevents these complications. Once clinical organ deterioration has begun, it may not be reversible.

• Chelation therapy indicated for transfusion-related iron overload from any cause. If transfusion burden >20 units of PRBCs and ferritin consistently >1000 ng/mL. Deferoxamine, 40 mg/kg SC or IV x 8-12 hrs continuous infusion. Deferasirox, 20-30 mg/kg PO qd can also be given. Side effects of deferasirox include mild to moderate GI disturbances and skin rash. Efficacy is similar to deferoxamine. Chelation therapy should be continued until ferritin levels of <1000 mg/L is maintained.

• Hydroxyurea, 15 - 35 mg/kg/d may benefit some patients with beta thalassemia.

• Stem marrow transplant should be considered in young patients with thalassemia major who have human leukocyte antigen (HLA)-identified donors.

• Surgery: Splenectomy considered in patients with accelerated >2 units/mo transfusion requirements. However, not recommended if patient is younger than 5-6 years because of the risk of sepsis.

  • To decrease the incidence of post-splenectomy sepsis, immunization against Pneumococcus, H. influenzae, and N. meningitidis should be administered at least 2 wks before surgery if not previously vaccinated.

Myelodysplastic Syndrome (MDS)

Definition: MDS is a clonal stem cell disorder, characterized by ineffective hematopoiesis resulting in peripheral cytopenias. Some patients progress to develop acute leukemia.

Classification: WHO

• Refractory anemia: Erythroid dysplasia, <5% myeloblasts in bone marrow.

  • With ring sideroblasts, >15% of nucleated marrow cells

  • Without ring sideroblasts

• Refractory cytopenias with multilineage dysplasia: Evidence of dysplasia in nonerythroid cell lines and <5% myeloblasts in bone marrow.

• Refractory anemia with excess blasts: 5-20% meyloblasts in bone marrow.

• 5q-syndrome: Favorable prognosis; may have thrombocytosis.

• MDS; unclassifiable.

Etiology:

• Idiopathic (70% of patients)

• Secondary (30% of patients) to prior radiation, chemotherapy, or toxin exposure.

Dxtic:

• CBC - cytopenias, macrocytosis.

• Peripheral smear:

  • Dysplasias with hypogranular or hypolobulated neutrophils (pseudo-Pelger-Huet anomaly), basophilic stippling, and megaloblastic changes in red cells.

  • Circulating blasts.

• Bone marrow exam with chromosomal analysis is necessary for Dx and classification.

• Iron stain to evaluate ring sideroblasts.

• Vitamin B₁₂ and folate levels to exclude megaloblastic anemia.

• Bone marrow blast count of >20% is Dxtic for acute leukemia.

• Erythropoietin (Epo), 40,000 units SC qwk or darbepoetin, 200-300 mg SC q2-3 wks may provide some improvement in erythropoiesis.

• Pyridoxine, 50-200 PO daily, with response rate 20% in patients with ring sideroblasts.

• Stem cell transplant should be considered in patients younger than 50 years who have an HLA-identical sibling.

• International Prognostic Scoring System

Tx:

• Therapy is based on prognosis at time of diagnosis.

• Low-risk MDS is treated with blood transfusion. This may result in iron overload.

• Intermediate and high risk for MDS can be treated with azacitidine and decitabine. Referral to a hematologist-oncologist is recommended.

Medications:

• 5-Azacitidine (Vidaza), 75 mg/m² SC x 7 days of a 28-day cycle.

  • Response rate of 15.7% (complete remission + partial remission).

  • Slows progression to AML and improves survival

  • Indicated for Pts with high risk MDS (class INT-2 and high) and for patients who are transfusion dependent).

  • SE: neutropenia, anemia, thrombocytopenia.

• Decitabine has also shown to increase overall improvement rates when compared to supprotive therapy.

• Immunosuppressive therapy with antithymocyte globulin, cyclosporine, and glucocorticoids are most effective in patients with a hypocellular (referring to bone marrow cellularity) MDS.

• Iron chelation therapy should be considered in patient with a low INT-1 risk after 50-100 units of PRBCs transfused.

• Lenalidomide, 10 mg PO daily x 21 days of a 28-day cycle is effective in patients with MDS and 5q-syndrome.

  • Myelopthisic process: teardrop or fragmented cells, normoblasts, or immature WBCs on peripheral blood smear and the setting of pancytopenia.

  • Elevated free erythrocyte protoporphyrin in Fe-def, lead poisoning.

  • High MCV results in hemolysis, vit B12, or folate def, intrinsic factor def, myelodysplasia or hepatic dysfunction, alcoholism.

  • Check DAT (direct antiglobulin test) for abs bound to surface of RBCs. If DAT is positive, an immune-mediated hemolysis is likely cause of anemia.

  • Check Sr. transferrin rcp level. Low Sr. transferrin rcp seen in acute inflammation, protein def, anemia of chronic dz.

  • Anemia of chronic disease: RA, CKD, chronic inf, inflammatory or connective tissue d/o: low Fe, high ferritin, low TIBC, low or norm Fe sat.

  • Sideroblastic: ETOH, INH, lead exposure. High Fe. Prussian blue stain.

  • In ACD, the Hct is rarely <25% unless renal failure or another cause of anemia coexists.

  • High doses of erythropoietin (30,000 - 60,000 U/wk) may be tried in patients with serum erythropoietin levels <200 IU/L.

    • Blood transfusion required.

    • Erythropoietin won't work if serum erythropoietin is >500 IU/L.

  • Tx of Vitamin B12:

    • Initial replacement Vit B12 100 mcg IM daily x 1 week, then qweek x 1 month.

    • Maintenance; 100 mcg IM qmonth.

    • Oral Vit B12 is also effective for routine replacement, provided patient is able to absorb. Recommended dose is 1 - 2 mg PO daily.

    • Oral folate: 1 mg PO daily. Before treating folate deficiency, exclude concomitant Vit B12 deficiency in order to prevent acute exacerbation of neurologic symptoms in patients who receive folate but are B12 deficient.

    • Treatment with vit B12 in patients with severe megaloblastic anemia can cause life threatening hypokalemia secondary to increased potassium uptake by the newly formed RBCs. Check Sr. K during first 48-hrs of Tx. Some physicians transfuse PRBCs in Pts with severe megaloblastic anemia before starting them on vitamin B12 supplementation.

Causes of B12/Folate deficiency