5 1 Relevant pages elsewhere: Transfusion (p. 456) 608 Anemia Anemia is defined as a low hemoglobin concentration due a decreased red cell mass. I f the low Hb concentration is due to increased plasma volume, as in pregnancy, the anemia i s then considered physiological. A low hemoglo- bin (Hb) level is <13.5 g/dL for men and <1 1.5 g/dL for women. Anemia may be due to reduced production or increased loss of red blood cells (RBCs) and has many causes. The cause of the anemia will be resolved by synthesis of the history, physical examination, and inspection of the blood smear. Symptoms Fatigue, dys pnea, palpitations, headache, tinnitus, anorexia, dyspepsia, bowel disturbance and angina i f there is preexisting coronary artery disease. Patients who have developed their anemia ra pidly are often more symptomatic than those who have developed anemia slowly, in which case there has been time for physiologic compensations for their anemia to occur. Signs Pal lor (evident in conjunctivae) and retinal hemorrhages. In severe anemia (Hb <8 g/dL), there may be signs of a hyperdynamic circulation, with tachycardia, a systolic ejection murmur, and cardiac enlargement. Later, heart failure may occur and, in this state, rapid blood tra nsfusion may be fatal. Types of anemia The first step in diagnosis is to look at the mean c ell volume (MCV, normal MCV is 80 \200\223100 fL ) and the red cell distribution width (RDW , a measure of the variability of the red cell size). Low MCV (microcytic): \212 \212 \212 \212 NB: Anemia of inflammation is distinguished from iron deficiency by iron studies : Serum iron, transferrin, and transferrin saturation will be reduced whereas ferritin will be normal or elevated. Both the anemia of inflamma- tion and some thalassemias tend to hav e near normal RDWs. Normal MCV (normocytic anemia) y g o o t a m e H l Iron-deficiency anemia (IDA, most common cause; Anemia of inflammation Thalassemia Siderobl astic anemia p. 609) \212 \212 \212 Anemia of chronic disease Bone marrow failure Chronic Kidney Disease \212 \212 \212 Hypothyroidism (or Hemolysis (or \206\221 MCV) Pregnancy \206\221 MCV) High MCV (macrocytic anemia) B \212 12 or folate deficiency \212 \212 \212 \212 \212 \212 \212 \212 \212 Myelodysplastic syndromes Marrow infiltration Hypothyroidism Antifolate drugs Bone marrow f ailure states Alcohol Liver disease Reticulocytosis Cytotoxics, e.g., hydroxyurea Hemolytic anemias: Do not fall neatly into the above classification as the anemia may be no rmochromic, or, if the reticulocyte percentage is very high, macrocytic. Suspect a hemolyti c anemia if there is a reticulocyto- sis (>2% of RBCs; or reticulocyte count >85 \227 10 9 /L), mild macrocytosis, haptoglobin \206\223 (p. 616), bilirubin \206\221 , and urobilin ogen \206\221 . If the RDW is very elevated (>20), consider a microangiopathic process suc h as disseminated intravascular coagulation (DIC) or thrombotic thrombocytopenic purpura (T TP). Blood transfusion Avoid unless Hb has fallen acutely and the patient is symptomatic. T ransfusion decisions will depend on the severity, the cause, and the underlying medical sta tus of the patient. If risk of hemorrhage (e.g., active peptic ulcer), transfuse up to 8 g/ dL. In severe anemia with heart fail- ure, transfusion is vital to restore Hb to safe level s: e.g., 8 \200\22310/dL, but must be done with great care. Give packed cells slowly with 1 0 \200\22340 mg furosemide IV/PO with alternate units (dose depends on previous exposure to diuret- ics). Check for rising jugular venous pressure (JVP) and basal crackles. 609 Iron-deficiency anemia Iron deficiency is common (seen in up to 14% of menstruating women) and, worldwide, is the most frequent cause of nutritional anemias. The most common cause is blood loss, particularly menorrhagia or GI bleeding from esophagitis, peptic ulcer, carcin oma, colitis, or diverticulitis. In the tropics, hookworm (GI blood loss) is the most common cause. Poor diet may cause iron-deficiency anem ia (IDA) in infants and children, those on special diets, strict vegetarians, or wherever t here is poverty. Iron deficiency anemia due to malabsorption (gastric surgery, gastric bypa ss, celiac disease, Whipple \200\231s disease, inflammatory bowel disease) may be accompani ed by other defi- ciency states, such as of folate and B 12 . See Table 15.1. Symptoms: Ass ociated symptoms include ice craving (pagophagia), restless leg syndrome, and short-term me mory loss (adolescents). Signs: Koilonychia (p. 43), atrophic glossitis, and, rarely, postc ricoid webs. Investigations: Microcytic, hypochromic blood movie showing anisocytosis and p oikilocytosis (p. 612). Confirmed by showing serum iron \206\223 and ferritin \206\223 (m ore representative of total body iron) with TIBC \206\221 . If MCV \206\223 , and there i s a good history of menorrhagia, oral iron may be started without further tests. Otherwise investigate: Fecal occult blood, barium enema or colonos- copy, gastroscopy, microscope sto ol for ova. Iron deficiency without an obvi- ous source of bleeding mandates a careful gi w orkup . Treatment: If the MCV is low and there is a history of menorrhagia, oral iron may b e started without further diagnostic workup: Oral iron salts (e.g., ferrous sulfate 324 mg bid or tid PO). Side effects (Se) : Constipation, black stools. Hb should rise by 1 g/dL/wk , with a modest reticulocytosis (i.e., young RBC [p. 612]). Continue until Hb is normal and for at least 3 months to replenish stores. Parenteral iron is reserved for patients who fa il oral iron trials or dialysis patients and is available as iron gluconate, sucrose, or fe rumoxytol (well tolerated) or iron dextran (higher side-effect profile). Refractory anemia The usual reason that IDA fails to respond to iron replacement is failure of compliance, of ten because of GI disturbance. Altering the dose of elemental iron or the formulation of el emental iron may be helpful, or considere IV iron in appropriate situations. Other rea- son s for failure of oral iron supplementation include continued blood loss or malabsorption. I mportantly, anemia of inflammation or thalassanemia will not respond to iron supplementatio n. The anemia of chronic disease This is associated with many diseases, including infection, c ollagen vascu- lar disease, rheumatoid arthritis, malignancy, and chronic kidney disease. I nvestigations: Mild normocytic anemia (e.g., Hb >8 g/dL), TIBC \206\223 serum iron \206 \223 , ferritin normal or \206\221 . Treatment: Treat the underlying disease. The anemia o f chronic kidney disease is partly due to erythropoietin deficiency, and recombinant erythr opoietin is effective in raising the hemoglobin level (maintenance dose example: 50 \200 \223150 U/kg twice weekly; se : Hypertension in patients with chronic kidney disease). It i s also effective in raising HB and improving quality of life in those with HIV-related anem ia, chemotherapy induced-anemia, chronic bone marrow failure states, and the anemia of many chronic inflammatory states. 610 Sideroblastic anemia Characterized by dyserythropoiesis and iron loading (bone marrow) and sometimes hemosiderosis (endocrine, liver, and cardiac damage), sidero- blastic anemia (SA) may be congenital (rare, X-linked) or acquired (usually idiopathic, part of the spectrum o f the myelodysplastic disorders), but may follow alcohol or lead excess, myeloproliferative disease, malignancy, mal- absorption, or anti-tuberculosis (TB) drugs. Stippled, hypochrom ic RBCs are seen on the blood movie with sideroblasts in the marrow (erythroid pre- cursors with iron deposited in mitochondria in a ring around the nucleus). y g o o t a m e H Table 15.1 Interpretation of iron studies l Iron \206\223 \206\223 \206\221 \206\221 \206\221 \206\221 tibc \206\221 \206\223 \206\223 \206\223 (or \206\224 ) \206\221 \206\224 Ferritin \206\223 \206\221 \206\221 \206\221 \206\224 \206\221 Iron deficiency Anemia of chronic disease Chronic hemolysis Hemochromatosis Pregnancy Sider oblastic anemia Treatment is supportive; pyridoxine may occasionally be of benefit (e.g., 10 mg/24 h PO; hi gher doses may cause neuropathy); remove the cause if pos- sible. In myelodysplasia, erythr opoietin, with or without human granulocyte colony-stimulating factor (G-CSF) may be effect ive, although the cost ben- efit of this approach is controversial. The peripheral blood movie Many primary hematological diagnoses and other systemic diagnose s can be made by careful examination of the peripheral blood movie. It is also nec- essary for interpretation of the RBC indices. Acanthocytes: RBCs show many spicules. Anisocytosis: Variation in red cell size. Basophilic stippling: Stippling of RBCs is seen in lead poison ing, thalassemia, and other dyserythropoietic anemias. Blasts: Nucleated precursor cells; t hey are not normally seen in peripheral blood. Burr cells: Irregularly shaped cells occurri ng in uremia or liver disease. Dimorphic picture: A mixture of RBC sizes (e.g., partially t reated iron defi- ciency, mixed deficiency [Fe with B 12 or folate deficiency], post-transf usion, sideroblastic anemia). Howell \200\223Jolly bodies: Nuclear remnants seen in RBCs po st splenectomy; rarely leukemia, megaloblastic anemia, IDA, hyposplenism (e.g., celiac dise ase, neo- nates, thalassanemia, SLE, lymphoma, leukemia, amyloid). Hypersegmentation: Hyper segmented neutrophils (>5 lobes to nucleus) seen in megaloblastic anemia, uremia, and liver disease. Hypochromia: Less dense staining of RBCs seen in IDA, thalassemia, and sideroblas tic anemia (iron stores unusable). Left shift: Immature white cells seen in circulating blo od in any marrow outpouring, such as infection or marrow infiltration. Leukoerythroblastic anemia: Immature cells (myelocytes, nucleated red blood cells, and large platelets) seen in movie. Due to extramedullary hematopoiesis associated with marrow infiltration, hypoxia, m arrow fibrosis, or severe anemia. Leukemoid reaction: A marked reactive leukocytosis. Usual ly granulocytic, and observed in severe infection, burns, acute hemolysis, metastatic cance r. Myelocytes, promyelocytes, metamyelocytes, normoblasts: Immature cells seen in the blood in leukoerythroblastic anemia. Normoblasts or nucleated red cells: Immature red cells with a nucleus. Seen in leukoerythroblastic anemia, marrow infiltration, hemolysis, hypoxia. 611 Pappenheimer bodies: Granules of siderocytes (e.g., lead poisoning, carcino- matosis, post splenectomy). Poikilocytosis: Variation in red cell shape. Polychromasia: RBCs of different ages stain unevenly, the younger erythro- cytes being bluer. An indirect assessment of ret iculocytosis. Reticulocytes: (Normal: 0.8 \200\2232%; or <85 \227 10 9 /L) Young, larger R BCs (contain RNA) signifying active erythropoiesis. Elevated in hemolysis, hemorrhage, and if B 12 , iron or folate is given to marrow that lack these. Rouleaux formation: Red cells stack on each other (the visual \200\234analog \200\235 of a high erythrocyte sedimentatio n rate [ESR, p. 612]). Schistocytes: Fragmented RBCs sliced by fibrin bands observed in mic roan- giopathic hemolytic processes (DIC, TTP, malignant hypertension). Spherocytes: Red bl ood cells lacking central pallor. Observed in extravascu- lar hemolytic processes such as a utoimmune hemolysis, hereditary sphero- cytosis, burns. Target cells: RBCs with central sta ining, a ring of pallor, and an outer rim of staining seen in liver disease, thalassemia, o r sickle-cell disease, and, in small numbers, in IDA. The differential white cell count Neutrophils 2 \200\2237.5 \227 10 9 /L (40 \200\22375% o f the total white blood cell (WBC) count; absolute values are more meaningful than percenta ges). Elevated in: \212 \212 \212 Bacterial infections Trauma, surgery, burns, hemorrhage Inflammation, infarction, polymyalg ia rheumatica, polyarteritis nodosa (PAN) Myeloproliferative disorders Steroids Disseminate d malignancy \212 \212 \212 Reduced in: \212 Viral infections, HIV, liver disease, hepatitis C, brucellosis, typhoid, kala-azar, TB Drug s (e.g., hydroxyurea, sulfonamides) Hypersplenism or neutrophil antibodies (seen in SLE and rheumatoid arthritis); increased destruction \212 \212 B \212 12 or folate deficiency; in bone marrow failure states, stem cell disorders; decreased production (p. 613) Lymphocytes 1.3 \200\2233.5 \227 10 9 /L (20 \200\22345%). Elevated in: \212 \212 Large numbers of abnormal ( \200\234atypical \200\235) lymphocytes are characteristically seen wi th Epstein-Barr virus (EBV) infection: These are T-cells reacting against EBV-infected B-ce lls. They have a large amount of clear cytoplasm with a blue rim that flows around neighbor ing RBCs ( \200\234Dutch skirting \200\235). Other causes of \200\234atypical \200\235 lym phocytes: Reduced in: \212 612 Viral infections, toxoplasmosis; whooping cough; brucellosis Chronic lymphocytic leukemia Steroid therapy, systemic lupus erythematosus (SLE), uremia, legion- naire \200\231s diseas e, HIV infection, marrow infiltration, post chemotherapy or radiotherapy T-lymphocyte subset reference values: CD4 count: 537 \200\2231,571/mm 3 (low in HIV infecti on). CD8 count: 235 \200\223753/mm 3 ; CD4/CD8 ratio: 1.2 \200\2233.8. Eosinophils 0.04 \200\2230.44 \227 10 9 /L (1 \200\2236%). Elevated in: Asthma/atopy, parasitic infections (especially invasive helminths), PAN, skin disease (especially pem- phigus), urticaria, mal ignant disease (including lymphomas and eosinophilic leukemia, systemic mastocytosis), adre nal insufficiency, irradiation, L ffler \200\231s syndrome, during the convalescent phas e of any infection. The hypereosinophilic syndrome is seen when there is development of end -or- gan damage (restrictive cardiomyopathy, neuropathy, hepatosplenomegaly) in association with a raised eosinophil count (>1.5 \227 10 9 /L) for >6 wks. Monocytes 0.2 \200\2230.8 \227 10 9 /L(2 \200\22310%). Elevated in: Acute and chronic infections (e.g., TB, brucello sis, protozoa); malignant disease, including M4 and M5 acute myeloid leukemia (p. 627) and Hodgkin \200\231s disease; myelodysplasia. Basophils 0 \200\2230.1 \227 10 9 /L (0 \200 \2231%). Elevated in: Viral infections, urticaria, myxedema, post splenectomy, chronic myel oid leukemia (CML), ulcerative colitis (UC), malignancy, systemic mastocytosis (urticaria p igmentosa), hemolysis, chronic myeloproliferative neoplasms. y g o o t a m e H l Macrocytic anemia Macrocytosis ( MCV >100 fl ) is a common finding, often due to alcoholism (usually without any accompanying anemia). Causes of macrocytosis ( MCV >110 fL):Vitamin B 12 or folate deficiency; hydroxyurea. MCV 100 \200\223110 FL: \212Drugs: Alcohol, azathio prine, zidovudine \212 \212 Marrow infiltration Hemolysis \212 \212 Liver disease Pregnancy \212 \212 Hypothyroidism Myelodysplasia Investigations Blood movie: May show hypersegmented polymorphs (B 12 \206\223 ) or target cells (liver disease). Other tests: ESR (malignancy),liver function tests (LFTs) (include -glutamyl transpeptidase [GGT]), T4, serum B 12 , and serum folate (or red cell folate). Bone marrow biopsy is indicated if the cause is not revealed by the above tests. It is like ly to show one of these four states: \212 B 12 or folate deficiency (or cytotoxic drugs). (A megalo- Megaloblastic: blast is a cell i n which cytoplasmic and nuclear maturation are out-of- phase because nuclear maturation is slowed.) Normoblastic marrow: Increased erythropoiesis: Abnormal erythropoiesis: \212 \212 E.g., hemolysis \212 Sideroblastic anemia, leukemia, aplastic anemia If B 12 d eficiency, consider a Schilling test to help identify the cause. This determines whether a low B 12 is due to malabsorption (B 12 is absorbed from the terminal ileum) or to lack of i ntrinsic factor by comparing the proportion of an oral dose (1 mcg) of radioactive B 12 exc reted in urine with and without the concurrent administration of intrinsic factor. (The blo od must be saturated by giving an IM dose of 1,000 mcg of B 12 first.) If intrinsic factor enhances absorption, lack of it (e.g., pernicious anemia [p. 614]) is likely to be the caus e. Causes of a low B12 Pernicious anemia, post gastrectomy (no intrinsic factor to facilita te B 12 absorption in the terminal ileum), dietary deficiency Liver damage, myxedema 613 (vegans, children, and elderly living in vegetarian households); rarely, disease of termina l ileum (where B 12 is absorbed), e.g., Crohn \200\231s disease, resection, blind loops, di verticula, worms ( Diphyllobothrium ). B 12 is found in liver and all animal foods. Body st ores: Sufficient for 3 yrs. Causes of low folate Poor diet, heavy alcohol use, increased re quire- ments (pregnancy, hemolysis, malignancy, long-term hemodialysis), malab- sorption (e specially celiac disease, tropical sprue), drugs (phenytoin and trimethoprim). Folate is fo und in green vegetables, fruit, liver. Body stores: Sufficient for 3 months. Maternal folat e deficiency is associated with the development of fetal neural tube defects. NB: In ill pa tients with megaloblastic anemia, it may be necessary to treat before the results of serum B 12 and folate are at hand. Use large doses (e.g., hydroxocobalamin 1 mg/24 h IM, with fol ic acid 5 mg/24 h PO). Blood transfusions are very rarely needed (p. 456). Folate given alo ne for the treatment of megaloblastic anemia when low B 12 is the cause may precipitate, or worsen, subacute combined degeneration of the spinal cord. Pernicious anemia Pernicious anemia (PA) affects all cells of the body and is due to malab- sorption of B 12 resulting from atrophic gastritis and lack of gastric intrinsic factor se cretion. In B 12 deficiency, synthesis of thymidine, and hence DNA, is impaired and, conseq uently, red cell production is reduced. In addition, the central nervous system (CNS), peri pheral nerves, gut, and tongue may be affected. Incidence 1:1,000; increased with advancing age. Common features \212 \212 \212 \212 \212 \212 Other features \212 \212 \212 \212 \212 \212 Tiredness and weakness (90%) Dyspnea (70%) Paraesthesia (38%) Sore red tongue (25%) Diarrhe a Mild jaundice (lemon tinge to skin) Retinal hemorrhages Prematurely gray hair Retrobulbar neuritis Mild splenomegaly Fever Neur opsychiatric (dementia) Subacute combined degeneration of the spinal cord: This may be seen in any cause of a low B 12 . Posterior and lateral columns are often affected, not always together. Onset is usual ly insidious with peripheral neuropathy. Joint position and vibration sense are often affec ted first (dorsal columns) fol- lowed by distal paraesthesia (neuropathy). If untreated, st iffness and weak- ness ensue. The classical triad is: \212 \212 \212 Less common signs : Impaired cognition, reduced vision, absent knee jerks with brisk ankle jerks and flexor pla ntars, Lhermitte \200\231s sign (p. 373). Pain and temperature sensation may be intact even when joint position sense is severely affected. CNS signs can occur without anemia. Associ ations Thyroid disease ( 25%), vitiligo, Addison \200\231s disease, carci- noma of stomach (maintain a low threshold for endoscopy). Tests \212 \206\223 (3 \200\22311 g/dL) Hb \212 MCV > 110 fL \212 Hypersegmented neutrophils Extensor plantars Brisk knee jerks Absent ankle jerks 614 \212 \212 \212 Megaloblasts are abnormal red cell precursors in which nuclear matura- ti on is slower than cytoplasmic maturation. Antibodies to parietal cells (high sensitivity bu t low specificity) or to intrinsic factor (higher specificity but lower sensitivity) are pr esent in PA. The vast majority of B 12 deficient patients will have elevations in serum hom ocysteine and methylmalonic acid. However, both homocysteine and methylmalonic acid are ele vated in renal disease, and hyperhomocysteinemia is present in folate deficiency. A Schilli ng test (p. 613) may be appropriate occasionally (expect it to show that <7% of an orally a dministered dose of labeled B 12 is excreted unless concurrent intrinsic factor is given). Treatment Replenish stores with cyanocobalamin (B 12 ) 1 mg IM every day for 2 wks (or, if CNS signs, until improvement stops). Maintenance: 1 mg IM every month for life. Initial imp rovement is heralded by a marked reticulo- cytosis (after 4 \200\2235 d, but serum iron fal ls first). Watch for early hypokalemia and rebound thrombocytosis if severely B 12 deficien t. Practical hints \212 12 <200 pg/mL Serum B Reduced WCC and platelets Megaloblasts in the marrow y g o o t a m e H \206\223 l Beware of diagnosing pernicious anemia in those <40 yrs: Look for GI malabsorption (small b owel biopsy). Watch for hypokalemia in early days of therapy. Pernicious anemia with high-o utput congestive heart failure (CHF) may require exchange transfusion after blood for CBC, folate, B 12 , and mar- row sampling. As hematopoiesis accelerates on treatment, additional Fe and folate may be needed. WBC and platelet count should normalize in 1 wk. Hb rises 1 g/dL per week of treatment. Dramatic rebound thrombocytosis is often observed, is transient , and does not appear to be harmful. \212 \212 \212 \212 \212 Prognosis Complete neurological recovery is possible. Most see improve- ment in the first 3 \200\2236 months. Patients do best if treated as soon as possible after the onset of sympt oms. An approach to hemolytic anemia Hemolysis is the premature breakdown of RBCs. It may occur in the cir- culation (intravascular) or in the reticuloendothelial system (extravascu- lar) . Normal RBCs have a lifespan of 120 d. In sickle-cell anemia, e.g., the lifespan may be a s short as 5 d. If the bone marrow does not compensate sufficiently, a hemolytic anemia wil l result. Causes of hemolysis These are either genetic or acquired. Genetic: 1 Membrane: He reditary spherocytosis or elliptocytosis 2 Hemoglobin: Sickling disorders (p. 616), thalass emia 3 Enzyme defects: G6PD and pyruvate kinase deficiency Acquired: 1 Immune: Either isoim mune (hemolytic disease of newborn, blood trans- fusion reaction), autoimmune (warm or cold antibody mediated), or drug-induced 615 2 Nonimmune: Trauma (cardiac hemolysis, microangiopathic anemia [p. 617]), infection (malar ia, septicemia), membrane disorders (paroxys- mal nocturnal hemoglobinuria, liver disease) In searching for evidence of significant hemolysis (and, if present, its cause), try to ans wer these four questions: \212 Bilirubin \206\221 (unconjugated), urinary Is there increased red cell breakdown? urobilin ogen \206\221 , haptoglobin \206\223 (binds free Hb avidly, and is then removed by the li ver, so it is a good marker of hemolysis). Is there increased red cell production? polychro masia on the blood smear, macrocytosis, marrow hyperplasia. Extravascular hemolysis may Is the hemolysis mainly extra- or intravascular? lead to splenic hypertrophy. The features of intravascular hemolysis are methemalbuminemia, free plasma hemoglobin, hemoglobinuria, low hap- toglobin, and hemosiderinuria. Why is there hemolysis? \212 Demonstrated by reticulocytosis, \212 \212 See below and p. 617. History Ask about family history, race, jaundice, hematuria, dr ugs, previ- ous anemia. Examination Look for jaundice, hepatosplenomegaly, leg ulcers (seen in sickle-cell disease). Investigation \212 CBC, reticulocytes, bilirubin, lactate dehydrogenase (LDH), haptoglobin, urinary urobilinog en. Films may show polychromasia, macrocytosis, spherocytes, elliptocytes, fragmented cells or sickle cells, and nucleated RBCs if severe. Further investigations: Direct antiglobulin test (DAT; Coombs \200\231 test ). This will identify red cells coated with antibody or co mplement, and a positive result usually indicates an immune cause of the hemolysis. The non im- mune group are usually identifiable by associated features. RBC lifespan may be determi ned by chromium labeling, and the major site of RBC breakdown may also be identified. Urina ry hemosiderin (stains with Prussian blue) indicates chronic intravascular hemolysis. The c ause may now be obvious, but further tests may be needed. Membrane abnormalities are identi fied on the movie and can be confirmed by osmotic fragility testing. Hb electrophoresis wil l detect Hb variants. Enzyme assays are reserved for situations in which other causes have been excluded. \212 \212 \212 Causes of hemolytic anemia Sickle-cell disease (see p. 617). Hereditary spherocytosis Autos omal dominant RBC membrane defect (RBCs are osmotically fragile). Hemolysis is variable. Si gns: Splenomegaly \206\221 risk of gallstones. RBCs show increased fragility. Diagnosis : Hb 8 \200\22312 g/dL. Osmotic fragility tests. Movie: Many spherocytes. Treatment: Folate replacement; splenectomy if warranted (there are risks with ensuing hyposplenism). Heredit ary elliptocytosis Usually inherited as autosomal dominant. The degree of hemolysis is vari able; splenectomy may be indicated in severe cases. Glucose-6-phosphate dehydrogenase defic iency is the commonest RBC enzyme defect. Inheritance is sex-linked with 100 million affect ed in Africa, the Mediterranean, and the Middle/Far East. Neonatal jaundice occurs, but mos t are symptomless with normal Hb and blood movie. They are susceptible to oxidative crises precipitated by drugs (primaquine, sulfonamides, ciprofloxacin), exposure to fava beans (fa vism), or illness. Typically, there is rapid anemia and jaundice with RBC Heinz bodies (den atured Hb stained with methyl violet). Diagnosis: Enzyme assay. Don \200\231t do until some weeks after a crisis as young RBCs may have sufficient enzyme 616 to make the results appear normal. Treatment: Avoid/remove precipitants; transfusion if sev ere. Pyruvate kinase deficiency Usually inherited as autosomal recessive; homozygotes often have neonatal jaundice; later, chronic hemolysis with splenomegaly and jaundice. Diagnosis : Enzyme assay. Often well-tolerated. There is no specific therapy but splenectomy may help . Drug-induced immune hemolysis Due to formation of new RBC mem- brane antigens (e.g., peni cillin in prolonged, high dose), immune complex formation (many drugs, rare), or presence o f autoantibodies to the RBC: -methyldopa, mefenamic acid, L-dopa (rare, Coombs \200\231 +ve). Autoimmune hemolytic anemia (aiha) Causes: Warm or cold antibodies. They may be prima ry (idiopathic) or secondary, usually to lymphoma or generalized autoimmune disease (e.g., SLE). Warm aiha: Presents as chronic or acute anemia. Treatment: Steroids ( splenectomy). Cold aiha: Chronic anemia made worse by cold, often with Raynaud \200\231s or acrocyanosis . Treatment: Keep warm. Blood transfusion is the main therapy, but chlorambucil may help. M ycoplasma and EBV may produce cold agglutinins, but hemolysis is rare. Paroxysmal cold hemo globinuria is caused by Donath \200\223Landsteiner antibody (seen in mumps, measles, chicke n- pox, syphilis) sticking to RBCs in cold, which causes complement-mediated lysis on rewar ming. Cardiac hemolysis Cell trauma in prosthetic aortic valves. It may indicate valve malf unction. Microangiopathic hemolytic anemia (MAHA) Suspect if marked schistocytes and micros pherocytes on the blood smear. Includes hemolytic-uremic syndrome, TTP (p. 260), and pre-ec lampsia. Treat underlying disease; blood and fresh frozen plasma (FFP) transfusions, plasma exchange. Paroxysmal nocturnal hemoglobinuria RBCs are unusually sensitive to complement d ue to loss of complement-inactivating enzymes on their surface, causing pancytopenia, abdom inal pain, or thrombosis (e.g., Budd \200\223Chiari syndrome) and hemolysis. Diagnosis: Tes t for glycosylphosphatidylinositol (GPI)-linked antigen loss (CD55 and CD59). Treatment: An ticoagulation; blood product replacement; consider stem cell transplant, complement inhibit ors. Factors exacerbating hemolysis Infection often leads to increased hemolysis. Also, par voviruses cause ces- sation of marrow erythropoiesis. Parvovirus infection can cause acute decompensation in patients with chronic hemolytic anemias due to reticu- locytopenia associ ated with parvovirus B 19 . y g o o t a m e H l 617 Sickle-cell anemia Sickling disorders are due to the production of abnormal \222 -globins. An amino acid substitution in the \222 -globin gene (Glu \206\222 Val at position 6), re sults in the production of HbS rather than HbA. Hemoglobin S is preva- lent in individuals descended from malaria-endemic regions (sub-Saharan Africa, Southeast Asia, and the Middle East). 10% of African Americans have sickle-cell trait (HbAS), which causes no disability (and may protect from falciparum malaria) except in hypoxia, when veno-occlusive events may occur. Symptomatic sickling occurs in homozygotes and in com- pound heterozygotes with gen es coding other amino acid substitutions with sickling properties(e.g., HBSC and SD disease s). Homozygotes (CC, DD) have asymptomatic mild anemia. Individuals who are homozygous for hemoglobin S have sic kle-cell anemia. Pathogenesis HbS polymerizes when deoxygenated, causing RBCs to sickle. Si ckle cells are fragile, have a shortened red cell survival, and can obstruct small vessel c irculation. Tests Hb \211\210 6 \200\2238 g/dL; reticulocytes 10 \200\22320%: (hemolysis i s variable); \206\221 bilirubin. Hemoglobin electrophoresis : Distinguishes SS, AS, and ot her Hb variants. Blood smear : Polychromasia, nucleated red cells, sickle forms, targets. A im for diagnosis at birth to aid prompt pneumococcal prophylaxis (vaccine [p. 158] and peni cillin V). Signs and symptoms Early: Anemia and jaundice, with painful swelling of hands an d feet (dactylitis); also splenomegaly (rare if >10 yrs, as the spleen infarcts). Youngster s with sickle cell disease may have periods of good health with acute crises (below). Later : Adult complications of sickle-cell anemia include recurrent vaso-occlusive crisis, bone i nfarction and avascular necrosis, osteomyelitis, renal failure, leg ulcers, transfusional i ron overload, pulmonary hypertension, and stroke. Sickle-cell crises These may be from vaso -occlusive crisis, venous thrombosis, hemolysis (rare), red cell aplasia, sequestration, or stroke. Vaso-occlusive crisis: Common, often causing severe pain. Precipitated by cold, de hydration, infection, or physical stress. May mimic an acute abdo- men or pneumonia. CNS si gns: Seizures, focal signs. Transcranial Doppler can indicate risk of impending stroke (pre ventable by transfusion). Priapism may occur; if >24 h, arrange prompt cavernosus-spongiosu m shunting to prevent impotence; priapism also occurs in CML (p. 628). Acute chest syndrome : Defined as fever, infiltrate on chest x-ray, and chest pain. Must be monitored very close ly and red cell exchange arranged if clinical status deteriorates. Aplastic crises: These a re due to parvoviruses, characterized by sudden leth- argy and pallor and absent reticulocy tes. Urgent transfusion is needed. Sequestration/hepatic crises: Spleen and liver enlarge r apidly from trapped RBCs. Signs: Right upper quadrant (RUQ) pain, International Normalized Ratio (INR)/LFT \206\221 , Hb \206\223 \206\223 . Treatment includes red cell exchange tr ansfu- sion. Management of chronic disease \212 \212 Consider hydroxyurea if frequent crises. Chronic blood transfusion to keep HbS level <30% w ill prevent occur- rence of stroke and chest syndrome but there is a high incidence of deve l- opment of antibodies to red cell antigens and iron overload. Marrow transplant can be cu rative, but remains controversial. Splenic infarction leads to hyposplenism, and appropriat e prophylaxis, in terms of antibiotics and immunization, should be adopted. \212 \212 618 Prevention Genetic counseling; prenatal tests. Parental education and prompt medical attent ion for febrile illnesses prevents 90% of childhood deaths from infection, sequestration cr ises. Management of sickle-cell crisis Seek expert help. \212 \212 Give Cross-match blood. CBC, reticulocytes, blood cultures, chest x-ray (CXR). Rehydrate wi th IV fluids and keep warm. Give O Empiric antibiotics for fever after culturing. Measure h ematocrit (HCT), reticulocytes, liver, and spleen size daily. prompt , generous analgesia with opiates. \212 \212 \212 \212 2 by mask if P a O 2 \206\223 . Give blood transfusion if HCT or reticulocytes fall sharply, or if there are CNS or lung co mplications (when the proportion of sickled cells should be reduced to <30%). This may requ ire urgent exchange transfusion. The acute chest syndrome entails pulmonary infiltrates ass ociated with chest pain and fever. It is a serious condition. Incidence: 0.1 episodes/pati ent/ yr. 13% in the landmark Vichinsky study needed ventilation, 11% had CNS symptoms, and 9% of those >20 yrs old died. Prodromal painful crisis oc- cur 2.5 d before any abnormalit ies on CXR in 50% of patients. The chief causes of the infiltrates are fat embolism from bo ne marrow; infection with Chlamydia , Mycoplasma , or virus; and sickled RBCs. Bronchodilat ors have proved to be very effective in 20% having wheezing or obstructive pulmo- nary func tion at presentation. Antibiotics have an important role. Red cell transfusion improves oxy genation; red cell exchange should be emergently arranged if respiratory status deteriorate s. \212 y g o o t a m e H l Thalassemia Hemoglobin (Hb) is a tetramer consisting of 2 - and 2 \222 -globin molecule s. Hb is heterogeneous. Adults have 95% HbA ( 2 \222 2 ) and a little HbA 2 ( 2 2 ). HbF ( 2 2 ) predominates in fetal life and HbA predominates after birth. HbA 2 an d fetal hemoglobins may be relatively elevated in \222 -chain disorders such as \222 -tha lassemia and sickle cell anemia. The thalassemias are a group of disorders resulting from r educed rate of production of one or more globin chains. This leads to an imbalance between - and \222 -chains, precipitation of excess globin chains, and anemia due to ineffectiv e erythropoiesis and hemolysis. They are common in a band stretching from the Mediterranean to the Far East. The most important are - and \222 -thalassemia, in which there is red uced production of - and \222 -chains, respectively. Since there are two genes for \222 -globin and four for -globin in each individual, there are numerous varieties of ge netic defects associated with thalassemias. It is possible to correlate clinical severity w ith the specific genetic defect to some extent, although many other genetic and acquired fa ctors modify the clinical phenotype. \222 -thalassemia major: This is the homozygous form in which very few \222 -chains are formed, and it results in a severe anemia presenting in the first year, often as failure to thrive. Death results in 1 yr without transfusion. If adequate transfusion is given, development is normal but symptoms of iron overload appear a fter 10 yrs as endocrine failure, liver disease, and cardiac toxicity. Death usually occurs at 20 \200\22330 yrs due to cardiac siderosis if long-term iron chelation is not provided. If transfusion is inadequate, there is chronic anemia with reduced growth and skeletal def ormity due to bone marrow hyperplasia (bossing of skull). The smear shows very hypochromic, microcytic cells with target cells and nucleated RBCs. HbF \206\221 , HbA 2 variable, HbA absent. Prevalence of carriers: Cypriot 1:7; southern Italy 1:10; Greek 1:12; Turkish 1:20 ; English 1:100. \222 -Thalassemia minor: This is the heterozygous state, recognized as MC V <75 fL, HbA 2 >3.5%, and mild anemia (9 \200\22311 g/dL) that is usually well toler- ated but may be worsened in pregnancy. -Thalassemia: Four varieties are defined, depending o n the number of de- fective genes. Absence of one or two genes is common in individuals of African descent and is either undetectable or produces a mild microcytic anemia. Hb H di sease: In patients with three gene deletions, HbH ( \222 4 ) is present at 5 \200\22330 % throughout life with moderate hemolytic anemia and splenomegaly. Prognosis: Good. 619 Hb Barts: Infants are stillborn or have neonatal jaundice (hydrops fetalis). They lack all genes. Hb Barts is 4 , and physiologically useless. Obstetric problems are common. Th alassemia intermedia: This is a term used to describe individuals with thalassemia of inter mediate severity who are not transfusion-dependent but have severe anemia. They often have substantial splenic enlargement. Usu- ally the explanation for the mildness of the disease is a residual ability to make \222 -chains. Diagnosis Family history, CBC, MCV, smear, iro n, HbA 2 , HbF, Hb electrophoresis. Treatment \212 \212 Transfusion to keep Hb >9 g/dL Iron-chelating agent, e.g., deferoxamine. *Large doses of as corbic acid also increase iron output but can cause cardiac failure due to sudden, rapid ir on release, Perform splenectomy if hypersplenism exists. Give folate supplements. A histoco mpatible marrow transplant can offer the chance of a cure in childhood . 1 Genetic counseli ng should be offered. It may be particularly useful if abortion is an acceptable option. \212 \212 Bleeding disorders After trauma, three processes control hemorrhage: Vasoconstriction, plat e- let adhesion and aggregation, and fibrin deposition from activation of the coagulation c ascade. Disorders of hemostasis fall into these three groups. The pattern of bleeding is im portant to the diagnostic approach \200\224vascular and platelet disorders lead to prolonge d bleeding from cuts, purpura, and bleeding from mucous membranes, whereas coagulation diso rders produce prolonged bleeding after injury, into joints, muscle, and the GI and GU tract s. Vascular defects Causes may be congenital (Osler \200\223Weber \200\223Rendu) or acquire d (senile purpura, steroids, trauma, pressure, vasculitis, diabetes, connective tissue dise ase, scurvy). Platelet disorders These may be due to quantitative or qualitative platelet d efects. Causes of thrombocytopenia include: \212 Marrow failure states, megaloblastosis, drugs (che- Decreased production: motherapy), liver disease, alcohol Immune thrombocytopenia (ITP), inf ection (EBV), Increased destruction: DIC, drugs, SLE, TTP, hypersplenism, heparin induced t hrombocytopenia, pregnancy, sepsis \212 Qualitative platelet defects are most frequently acquired from drugs (aspi- rin, Plavix ), uremia, myeloproliferative disorders, or, less commonly, can be due to congenital platelet disorders (Glanzmann \200\231s thrombasthenia, Bernard \200\223Soulier). ITP may be acute or chronic. Acute ITP is most commonly observed in children after viral infections, with ra pid onset and spontaneous resolution within a year. Chronic ITP is the rule in adults, with a fluctuating course of bleeding, purpura, or epistaxis. Treatment is indicated when sympt om- atic bleeding occurs or when platelet counts are <20,000/mcL. Treatment options include steroids, splenectomy, high-dose immune globulin, or anti-D (WinRho). Other treatments inc lude rituximab and other immuno- suppressive agents and thrombopoietic mimetics. Platelets transfusions are only transiently successful and should be used if serious bleeding ensues. 620 1 Rund D. Rachmilewitz E. Beta-thalassemia. NE JM 2005; 353 :1135 \200\2231146.