Browse the corpus

Erythrocyte Disorders distribution width (RDW), which correlates with uniformity causes of anemia in adults include absolute or relative eryth- or variability in erythrocyte size. Reticulocytes are young ropoietin deftciency (chronic kidney disease and anemia of erythrocytes identified by stains for ribosomal material that inflammation, respectively), micronutrient deficiency (iron, persist in the cytoplasm for several days following release from cobalamin, folate), acute or chronic blood loss. and bone mar the marrow Physiologically, men have a higher hemoglobin row abnormalities and hematologic malignancy (e.g., myelo concentration than women because of the erythropoietic dysplasia, multiple myeloma). Acquired hemolytic anemia effects of androgens. can result from several potential causes but is less common. In assessing patients with anemia, reviewing the CBC, Anemia in hospitalized patients most often results from acute mean corpuscular volume (MCV), and reticulocyte count blood loss, the anemia of inflammation, or the anemia of along with the peripheral blood smear (PBS) can provide valu kidney disease. able diagnostic information. Defining the anemia as micro Normal pregnancy is associated with a physiologic dilu- cytic, macrocytic, or normocltic as well as by bone marrow tional anemia resulting from an increase in plasma volume response (elevatedvs. normal or suppressed reticulocyte pro that exceeds the increase in ery.throcyte mass, providing oxy duction) can narrow the differential diagnosis. The reticulo gen delivery to the developing fetus at low viscosity. Whether cyte count measures the marrow response to anemia. A anemia is a normal result of the aging process is a subject of normal marrow will produce reticulocytes in response to ane debate, although associated pathophysiologic states and, Iikely, mia or hypoxia. In contrast, patients with vitamin B,r, folate, nutritional deficiencies contributing to anemia are more or iron deficiency or those with marrow diseases such as common in older adults. myelodysplasia or aplastic anemia cannot make adequate Medications can cause anemia. Some suppress normal erythrocytes and have a low reticulocy,te count for their degree erythropoiesis (resulting in a normocytic anemia), others of anemia. The reticulocyte count may be reported as a per interfere with DNA synthesis (antimetabolites, including centage ofthe total erythroqte count or as the absolute num methotrexate and hydroxyurea) resulting in macrocytic ber of reticulocytes. anemia, and others induce hemolytic anemia (penicillin, Erythropoiesis is regulated by several factors, including trimethoprim sulfamethoxazole, methyldopa). erythropoietin production (synthesized in the kidney in An algorithm for the evaluation of anemia can be found in response to hypoxia), micronutrients necessary for hemo Figure 10. In addition to carefully reviewing the patient's globin production (iron, cobalamin, folate), and coordinated medications, the CBC, the reticulocl'te count, and the PBS, a bone marrow cellular function. Several pathophysiologic bone marrow aspirate and biopsy may be helpful in evaluating states affecting these factors can lead to anemia. Common anemia when the cause is unclear or if hematologic

distribution width (RDW), which correlates with uniformity causes of anemia in adults include absolute or relative eryth- or variability in erythrocyte size. Reticulocytes are young ropoietin deftciency (chronic kidney disease and anemia of erythrocytes identified by stains for ribosomal material that inflammation, respectively), micronutrient deficiency (iron, persist in the cytoplasm for several days following release from cobalamin, folate), acute or chronic blood loss. and bone mar the marrow Physiologically, men have a higher hemoglobin row abnormalities and hematologic malignancy (e.g., myelo concentration than women because of the erythropoietic dysplasia, multiple myeloma). Acquired hemolytic anemia effects of androgens. can result from several potential causes but is less common. In assessing patients with anemia, reviewing the CBC, Anemia in hospitalized patients most often results from acute mean corpuscular volume (MCV), and reticulocyte count blood loss, the anemia of inflammation, or the anemia of along with the peripheral blood smear (PBS) can provide valu kidney disease. able diagnostic information. Defining the anemia as micro Normal pregnancy is associated with a physiologic dilu- cytic, macrocytic, or normocltic as well as by bone marrow tional anemia resulting from an increase in plasma volume response (elevatedvs. normal or suppressed reticulocyte pro that exceeds the increase in ery.throcyte mass, providing oxy duction) can narrow the differential diagnosis. The reticulo gen delivery to the developing fetus at low viscosity. Whether cyte count measures the marrow response to anemia. A anemia is a normal result of the aging process is a subject of normal marrow will produce reticulocytes in response to ane debate, although associated pathophysiologic states and, Iikely, mia or hypoxia. In contrast, patients with vitamin B,r, folate, nutritional deficiencies contributing to anemia are more or iron deficiency or those with marrow diseases such as common in older adults. myelodysplasia or aplastic anemia cannot make adequate Medications can cause anemia. Some suppress normal erythrocytes and have a low reticulocy,te count for their degree erythropoiesis (resulting in a normocytic anemia), others of anemia. The reticulocyte count may be reported as a per interfere with DNA synthesis (antimetabolites, including centage ofthe total erythroqte count or as the absolute num methotrexate and hydroxyurea) resulting in macrocytic ber of reticulocytes. anemia, and others induce hemolytic anemia (penicillin, Erythropoiesis is regulated by several factors, including trimethoprim sulfamethoxazole, methyldopa). erythropoietin production (synthesized in the kidney in An algorithm for the evaluation of anemia can be found in response to hypoxia), micronutrients necessary for hemo Figure 10. In addition to carefully reviewing the patient's globin production (iron, cobalamin, folate), and coordinated medications, the CBC, the reticulocl'te count, and the PBS, a bone marrow cellular function. Several pathophysiologic bone marrow aspirate and biopsy may be helpful in evaluating states affecting these factors can lead to anemia. Common anemia when the cause is unclear or if hematologic Patient with anemia

distribution width (RDW), which correlates with uniformity causes of anemia in adults include absolute or relative eryth- or variability in erythrocyte size. Reticulocytes are young ropoietin deftciency (chronic kidney disease and anemia of erythrocytes identified by stains for ribosomal material that inflammation, respectively), micronutrient deficiency (iron, persist in the cytoplasm for several days following release from cobalamin, folate), acute or chronic blood loss. and bone mar the marrow Physiologically, men have a higher hemoglobin row abnormalities and hematologic malignancy (e.g., myelo concentration than women because of the erythropoietic dysplasia, multiple myeloma). Acquired hemolytic anemia effects of androgens. can result from several potential causes but is less common. In assessing patients with anemia, reviewing the CBC, Anemia in hospitalized patients most often results from acute mean corpuscular volume (MCV), and reticulocyte count blood loss, the anemia of inflammation, or the anemia of along with the peripheral blood smear (PBS) can provide valu kidney disease. able diagnostic information. Defining the anemia as micro Normal pregnancy is associated with a physiologic dilu- cytic, macrocytic, or normocltic as well as by bone marrow tional anemia resulting from an increase in plasma volume response (elevatedvs. normal or suppressed reticulocyte pro that exceeds the increase in ery.throcyte mass, providing oxy duction) can narrow the differential diagnosis. The reticulo gen delivery to the developing fetus at low viscosity. Whether cyte count measures the marrow response to anemia. A anemia is a normal result of the aging process is a subject of normal marrow will produce reticulocytes in response to ane debate, although associated pathophysiologic states and, Iikely, mia or hypoxia. In contrast, patients with vitamin B,r, folate, nutritional deficiencies contributing to anemia are more or iron deficiency or those with marrow diseases such as common in older adults. myelodysplasia or aplastic anemia cannot make adequate Medications can cause anemia. Some suppress normal erythrocytes and have a low reticulocy,te count for their degree erythropoiesis (resulting in a normocytic anemia), others of anemia. The reticulocyte count may be reported as a per interfere with DNA synthesis (antimetabolites, including centage ofthe total erythroqte count or as the absolute num methotrexate and hydroxyurea) resulting in macrocytic ber of reticulocytes. anemia, and others induce hemolytic anemia (penicillin, Erythropoiesis is regulated by several factors, including trimethoprim sulfamethoxazole, methyldopa). erythropoietin production (synthesized in the kidney in An algorithm for the evaluation of anemia can be found in response to hypoxia), micronutrients necessary for hemo Figure 10. In addition to carefully reviewing the patient's globin production (iron, cobalamin, folate), and coordinated medications, the CBC, the reticulocl'te count, and the PBS, a bone marrow cellular function. Several pathophysiologic bone marrow aspirate and biopsy may be helpful in evaluating states affecting these factors can lead to anemia. Common anemia when the cause is unclear or if hematologic Patient with anemia High Reticulocyte count Low or normal"

distribution width (RDW), which correlates with uniformity causes of anemia in adults include absolute or relative eryth- or variability in erythrocyte size. Reticulocytes are young ropoietin deftciency (chronic kidney disease and anemia of erythrocytes identified by stains for ribosomal material that inflammation, respectively), micronutrient deficiency (iron, persist in the cytoplasm for several days following release from cobalamin, folate), acute or chronic blood loss. and bone mar the marrow Physiologically, men have a higher hemoglobin row abnormalities and hematologic malignancy (e.g., myelo concentration than women because of the erythropoietic dysplasia, multiple myeloma). Acquired hemolytic anemia effects of androgens. can result from several potential causes but is less common. In assessing patients with anemia, reviewing the CBC, Anemia in hospitalized patients most often results from acute mean corpuscular volume (MCV), and reticulocyte count blood loss, the anemia of inflammation, or the anemia of along with the peripheral blood smear (PBS) can provide valu kidney disease. able diagnostic information. Defining the anemia as micro Normal pregnancy is associated with a physiologic dilu- cytic, macrocytic, or normocltic as well as by bone marrow tional anemia resulting from an increase in plasma volume response (elevatedvs. normal or suppressed reticulocyte pro that exceeds the increase in ery.throcyte mass, providing oxy duction) can narrow the differential diagnosis. The reticulo gen delivery to the developing fetus at low viscosity. Whether cyte count measures the marrow response to anemia. A anemia is a normal result of the aging process is a subject of normal marrow will produce reticulocytes in response to ane debate, although associated pathophysiologic states and, Iikely, mia or hypoxia. In contrast, patients with vitamin B,r, folate, nutritional deficiencies contributing to anemia are more or iron deficiency or those with marrow diseases such as common in older adults. myelodysplasia or aplastic anemia cannot make adequate Medications can cause anemia. Some suppress normal erythrocytes and have a low reticulocy,te count for their degree erythropoiesis (resulting in a normocytic anemia), others of anemia. The reticulocyte count may be reported as a per interfere with DNA synthesis (antimetabolites, including centage ofthe total erythroqte count or as the absolute num methotrexate and hydroxyurea) resulting in macrocytic ber of reticulocytes. anemia, and others induce hemolytic anemia (penicillin, Erythropoiesis is regulated by several factors, including trimethoprim sulfamethoxazole, methyldopa). erythropoietin production (synthesized in the kidney in An algorithm for the evaluation of anemia can be found in response to hypoxia), micronutrients necessary for hemo Figure 10. In addition to carefully reviewing the patient's globin production (iron, cobalamin, folate), and coordinated medications, the CBC, the reticulocl'te count, and the PBS, a bone marrow cellular function. Several pathophysiologic bone marrow aspirate and biopsy may be helpful in evaluating states affecting these factors can lead to anemia. Common anemia when the cause is unclear or if hematologic Patient with anemia High Reticulocyte count Low or normal" yes Bleeding Blood loss Peripheral blood smear no

yes Bleeding Blood loss Peripheral blood smear no Peripheral blood smear Microcyrtic Normocytic Macroqytic lron deficiency Kidney disease Brz deficiency Schistocytes = microangiopathy Thalassemia Anemia of inflammation Folate deficiency Spherocytes = warm antibodies Anemia of Hypothyroidism Myelodysplasia or hereditary spherocytosis inflammation Liver disease Drug toxicity Sickle cells = sickle cell disease Alcohol Bite cells = G6PD deficiency Hypothyroidism Target cells = thalassemia, liver disease Liver disease Erythrocyte inclusions = malaria, babesiosis t I G U R E 1 0. Diagnostic algorithm for the evaluation of a patient with anemia 'Reliculocyte count may be low or normal in some patients with bleeding 0r hemolysis. 20

Erythrocyte Disorders nliligrlrrnc),or stem cell disorders (c.g.. lymphonra. rrrultiple Anemia Due to Erythroqrte r-n1,elonr:r. :rplastic irnentia. m1'ckrdt,splastic sy'ndrome. or acute leukemia) are suspected. Anemiir combinecl r,r,ith other Underproduction or cytolrerrias increascs the likelil.rooci ol a prinrary nlArro\{ Maturation Defects cause. Anemia should never be consiclered a final diagr-rosis: lron Deficiency the r':ruse must be iclentified. Recognizing thc unclerlf ing cause lerds to more fircnsed treirturent be1'ond trlnsfusion to Iron is an essential compolrcllt of the herlogl<.rltitt ntolecttle. Itt acldition to its critical role in oxygen delir,erl: iron is irlso tteccs corrcct the aner-nia. as rvell as therapeutic opportunities linked to the specific cause. srry fbr l)NA synthesis ar.rd ccllular transport. l\4ost of thc irrtn in the bocl1,' is contained in thc en,thr)11: exch millilitcr ol t(EY P0tt{Is packed red bkxxl cells contlins about 1 t-ng ol elemental irott. . Anemia is not il final diagnosisi recognizing its callse Ilcpcidin. tl.rc kcl peptide irloh'ed in iron rcgnlittior.t. i: 1.rrrr leads to focused treatment. duced in the liver and is a ncgiitive regnlirtor of iron absrlrlr . Symptoms from anemia are related to its severity and tion. Hepciclin productior-r inc'reases with int'l:rnrmatior-r uncl hou,rapidly it occurs. as \ ell as to rvhether underlying tlccreases in rcsponse to hy1-loxiir. anemia. lnrl iror-r deficiencli organ or vascular disease is present. I lepcidir.r procluction is regr-rlate cl l.ll sereral protcins. including

nliligrlrrnc),or stem cell disorders (c.g.. lymphonra. rrrultiple Anemia Due to Erythroqrte r-n1,elonr:r. :rplastic irnentia. m1'ckrdt,splastic sy'ndrome. or acute leukemia) are suspected. Anemiir combinecl r,r,ith other Underproduction or cytolrerrias increascs the likelil.rooci ol a prinrary nlArro\{ Maturation Defects cause. Anemia should never be consiclered a final diagr-rosis: lron Deficiency the r':ruse must be iclentified. Recognizing thc unclerlf ing cause lerds to more fircnsed treirturent be1'ond trlnsfusion to Iron is an essential compolrcllt of the herlogl<.rltitt ntolecttle. Itt acldition to its critical role in oxygen delir,erl: iron is irlso tteccs corrcct the aner-nia. as rvell as therapeutic opportunities linked to the specific cause. srry fbr l)NA synthesis ar.rd ccllular transport. l\4ost of thc irrtn in the bocl1,' is contained in thc en,thr)11: exch millilitcr ol t(EY P0tt{Is packed red bkxxl cells contlins about 1 t-ng ol elemental irott. . Anemia is not il final diagnosisi recognizing its callse Ilcpcidin. tl.rc kcl peptide irloh'ed in iron rcgnlittior.t. i: 1.rrrr leads to focused treatment. duced in the liver and is a ncgiitive regnlirtor of iron absrlrlr . Symptoms from anemia are related to its severity and tion. Hepciclin productior-r inc'reases with int'l:rnrmatior-r uncl hou,rapidly it occurs. as \ ell as to rvhether underlying tlccreases in rcsponse to hy1-loxiir. anemia. lnrl iror-r deficiencli organ or vascular disease is present. I lepcidir.r procluction is regr-rlate cl l.ll sereral protcins. including . Anenlia is a normal physiologic response during preg the HFE protcin. hemojuvclin, nlatriptase 2. irncl transfi:rrin reccptor l ancl 2 (Figure ll).'l'hese proteius ilre inlportant irl nancy. hcreditary inrn overload strles cliscussecl later in tl-ris chaptcr.

. Anenlia is a normal physiologic response during preg the HFE protcin. hemojuvclin, nlatriptase 2. irncl transfi:rrin reccptor l ancl 2 (Figure ll).'l'hese proteius ilre inlportant irl nancy. hcreditary inrn overload strles cliscussecl later in tl-ris chaptcr. $ g(} Hepatocyte Hepcidin Transfunin receptor 2 Transfunin receptor I tIGURE 11. Dietaryiron sabsorbed{romthegut(mainlytheduodenum)intothebloodstreamviaenter0cytes(lnset).Ihisprocessisfacilitatedbythedivalentmetal increased iron stores and inflanrmation. 21

Erythrocyte Disorders Iron is derived from the diet as heme-based iron from red v' . &.f,'o .p*, T ? meat, poultry and fish and non-heme-based iron from green leafy vegetables, lentils, beans, and peas. Vegetable iron has a more limited uptake because of phytates and oxalates that -.^_ form complexes with iron and limit bioavailability. The typical adult diet contains 5 mg of iron for every 1000 calories. Only lOnL to 2O"/,, of oral iron is absorbed. In a normal physiologic state, iron absorption is about equal to iron loss. The typical adult man loses approximately 1 mg of iron daily from gastro- fi}r:F;^e" ff#-"'pk intestinal mucosal turnover, whereas the typical woman, dur- ing reproductive years, loses approximately 1.5 mg of iron daily through mucosal turnover and menstrual blood loss. Iron intake, use, and loss exist in a fine balance. Iron defi- ciency may be more prevalent during periods of increased demand (e.g., pregnancy and lactation) and during normal growth and development in infants and children. The prevalence t6,* oesci *.tsos ? is also increased in regions where endemic helminthic infections increase gastrointestinal blood loss. Iron deficiency in adults n{ rarelyoccurs secondaryto decreased oral intakebut is more com- monly secondary to blood loss. For premenopausal women, this 'g$* is typically secondary to menstrual blood loss, but for men or FIGURE 12. Hypochromiaandmicrocytosiswithanisopoikilocytosis(variation postmenopausal women, occult gastrointestinal blood loss in erythrocyte shape and size) in a patient with iron deficiency.

*.tsos ? is also increased in regions where endemic helminthic infections increase gastrointestinal blood loss. Iron deficiency in adults n{ rarelyoccurs secondaryto decreased oral intakebut is more com- monly secondary to blood loss. For premenopausal women, this 'g$* is typically secondary to menstrual blood loss, but for men or FIGURE 12. Hypochromiaandmicrocytosiswithanisopoikilocytosis(variation postmenopausal women, occult gastrointestinal blood loss in erythrocyte shape and size) in a patient with iron deficiency. should be suspected, and bidirectional endoscopy is recom- mended; it is especially important to rule out an occult colonic neoplasm. Iron is absorbed in the proximal small bowel, and Patients with iron deficiency may be asymptomatic or patients with celiac disease, inflammatory bowel disease, or sur- may experience fatigue, lack of a sense of well-being, irritabil gical resection (including bariatric surgery for weight loss) can ity, headache, and decreased exercise tolerance (sometimes experience iron malabsorption. Iron malabsorption may occur in disproportionately more severe than the degree of anemia). the absence ofdiarrhea, steatorrhea, andweightloss. Helicnbocter Pica, the tendency to eat or crave starch, clay, paper, ice. or pylon infection is associated with iron deficiency because of other crunchy foodstuffs, can be seen in patients with severe impaired iron uptake (this mechanism is not well established) iron deficiency. The pathophysiologz of pica remains poorly and increased iron loss from gastritis or peptic ulcer disease. understood. Common causes of iron deflciency anemia are listed in Table Ul. Physical examination findings may be normal in patients with early anemia from iron deficiency. Conjunctival rim pal lor is highly specific for a hemoglobin level less than l0 g/dl TABLE 1 2. Causes of lron Deficiency Anemia (1oo g/L). Symptomatic patients can experience tachycardia, Loss of iron glossitis, and stomatitis. Severe iron deficiency can cause Bleeding spooning of the nails (koilonychia). Menstruation A low MCV, elevated RDW and PBS showing microc)'tosis and anisopoikilocytosis (Figure 12) are virtually diagnostic of Gastrointestinal bleeding (can be microscopic) iron deficiency, especially in premenopausal women; these Other overt or occult blood loss findings may obviate the need for additional laboratory test- Chronic or intermittent intravascular hemolysis ing, provided that a follow up CBC is performed to assess Decreased intake response to iron therapy. A low serum iron level, elevated total Nutritional deficiency iron-binding capacity, low transferrin saturation (less than Decreased absorption 15%; iron/total iron-binding capacity x 100), and serum ferri tin level less than 14 nglmL Oa pglL) confirm the diagnosis of After gastric/d uodenal su rgery iron deficiency. This ferritin value is highly specific (ggU\ Celiac disease but has a low sensitivity (59'1,), resulting in potentially false H e li cob acte r pylori i nfection negative results and missed diagnosis of iron deficiency. To Autoimmune atrophic Aastritis maximize sensitivity, the American Gastroenterological Society lncreased iron requirements recommends a ferritin cut-off value of less than 45 ng/ml (+S 1tg/L) (sensitivity, 85%; specificily, 92%) . Although ferritin Pregnancy, lactation is an acute phase reactant that increases with inflammation, lnfancy, childhood a ferritin level greater than 100 ng/ml (100 pg/L) virtually

should be suspected, and bidirectional endoscopy is recom- mended; it is especially important to rule out an occult colonic neoplasm. Iron is absorbed in the proximal small bowel, and Patients with iron deficiency may be asymptomatic or patients with celiac disease, inflammatory bowel disease, or sur- may experience fatigue, lack of a sense of well-being, irritabil gical resection (including bariatric surgery for weight loss) can ity, headache, and decreased exercise tolerance (sometimes experience iron malabsorption. Iron malabsorption may occur in disproportionately more severe than the degree of anemia). the absence ofdiarrhea, steatorrhea, andweightloss. Helicnbocter Pica, the tendency to eat or crave starch, clay, paper, ice. or pylon infection is associated with iron deficiency because of other crunchy foodstuffs, can be seen in patients with severe impaired iron uptake (this mechanism is not well established) iron deficiency. The pathophysiologz of pica remains poorly and increased iron loss from gastritis or peptic ulcer disease. understood. Common causes of iron deflciency anemia are listed in Table Ul. Physical examination findings may be normal in patients with early anemia from iron deficiency. Conjunctival rim pal lor is highly specific for a hemoglobin level less than l0 g/dl TABLE 1 2. Causes of lron Deficiency Anemia (1oo g/L). Symptomatic patients can experience tachycardia, Loss of iron glossitis, and stomatitis. Severe iron deficiency can cause Bleeding spooning of the nails (koilonychia). Menstruation A low MCV, elevated RDW and PBS showing microc)'tosis and anisopoikilocytosis (Figure 12) are virtually diagnostic of Gastrointestinal bleeding (can be microscopic) iron deficiency, especially in premenopausal women; these Other overt or occult blood loss findings may obviate the need for additional laboratory test- Chronic or intermittent intravascular hemolysis ing, provided that a follow up CBC is performed to assess Decreased intake response to iron therapy. A low serum iron level, elevated total Nutritional deficiency iron-binding capacity, low transferrin saturation (less than Decreased absorption 15%; iron/total iron-binding capacity x 100), and serum ferri tin level less than 14 nglmL Oa pglL) confirm the diagnosis of After gastric/d uodenal su rgery iron deficiency. This ferritin value is highly specific (ggU\ Celiac disease but has a low sensitivity (59'1,), resulting in potentially false H e li cob acte r pylori i nfection negative results and missed diagnosis of iron deficiency. To Autoimmune atrophic Aastritis maximize sensitivity, the American Gastroenterological Society lncreased iron requirements recommends a ferritin cut-off value of less than 45 ng/ml (+S 1tg/L) (sensitivity, 85%; specificily, 92%) . Although ferritin Pregnancy, lactation is an acute phase reactant that increases with inflammation, lnfancy, childhood a ferritin level greater than 100 ng/ml (100 pg/L) virtually 22

Erythrocyte Disorders excludes iron deficiency. Thrombocytosis occurs frequently with malignancy. Because these conditions are considered with iron deficiency caused by blood loss. chronic diseases, these anemic states were often referred to as Iron deficiency is typically managed with oral iron salts. anemiaof chronic d,seose. From a pathophysiologic standpoint, Oral ferrous sulfate is the least expensive preparation, with anemia of inflammation is a more appropriate term because each 325-mg tablet containing 65 mg of elemental iron. Oral these anemias are related to increased hepcidin production in absorption can be increased with supplemental vitamin C; response to inflammatory mediators such as interleukin 6. conversely, medications such as antacids and fiber can reduce Hepcidin causes intemalization and proteolysis of ferroportin in absorption. Frequent dosing (two or three times daily) of oral the enterocyte and macrophage, leading to decreased iron iron can lead to increased hepcidin production, which actually absorption from the gut and decreased iron transfer from mac- reduces iron absorption. For this reason, a single daily or rophages to erythroid precursors. lnflammatory cJ'tokines also every other day dose of oral iron sulfate may be the best blunt the erythropoietin response to anemia. replacement dose. Although oral ferrous fumarate, ferrous In patients with anemia of inflammation, the PBS usually gluconate, and other oral iron salts are available, none has shows a normochromic, normocytic anemia. Over time, proven superior to ferrous sulfate in tolerability, efficacy, or microcytosis can be seen. Normally, these patients have a cost. Delayed-release and slow-release preparations may be hemoglobin level of B to 10 g/dL (80-100 g/L). The reticulocyte better tolerated, but they are more expensive and are associ count is typically low fbr the degree of anemia. The character- ated with reduced iron absorption because they can bypass istic iron study pattern shows an increased serum ferritin the intestinal sites where iron absorption occurs. Although level, a low serum iron level, and a reduced total iron-binding oral iron is typically well tolerated, symptoms can include capacity. Table 13 lists characteristic laboratory features uselul gastrointestinal upset, constipation, and abdominal pain. Iron in distinguishing iron deficiency from anemia of inflamma replacement usually results in reticulocytosis within days. tion. Although seldom necessary a bone marrow biopsy speci Hemoglobin levels typically increase by approximately 1g per men would show adequate stainable iron stores. week. Oral iron replacement typically Iasts 3 to 6 months after Patients with diabetes or heart failure can also have an normalization of hemoglobin to replace iron stores. increase in inflammatory cytokines and related anemia of For patients undergoing dialysis who require large doses of inflammation. In some patients with findings consistent with iron or for patients with celiac disease, inflammatory bowel anemia of inflammation, the inflammatory state is not obvi disease, or those who have undergone resection ofthe stomach ous. These patients do not require extensive evaluation for an or small bowel, oral iron may not be adequate treatment. These occult neoplasm or other source of inflammation. patients tlpically require parenteral iron. Newer parenteral iron Anemia of inflammation seldom requires treatment, and preparations have better safety profiles (less anaphylaxis) and patients should improve after treatment of the underlying inflam bioavailabililz than historically used iron dextran; these include matory condition, if identified. Iron replacement is ineffective, and iron sucrose, ferric gluconate, ferumoxltol, and ferric carboxy blood transfusion is unnecessary in asymptomatic persons. maltose. Data are inadequate to recommend one newer paren Although supplemental erythropoietin can correct anemia in teral agent over another for patients requiring parenteral iron. inllammatory states, it can also lead to hypertension and thrombo- sis and should be used with extreme caution. Patients with cancer XEY POIilTI who experienced anemia with chemotherapy and who received HVC o A low mean corpuscular volume, elevated red cell distri- erythropoietin felt better and had better blood counts, but cancer bution width, and peripheral blood smear showing micro mortality was increased in some studies. Use ol erythropoietin cytosis and anisopoikilorytosis are virhrally diagnostic of during cancer chemotherapy seems best suited for ryrnptomatic iron deficiency, especially in premenopausal women; these patients with a hemoglobin level less than 10 g/dl (100 g/L) who findings may render additional testing unnecessary pro- are undergoing treatment that is not curative in intent. vided the response to iron therapy is monitored. . Men and postmenopausal women with iron deficiency TEY POIilI' should be evaluated for a source ofoccult gastrointestinal o Patients with anemia of inflammation have a hemoglobin blood loss. level of8 to 10 g/dl (80-100 g/L) and a peripheral blood HVC . Iron deficiency is typically treated with oral iron salts, smear showing a normochromic, normorytic anemia optimally dosed once daily or every other day; oral fer associated with an elevated serum ferritin level, low serum rous sulfate is the preferred preparation because of its iron level, and a reduced total iron-binding capacity tolerability, efficacy, and cost. o Blood transfusion is seldom necessary and iron replace- HvC ment is ineffective in the treatment of anemia of inflammation; although supplemental erythropoietin Anemia of tnflammation improves anemia, it is associated with worsening hyper- Anemia has been recognized in conjunction with chronic infec tension, thrombotic complications, and, in patients with tions such as tuberculosis or osteomyelitis; with autoimmune cancer, increased mortality. conditions or rheumatic disease, such as rheumatoid arthritis; or

excludes iron deficiency. Thrombocytosis occurs frequently with malignancy. Because these conditions are considered with iron deficiency caused by blood loss. chronic diseases, these anemic states were often referred to as Iron deficiency is typically managed with oral iron salts. anemiaof chronic d,seose. From a pathophysiologic standpoint, Oral ferrous sulfate is the least expensive preparation, with anemia of inflammation is a more appropriate term because each 325-mg tablet containing 65 mg of elemental iron. Oral these anemias are related to increased hepcidin production in absorption can be increased with supplemental vitamin C; response to inflammatory mediators such as interleukin 6. conversely, medications such as antacids and fiber can reduce Hepcidin causes intemalization and proteolysis of ferroportin in absorption. Frequent dosing (two or three times daily) of oral the enterocyte and macrophage, leading to decreased iron iron can lead to increased hepcidin production, which actually absorption from the gut and decreased iron transfer from mac- reduces iron absorption. For this reason, a single daily or rophages to erythroid precursors. lnflammatory cJ'tokines also every other day dose of oral iron sulfate may be the best blunt the erythropoietin response to anemia. replacement dose. Although oral ferrous fumarate, ferrous In patients with anemia of inflammation, the PBS usually gluconate, and other oral iron salts are available, none has shows a normochromic, normocytic anemia. Over time, proven superior to ferrous sulfate in tolerability, efficacy, or microcytosis can be seen. Normally, these patients have a cost. Delayed-release and slow-release preparations may be hemoglobin level of B to 10 g/dL (80-100 g/L). The reticulocyte better tolerated, but they are more expensive and are associ count is typically low fbr the degree of anemia. The character- ated with reduced iron absorption because they can bypass istic iron study pattern shows an increased serum ferritin the intestinal sites where iron absorption occurs. Although level, a low serum iron level, and a reduced total iron-binding oral iron is typically well tolerated, symptoms can include capacity. Table 13 lists characteristic laboratory features uselul gastrointestinal upset, constipation, and abdominal pain. Iron in distinguishing iron deficiency from anemia of inflamma replacement usually results in reticulocytosis within days. tion. Although seldom necessary a bone marrow biopsy speci Hemoglobin levels typically increase by approximately 1g per men would show adequate stainable iron stores. week. Oral iron replacement typically Iasts 3 to 6 months after Patients with diabetes or heart failure can also have an normalization of hemoglobin to replace iron stores. increase in inflammatory cytokines and related anemia of For patients undergoing dialysis who require large doses of inflammation. In some patients with findings consistent with iron or for patients with celiac disease, inflammatory bowel anemia of inflammation, the inflammatory state is not obvi disease, or those who have undergone resection ofthe stomach ous. These patients do not require extensive evaluation for an or small bowel, oral iron may not be adequate treatment. These occult neoplasm or other source of inflammation. patients tlpically require parenteral iron. Newer parenteral iron Anemia of inflammation seldom requires treatment, and preparations have better safety profiles (less anaphylaxis) and patients should improve after treatment of the underlying inflam bioavailabililz than historically used iron dextran; these include matory condition, if identified. Iron replacement is ineffective, and iron sucrose, ferric gluconate, ferumoxltol, and ferric carboxy blood transfusion is unnecessary in asymptomatic persons. maltose. Data are inadequate to recommend one newer paren Although supplemental erythropoietin can correct anemia in teral agent over another for patients requiring parenteral iron. inllammatory states, it can also lead to hypertension and thrombo- sis and should be used with extreme caution. Patients with cancer XEY POIilTI who experienced anemia with chemotherapy and who received HVC o A low mean corpuscular volume, elevated red cell distri- erythropoietin felt better and had better blood counts, but cancer bution width, and peripheral blood smear showing micro mortality was increased in some studies. Use ol erythropoietin cytosis and anisopoikilorytosis are virhrally diagnostic of during cancer chemotherapy seems best suited for ryrnptomatic iron deficiency, especially in premenopausal women; these patients with a hemoglobin level less than 10 g/dl (100 g/L) who findings may render additional testing unnecessary pro- are undergoing treatment that is not curative in intent. vided the response to iron therapy is monitored. . Men and postmenopausal women with iron deficiency TEY POIilI' should be evaluated for a source ofoccult gastrointestinal o Patients with anemia of inflammation have a hemoglobin blood loss. level of8 to 10 g/dl (80-100 g/L) and a peripheral blood HVC . Iron deficiency is typically treated with oral iron salts, smear showing a normochromic, normorytic anemia optimally dosed once daily or every other day; oral fer associated with an elevated serum ferritin level, low serum rous sulfate is the preferred preparation because of its iron level, and a reduced total iron-binding capacity tolerability, efficacy, and cost. o Blood transfusion is seldom necessary and iron replace- HvC ment is ineffective in the treatment of anemia of inflammation; although supplemental erythropoietin Anemia of tnflammation improves anemia, it is associated with worsening hyper- Anemia has been recognized in conjunction with chronic infec tension, thrombotic complications, and, in patients with tions such as tuberculosis or osteomyelitis; with autoimmune cancer, increased mortality. conditions or rheumatic disease, such as rheumatoid arthritis; or 23

1 1 : Erythrocyte Disorders : TABLE 1 3. Laboratory Characteristics of Anemia of lnflammation, lron Deficiency Anemia, and lron Deficiency Anemia : With lnflammation Finding Type of Anemia Anemia of lnflammation IDA lDAWith lnflammation MCV 72-100tL <80 fL <100 fL Serum iron <60Ug/dL(11pmol/L) <60 pg/dL(11 pmol/L) <60 pg/dL (1 1 pmol/L) TIBC <250 pg/dL (45 pmol/L) >4001t9/dL(72 pmol/L) <4001t9/dL(72 pmol/L) Transferrin saturationu 2"/"-20Y" <15% (usually <10%) <15% Ferritin >35 ng/mL(35 pgll) <1 5 ng/ml (1 5 pgll) <100 ng/mL(100pg/L) Serum soluble transferrin Normal lncreased I ncreased receptor concentration Stainable iron in bone marrow Present Absent Absent I DA = iron deficiency anemia; MCV = mean corpuscular volume; Tl BC = total iron-binding capacity. uSerum iron/transferrin level.

With lnflammation Finding Type of Anemia Anemia of lnflammation IDA lDAWith lnflammation MCV 72-100tL <80 fL <100 fL Serum iron <60Ug/dL(11pmol/L) <60 pg/dL(11 pmol/L) <60 pg/dL (1 1 pmol/L) TIBC <250 pg/dL (45 pmol/L) >4001t9/dL(72 pmol/L) <4001t9/dL(72 pmol/L) Transferrin saturationu 2"/"-20Y" <15% (usually <10%) <15% Ferritin >35 ng/mL(35 pgll) <1 5 ng/ml (1 5 pgll) <100 ng/mL(100pg/L) Serum soluble transferrin Normal lncreased I ncreased receptor concentration Stainable iron in bone marrow Present Absent Absent I DA = iron deficiency anemia; MCV = mean corpuscular volume; Tl BC = total iron-binding capacity. uSerum iron/transferrin level. Thalassemia Hemoglobin is a tetramer containing two cr chains, two F chains (arp), and the iron containing tetrapyrrole heme moi eU/. Production of o and B chains normally occurs in a balanced fashion from genes located on chromosomes 16 and 11, respec tively. Thalassemia is an inherited disorder caused by a muta tion of the o or B gene that results in impaired production of the corresponding c[ or p chains and subsequent imbalance of cx to p chain ratio. Unpaired a or p chains precipitate, resulting in impaired production of hemoglobin and destruction of eryth- roc).te precursors in the marrow (ineffective erythropoiesis). This manifests in variable degrees of anemia, extramedullary hematopoiesis, bone changes, impaired growth, and iron over load. In patients with thalassemia, iron overload-related heart t I G U R E 1 3. Target rells are seen in o- and p{halassemia. Iarget cells have an failure and arrhythmias are the major causes of death. Baseline area of central density surrounded by a periphery of pallor and a final rim of density iron studies should be obtained. and serial measurements of to create a larget-like appearance.The normal erythrocyte is tharacterized by a

Thalassemia Hemoglobin is a tetramer containing two cr chains, two F chains (arp), and the iron containing tetrapyrrole heme moi eU/. Production of o and B chains normally occurs in a balanced fashion from genes located on chromosomes 16 and 11, respec tively. Thalassemia is an inherited disorder caused by a muta tion of the o or B gene that results in impaired production of the corresponding c[ or p chains and subsequent imbalance of cx to p chain ratio. Unpaired a or p chains precipitate, resulting in impaired production of hemoglobin and destruction of eryth- roc).te precursors in the marrow (ineffective erythropoiesis). This manifests in variable degrees of anemia, extramedullary hematopoiesis, bone changes, impaired growth, and iron over load. In patients with thalassemia, iron overload-related heart t I G U R E 1 3. Target rells are seen in o- and p{halassemia. Iarget cells have an failure and arrhythmias are the major causes of death. Baseline area of central density surrounded by a periphery of pallor and a final rim of density iron studies should be obtained. and serial measurements of to create a larget-like appearance.The normal erythrocyte is tharacterized by a serum ferritin can monitor iron stores, particularly if translu central area of pallor surrounded by a thick rim o{ density.

Thalassemia Hemoglobin is a tetramer containing two cr chains, two F chains (arp), and the iron containing tetrapyrrole heme moi eU/. Production of o and B chains normally occurs in a balanced fashion from genes located on chromosomes 16 and 11, respec tively. Thalassemia is an inherited disorder caused by a muta tion of the o or B gene that results in impaired production of the corresponding c[ or p chains and subsequent imbalance of cx to p chain ratio. Unpaired a or p chains precipitate, resulting in impaired production of hemoglobin and destruction of eryth- roc).te precursors in the marrow (ineffective erythropoiesis). This manifests in variable degrees of anemia, extramedullary hematopoiesis, bone changes, impaired growth, and iron over load. In patients with thalassemia, iron overload-related heart t I G U R E 1 3. Target rells are seen in o- and p{halassemia. Iarget cells have an failure and arrhythmias are the major causes of death. Baseline area of central density surrounded by a periphery of pallor and a final rim of density iron studies should be obtained. and serial measurements of to create a larget-like appearance.The normal erythrocyte is tharacterized by a serum ferritin can monitor iron stores, particularly if translu central area of pallor surrounded by a thick rim o{ density. sion requirements increase. A hemoglobinopathy most com monly results from a mutation in the B globin gene, Ieading to increased lactate dehydrogenase, increased unconjugated bili- an altered sequence or structure of the p chain (Hgb S. Hgb C) rubin, and decreased haptoglobin levels. and can be coinherited with thalassemia. The worldwide incidence of p thalassemia is 1'1, to 5'l,1 the incidence of cr{halassemia cr thalassemia is even higher. Thalassemia is common in The normal human genome contains four copies of the African and Mediterranean countries. the Middle East. and a globin gene (two copies on each chromosome 16) leading to Southeast Asia. Homozygous thalassemia manifests at an early several genotypes of a-thalassemia. Patients with a single age, whereas heterozygous disease may have minimal or no o gene mutation (o /cxo) are silent carriers and are healthy. A symptoms, leading to a diagnosis later in life. two gene mutation results in o thalassemia trait (cr /o , more In patients with thalassemia, the PBS typically shows common among Black patients; or oo/--, more common microcytosis, nucleated erythrocltes, and target cells (Figure 13). among Asian patients) characterized by a hemoglobin level ol Unlike other underproduction anemias, patients with hetero approximately 10 g/dL (100 g/L) with microcytosis. Diagnosis zygous thalassemia typically have a preserved or even an is usually achieved by excluding other causes of hypochromic increased erythrocy.te count associated with a decreased MCV. microcytic anemiai hemoglobin electrophoresis results are Although patients with iron deficiency typically have consid normal. Select reference laboratories can establish the diagno erable variation in cell shape and size (anisopoikilocytosis), sis through direct sequencing of the globin genes. Patients leading to elevation in RDW the microcytic cells in thalas with a three gene mutation (a-/--) have more severe anemia semia are more uniform. and the RDW is normal. Because of and make a tetramer of p globin called hemoglobin H that can ineffective erythropoiesis. thalassemia can be associated with be identified on electrophoresis.

sion requirements increase. A hemoglobinopathy most com monly results from a mutation in the B globin gene, Ieading to increased lactate dehydrogenase, increased unconjugated bili- an altered sequence or structure of the p chain (Hgb S. Hgb C) rubin, and decreased haptoglobin levels. and can be coinherited with thalassemia. The worldwide incidence of p thalassemia is 1'1, to 5'l,1 the incidence of cr{halassemia cr thalassemia is even higher. Thalassemia is common in The normal human genome contains four copies of the African and Mediterranean countries. the Middle East. and a globin gene (two copies on each chromosome 16) leading to Southeast Asia. Homozygous thalassemia manifests at an early several genotypes of a-thalassemia. Patients with a single age, whereas heterozygous disease may have minimal or no o gene mutation (o /cxo) are silent carriers and are healthy. A symptoms, leading to a diagnosis later in life. two gene mutation results in o thalassemia trait (cr /o , more In patients with thalassemia, the PBS typically shows common among Black patients; or oo/--, more common microcytosis, nucleated erythrocltes, and target cells (Figure 13). among Asian patients) characterized by a hemoglobin level ol Unlike other underproduction anemias, patients with hetero approximately 10 g/dL (100 g/L) with microcytosis. Diagnosis zygous thalassemia typically have a preserved or even an is usually achieved by excluding other causes of hypochromic increased erythrocy.te count associated with a decreased MCV. microcytic anemiai hemoglobin electrophoresis results are Although patients with iron deficiency typically have consid normal. Select reference laboratories can establish the diagno erable variation in cell shape and size (anisopoikilocytosis), sis through direct sequencing of the globin genes. Patients leading to elevation in RDW the microcytic cells in thalas with a three gene mutation (a-/--) have more severe anemia semia are more uniform. and the RDW is normal. Because of and make a tetramer of p globin called hemoglobin H that can ineffective erythropoiesis. thalassemia can be associated with be identified on electrophoresis. 24

Erythrocyte Disorders Patients with cr-thalassemia trait should receive supple - \-rry \t I mental iblate and genetic counseling before starting a family. Patients with hemoglobin H disease typically have hemo *& & (T & & globin concentrations of approximately 7 to B g/dl (70 B0 g/L) and seldom rely on transfusion. Care should be taken to avoid supplemental iron because these patients absorb iron more 6 *..", 1r-. & 1@@ { elficiently and are at increased risk of iron overload and injury to the liver, heart, and other organs. Routine transfusions L t SCr L-' ## should also be avoided. 6I .?# B-Thalassemia More than 250 mutations have been described in the p globin gene resulting in a spectrum of diseases from mild reduction in p chain synthesis (B*-thalassemia) to complete absence of q@ F IG U R E I 4. Echinocytes reflect the presence of an abnormal cell membrane B chain synthesis (p0 thalassemia). As such, the clinical spec- characterized by many small, evenly spaced projections. Also called burr cells, trum of disease in p thalassemia includes p thalassemia echinocytes are often an artifact related to blood storage and have been associated

globin concentrations of approximately 7 to B g/dl (70 B0 g/L) and seldom rely on transfusion. Care should be taken to avoid supplemental iron because these patients absorb iron more 6 *..", 1r-. & 1@@ { elficiently and are at increased risk of iron overload and injury to the liver, heart, and other organs. Routine transfusions L t SCr L-' ## should also be avoided. 6I .?# B-Thalassemia More than 250 mutations have been described in the p globin gene resulting in a spectrum of diseases from mild reduction in p chain synthesis (B*-thalassemia) to complete absence of q@ F IG U R E I 4. Echinocytes reflect the presence of an abnormal cell membrane B chain synthesis (p0 thalassemia). As such, the clinical spec- characterized by many small, evenly spaced projections. Also called burr cells, trum of disease in p thalassemia includes p thalassemia echinocytes are often an artifact related to blood storage and have been associated minor, p thalassemia intermedia, and p thalassemia major. with uremia, hypomagnesemia and hypophosphatemia, and pyruvate kinase deficiency. B Thalassemia minor (trait) is characterized by a microcytic anemia (MCV 60 70 fL) with a hemoglobin level of 10 to 12 g/dl is also associated with increased morbidity and mortality from (100 120 g/L). Unlike cr thalassemia trait, B-thalassemia heart disease and stroke in patients undergoing dialysis. minor produces an abnormal hemoglobin electrophoresis Supplemental use of erythropoiesis stimulating agents (ESAs) with an increase in hemoglobin A, (o262) because of a substitu- can improve anemia in patients with kidney disease. tion of 6 globin for B globin. Hemoglobin F may also be Guidelines recommend that ESAs be withheld in patients with increased depending on the specific mutation. Patients with chronic kidney disease not requiring dialysis who have a p thalassemia intermedia have hemoglobin levels of 7 gldL hemoglobin level greater than 10 g/dl (100 g/L). For patients (7O glL) without relying on transfusion. with chronic kidney disease with a hemoglobin level less than Patients with B thalassemia trait should receive genetic 10 g/dl (100 g/L), ESA treatment should be individualized counseling, and folate supplementation may be helpful if they based on symptoms, speed of hemoglobin decline, and trans- are anemic. As with a-thalassemia, supplemental iron should fusion needs. For patients undergoing dialysis, ESAs should be be avoided. initiated fbr hemogl<-rbin levels less than 10 g/dl (100 g/L). xtY P0ttI Hemoglobin concentrations should not exceed 11.5 g/dl (115 g/L) to avoid adverse efflects, including worsening hyper- HVC o Patients with thalassemia should receive supplemental folate and avoid iron supplementation because they may tension, volume overload, and thrombotic complications. develop iron overload. Because of high iron requirements in patients taking ESAs, parenteral iron is typically used to maintain a serum ferritin Anemia of Kidney Disease level greater than 100 ng/ml (too pg/L) with a transferrin saturation of at least 20'2,. Although more than 95'1, of Because erythropoietin is made in the renal cortex in response patients respond to ESAs, insufficient response can result to anemia and hypoxia, patients with kidney disease can have fiom iron deficiency, fblate deficiency, aluminum toxicity, anemia, with incidence increasing as the glomerular filtration blood loss, or inflammation. Regular monitoring of iron and rate declines.'fhe anemia is typically normochromic and nor ferritin levels is necessary to ensure an appropriate erythro mocytic, and the reticulocyte count is typically low because of poietic response. a relative erythropoietin deficiency. The PBS may show burr cells (echinocytes) (Figure 14) in patients with uremia. XEY POITTS Because kidney disease is also associated with platelet . Patients with anemia of kidney disease who have a HVC defects and gastrointestinal bleeding from ulcer disease or hemoglobin level greater than 10 g/dl (100 g/L) should angiodysplasia, microcytosis in the setting of kidney disease not receive erythropoiesis stimulating agents. should raise the suspicion lor iron deficiency. In some patients, . For patients undergoing dialysis who have confirmed HVC minor elevations in the serum creatinine level can be associ- adequate iron stores, erythropoiesis stimulating agents ated with low erythropoietin levels and anemia. Although it is should be initiated for hemoglobin levels less than important to lirst rule out other causes of anemia, measuring 10 g/dl (100 g/L), but target hemoglobin concentrations the erythropoietin level can be helpf'ul in evaluating anemia in should not exceed 11.5 g/dl (115 g/L) to avoid adverse patients with mild kidney disease. effects, including worsening hypertension, volume Anemia of kidney disease can be associated with fatigue, overload, and thrombotic complications. depression, dyspnea, and decreased exercise tolerance. Anemia

minor, p thalassemia intermedia, and p thalassemia major. with uremia, hypomagnesemia and hypophosphatemia, and pyruvate kinase deficiency. B Thalassemia minor (trait) is characterized by a microcytic anemia (MCV 60 70 fL) with a hemoglobin level of 10 to 12 g/dl is also associated with increased morbidity and mortality from (100 120 g/L). Unlike cr thalassemia trait, B-thalassemia heart disease and stroke in patients undergoing dialysis. minor produces an abnormal hemoglobin electrophoresis Supplemental use of erythropoiesis stimulating agents (ESAs) with an increase in hemoglobin A, (o262) because of a substitu- can improve anemia in patients with kidney disease. tion of 6 globin for B globin. Hemoglobin F may also be Guidelines recommend that ESAs be withheld in patients with increased depending on the specific mutation. Patients with chronic kidney disease not requiring dialysis who have a p thalassemia intermedia have hemoglobin levels of 7 gldL hemoglobin level greater than 10 g/dl (100 g/L). For patients (7O glL) without relying on transfusion. with chronic kidney disease with a hemoglobin level less than Patients with B thalassemia trait should receive genetic 10 g/dl (100 g/L), ESA treatment should be individualized counseling, and folate supplementation may be helpful if they based on symptoms, speed of hemoglobin decline, and trans- are anemic. As with a-thalassemia, supplemental iron should fusion needs. For patients undergoing dialysis, ESAs should be be avoided. initiated fbr hemogl<-rbin levels less than 10 g/dl (100 g/L). xtY P0ttI Hemoglobin concentrations should not exceed 11.5 g/dl (115 g/L) to avoid adverse efflects, including worsening hyper- HVC o Patients with thalassemia should receive supplemental folate and avoid iron supplementation because they may tension, volume overload, and thrombotic complications. develop iron overload. Because of high iron requirements in patients taking ESAs, parenteral iron is typically used to maintain a serum ferritin Anemia of Kidney Disease level greater than 100 ng/ml (too pg/L) with a transferrin saturation of at least 20'2,. Although more than 95'1, of Because erythropoietin is made in the renal cortex in response patients respond to ESAs, insufficient response can result to anemia and hypoxia, patients with kidney disease can have fiom iron deficiency, fblate deficiency, aluminum toxicity, anemia, with incidence increasing as the glomerular filtration blood loss, or inflammation. Regular monitoring of iron and rate declines.'fhe anemia is typically normochromic and nor ferritin levels is necessary to ensure an appropriate erythro mocytic, and the reticulocyte count is typically low because of poietic response. a relative erythropoietin deficiency. The PBS may show burr cells (echinocytes) (Figure 14) in patients with uremia. XEY POITTS Because kidney disease is also associated with platelet . Patients with anemia of kidney disease who have a HVC defects and gastrointestinal bleeding from ulcer disease or hemoglobin level greater than 10 g/dl (100 g/L) should angiodysplasia, microcytosis in the setting of kidney disease not receive erythropoiesis stimulating agents. should raise the suspicion lor iron deficiency. In some patients, . For patients undergoing dialysis who have confirmed HVC minor elevations in the serum creatinine level can be associ- adequate iron stores, erythropoiesis stimulating agents ated with low erythropoietin levels and anemia. Although it is should be initiated for hemoglobin levels less than important to lirst rule out other causes of anemia, measuring 10 g/dl (100 g/L), but target hemoglobin concentrations the erythropoietin level can be helpf'ul in evaluating anemia in should not exceed 11.5 g/dl (115 g/L) to avoid adverse patients with mild kidney disease. effects, including worsening hypertension, volume Anemia of kidney disease can be associated with fatigue, overload, and thrombotic complications. depression, dyspnea, and decreased exercise tolerance. Anemia 25

Erythrocyte Disorders Cobalamin Deficiency Pancltopenia resulting from ineffective hematopoiesis can Cobalamin (vitamin B,r) is necessary for DNA synthesis. also be seen. Other laboratory findings are consistent with Humans cannot synthesize cobalamin but must consume it in intramedullary hemolysis caused by ineffective erythropoie- their diet; it is found in animal meats, shellfish, and dairy prod- sis, including decreased haptoglobin, elevated lactate dehydro ucts. Dietary deficiency is an uncommon cause of cobalamin genase, and indirect hyperbilirubinemia. The reticulocyte deficienry because body stores are typically available for many count is low in patients with cobalamin deficiency. years. Instead, cobalamin deficiency is nearly always a result of The serum vitamin B,, level is approximately 957, sensi- malabsorption. Dietary cobalamin is more available for absorp- tive in diagnosing vitamin B,, deficiency in symptomatic tion in an acid environment and requires binding with intrinsic patients. Levels greater than 300 pglmL (2zt pmol/L) effec- factor to enhance absorption in the terminal ileum. tively exclude vitamin B,, deficiency. Lower levels may not Cobalamin deficiency may be the result of decreased adequately represent tissue vitamin B,, levels; as such, an ele bioavailability, which may result from age-related gastric vated concentration of methylmalonic acid is a more sensitive achlorhydria or the use of proton pump inhibitors, or both. indicator of cobalamin deficienry. Cobalamin malabsorption can also occur in patients with Although supplemental folate can improve the anemia more generalized malabsorptive states such as inflammatory occurring with cobalamin deficiency, folate does not correct bowel disease, pancreatic insufficiency, bacterial overgrowth, or prevent the associated neuropsychiatric complications. An and metformin use. important distinction to make is that folate deficiency leads to Pernicious anemia, characterized by autoimmune gastri- an elevation in homocysteine levels with normal levels of tis and intrinsic factor deficiency, is another cause ofcobala methylmalonic acid, whereas cobalamin deficiency causes min deficiency. Antibodies to parietal cells are found in 90% of increases in both metabolites. patients with pernicious anemia, whereas antibodies to Patients with cobalamin deficiency can be treated with intrinsic factor are detected in about 70'l. ofpatients. Although oral cobalamin (1000-2000 pg/d) regardless ofcause; an ade antibody testing is sometimes used in the diagnosis of perni- quate amount of this dose will be absorbed, even if intrinsic cious anemia, the varied sensitivity and specificity of these factor is lacking or malabsorption is ongoing. Parenteral cobal- tests limits their utility. amin is more expensive and more cumbersome to administer. Patients with cobalamin deficiency can present with Intranasal and oral gel preparations are also available but are weight loss, glossitis, and "lemon-yellow" skin because of pal not clearly superior to tablet preparations. When cobalamin is lor and jaundice resulting from ineffective erythropoiesis. replaced, megaloblastic changes in the marrow improve Cobalamin deficiency can cause neurologic symptoms, includ within hours. Reticulocytosis appears in several days, and the ing loss of vibratory sense, loss of proprioception, spastic hemoglobin level increases by approximately I g per week. ataxia, and other dorsal column symptoms. Psychiatric symp- If the response to cobalamin is inadequate, an alternative toms (megaloblastic mania) can manifest as dementia, hallu diagnosis, such as myelodysplasia, should be considered. cinations, and frank psychosis. Neurologic changes may not be reversible with replacement. In patients with cobalamin deficiency, the PBS shows oval macrocytes and hypersegmented neutrophils (Figure 15). TEI TOITTT o An elevated serum methylmalonic acid level accurately

Cobalamin Deficiency Pancltopenia resulting from ineffective hematopoiesis can Cobalamin (vitamin B,r) is necessary for DNA synthesis. also be seen. Other laboratory findings are consistent with Humans cannot synthesize cobalamin but must consume it in intramedullary hemolysis caused by ineffective erythropoie- their diet; it is found in animal meats, shellfish, and dairy prod- sis, including decreased haptoglobin, elevated lactate dehydro ucts. Dietary deficiency is an uncommon cause of cobalamin genase, and indirect hyperbilirubinemia. The reticulocyte deficienry because body stores are typically available for many count is low in patients with cobalamin deficiency. years. Instead, cobalamin deficiency is nearly always a result of The serum vitamin B,, level is approximately 957, sensi- malabsorption. Dietary cobalamin is more available for absorp- tive in diagnosing vitamin B,, deficiency in symptomatic tion in an acid environment and requires binding with intrinsic patients. Levels greater than 300 pglmL (2zt pmol/L) effec- factor to enhance absorption in the terminal ileum. tively exclude vitamin B,, deficiency. Lower levels may not Cobalamin deficiency may be the result of decreased adequately represent tissue vitamin B,, levels; as such, an ele bioavailability, which may result from age-related gastric vated concentration of methylmalonic acid is a more sensitive achlorhydria or the use of proton pump inhibitors, or both. indicator of cobalamin deficienry. Cobalamin malabsorption can also occur in patients with Although supplemental folate can improve the anemia more generalized malabsorptive states such as inflammatory occurring with cobalamin deficiency, folate does not correct bowel disease, pancreatic insufficiency, bacterial overgrowth, or prevent the associated neuropsychiatric complications. An and metformin use. important distinction to make is that folate deficiency leads to Pernicious anemia, characterized by autoimmune gastri- an elevation in homocysteine levels with normal levels of tis and intrinsic factor deficiency, is another cause ofcobala methylmalonic acid, whereas cobalamin deficiency causes min deficiency. Antibodies to parietal cells are found in 90% of increases in both metabolites. patients with pernicious anemia, whereas antibodies to Patients with cobalamin deficiency can be treated with intrinsic factor are detected in about 70'l. ofpatients. Although oral cobalamin (1000-2000 pg/d) regardless ofcause; an ade antibody testing is sometimes used in the diagnosis of perni- quate amount of this dose will be absorbed, even if intrinsic cious anemia, the varied sensitivity and specificity of these factor is lacking or malabsorption is ongoing. Parenteral cobal- tests limits their utility. amin is more expensive and more cumbersome to administer. Patients with cobalamin deficiency can present with Intranasal and oral gel preparations are also available but are weight loss, glossitis, and "lemon-yellow" skin because of pal not clearly superior to tablet preparations. When cobalamin is lor and jaundice resulting from ineffective erythropoiesis. replaced, megaloblastic changes in the marrow improve Cobalamin deficiency can cause neurologic symptoms, includ within hours. Reticulocytosis appears in several days, and the ing loss of vibratory sense, loss of proprioception, spastic hemoglobin level increases by approximately I g per week. ataxia, and other dorsal column symptoms. Psychiatric symp- If the response to cobalamin is inadequate, an alternative toms (megaloblastic mania) can manifest as dementia, hallu diagnosis, such as myelodysplasia, should be considered. cinations, and frank psychosis. Neurologic changes may not be reversible with replacement. In patients with cobalamin deficiency, the PBS shows oval macrocytes and hypersegmented neutrophils (Figure 15). TEI TOITTT o An elevated serum methylmalonic acid level accurately ffi ilp' * reflects tissue cobalamin stores and confirms cobalamin deficienry in patients with borderline or low-normal serum cobalamin levels. o Treatment for cobalamin deficiency should be instituted HVC with 1000 to 2000 pgld of oral cobalamin, which is absorbed well even in patients with malabsorption,

ffi ilp' * reflects tissue cobalamin stores and confirms cobalamin deficienry in patients with borderline or low-normal serum cobalamin levels. o Treatment for cobalamin deficiency should be instituted HVC with 1000 to 2000 pgld of oral cobalamin, which is absorbed well even in patients with malabsorption, (3 eliminating the need for parenteral therapy. # .d Folate Deficiency Folate is a common component of most diets in the United States and is found in green leatz vegetables and most fruits. Supplemental folate has been added to grains in the United {t States for many years to prevent birth defects. As such, dietary folate deficiency is uncommon except in patients with malnu- trition. Persons who consume excess alcohol are apt to have FIGU R E 1 5. Hypersegmented polymorphonuclear (PMN) cell in a patient with pernicious anemia. The presence of hypersegmented PMNs becomes significant inadequate dietary intake of folate in addition to impaired when they constitute greater than 570 of PMNs with five or more lobes or 1 % with absorption. Folate is poorly stored, and deficiency can develop six or more lobes. in weeks to months in patients with insufficient folate 26

Erythrocyte Disorders ingestion. Patients with disease states characterized by rapid primarily inherited and extrinsic causes are acquired, but cell turnover, such as pregnancy, hemolysis, or desquamating exceptions exist. Cellular destruction can occur predomi skin disorders (psoriasis), have increased folate requirements. nantly within blood vessels (intravascular hemolysis), by mac Drugs such as triamterene, phenytoin, or methotrexate rophages in the liver or spleen (extravascular hemolysis), or, in can lead to folate deficiency by either inhibiting folate absorp- some cases, both. The typical bone marrow response to exces tion or conversion to its active form. Because folate is absorbed sive erythrocyte destruction is increased erythropoiesis. The in the jejunum, gastric bypass and small bowel diseases such degree of anemia occurring with hemolysis depends on the as celiac disease or inflammatory bowel disease can also rate of destruction and the ability of the marrow to compen inhibit folate absorption. sate. If the rate of breakdown is mild and erythrocyte produc The PBS in fblate deficiency is identical to that ofcobala- tion can be maintained, the hemoglobin level may remain min deficiency. Serum fblate measurement, if very low, helps normal. However, if destruction is brisk or the marrow is establish the diagnosis; however, a normal level maybe unreli- unable to compensate because of concomitant problems that able because a single meal can normalize levels. Although impair erythropoiesis (e.9., nutritional deficiency), anemia folate levels in erythrocytes may better reflect chronic folate occurs. balance, an elevated serum homocysteine level has a sensitiv- Symptoms depend on anemia severity and the underlying ity and specificity of greater than 90'1, in diagnosing folate cause. Patients may report fatigue, dyspnea, lightheadedness, deficiency and is the preferred test when deficiency is sus- jaundice, and darkened urine. Release of free hemoglobin pected despite a normal serum folate level. causes decreased nitrous oxide, and symptoms such as esoph After cobalamin deficiency is excluded, patients with ageal spasm or development of pulmonary hypertension can folate deficiency should receive oral folate, 1to 5 mg/d. occur in patients with chronic hemolysis; splenomegaly accompanies several causes. Laboratory findings include XEY POItITS increased indirect bilirubin, elevated lactate dehydrogenase, o An elevated serum homocysteine level is more than and low haptoglobin levels. Increased plasma free hemoglobin 90% sensitive and specific in diagnosing folate defi- and urobilinogen excretion can also be seen. As long as no ciency and is the preferred test when deficiency is additional conditions that would impair erythropoiesis are suspected despite a normal serum folate level. present, increased reticulocytes and an elevated MCV are r Cobalamin deficiency should be excluded before noted. Morphologic changes in erythrocytes seen on PBS can patients receive folate therapy; although blood abnor- help determine the underlying cause; examples include bite or malities may improve with folate supplementation, the blister cells seen with glucose 6 phosphate dehydrogenase neurologic complications of cobalamin deflcienry would (G6PD) deficiency, schistocytes seen with thrombotic micro continue to progress. angiopathies, and agglutination in cold agglutinin disease.

ingestion. Patients with disease states characterized by rapid primarily inherited and extrinsic causes are acquired, but cell turnover, such as pregnancy, hemolysis, or desquamating exceptions exist. Cellular destruction can occur predomi skin disorders (psoriasis), have increased folate requirements. nantly within blood vessels (intravascular hemolysis), by mac Drugs such as triamterene, phenytoin, or methotrexate rophages in the liver or spleen (extravascular hemolysis), or, in can lead to folate deficiency by either inhibiting folate absorp- some cases, both. The typical bone marrow response to exces tion or conversion to its active form. Because folate is absorbed sive erythrocyte destruction is increased erythropoiesis. The in the jejunum, gastric bypass and small bowel diseases such degree of anemia occurring with hemolysis depends on the as celiac disease or inflammatory bowel disease can also rate of destruction and the ability of the marrow to compen inhibit folate absorption. sate. If the rate of breakdown is mild and erythrocyte produc The PBS in fblate deficiency is identical to that ofcobala- tion can be maintained, the hemoglobin level may remain min deficiency. Serum fblate measurement, if very low, helps normal. However, if destruction is brisk or the marrow is establish the diagnosis; however, a normal level maybe unreli- unable to compensate because of concomitant problems that able because a single meal can normalize levels. Although impair erythropoiesis (e.9., nutritional deficiency), anemia folate levels in erythrocytes may better reflect chronic folate occurs. balance, an elevated serum homocysteine level has a sensitiv- Symptoms depend on anemia severity and the underlying ity and specificity of greater than 90'1, in diagnosing folate cause. Patients may report fatigue, dyspnea, lightheadedness, deficiency and is the preferred test when deficiency is sus- jaundice, and darkened urine. Release of free hemoglobin pected despite a normal serum folate level. causes decreased nitrous oxide, and symptoms such as esoph After cobalamin deficiency is excluded, patients with ageal spasm or development of pulmonary hypertension can folate deficiency should receive oral folate, 1to 5 mg/d. occur in patients with chronic hemolysis; splenomegaly accompanies several causes. Laboratory findings include XEY POItITS increased indirect bilirubin, elevated lactate dehydrogenase, o An elevated serum homocysteine level is more than and low haptoglobin levels. Increased plasma free hemoglobin 90% sensitive and specific in diagnosing folate defi- and urobilinogen excretion can also be seen. As long as no ciency and is the preferred test when deficiency is additional conditions that would impair erythropoiesis are suspected despite a normal serum folate level. present, increased reticulocytes and an elevated MCV are r Cobalamin deficiency should be excluded before noted. Morphologic changes in erythrocytes seen on PBS can patients receive folate therapy; although blood abnor- help determine the underlying cause; examples include bite or malities may improve with folate supplementation, the blister cells seen with glucose 6 phosphate dehydrogenase neurologic complications of cobalamin deflcienry would (G6PD) deficiency, schistocytes seen with thrombotic micro continue to progress. angiopathies, and agglutination in cold agglutinin disease. Hemolytic Anemias Intrinsic Erythrocyte Abnormalities Hemolysis occurs with accelerated erythrocyte destruction. Erythrocyte Membrane Defects It can be caused by intrinsic abnormalities of the erl.throcyte Interaction between the erythrocyte cytoskeleton and lipid or through external factors (Figure 16). Intrinsic causes are bilayer helps determine its size, shape, flexibility, and survival.

Hemolytic Anemias Intrinsic Erythrocyte Abnormalities Hemolysis occurs with accelerated erythrocyte destruction. Erythrocyte Membrane Defects It can be caused by intrinsic abnormalities of the erl.throcyte Interaction between the erythrocyte cytoskeleton and lipid or through external factors (Figure 16). Intrinsic causes are bilayer helps determine its size, shape, flexibility, and survival. Hemolytic Anemia lntrinsic to the Erythrocyte Extrinsic to the Erythrocyte Hemogtobinopathies Membrane defecrs Enzyme defects Other Immune lnfeqtious Thrombotic G6PD Paroxysmal mediated Malaria microangiopathy Sickle cell syndromes Spherocytes Thalassemias Elliptocytes deficiency nocturnal WAIHA Babesiosis Mechanical valve Stomatocytosis hemoglobinuria Cold agglutinin Dtc Spur cell anemia disease TTP Medications Atypical HUS Drugs tIGURE 16. Flowchartdepictingthecategorizationo{hemolyticanemia.DlC=disseminatedintravascularcoagulation; HUS=hemolyticuremicsyndrome; TTP = thrombotic thrombocytopenic purpura; WAIHA = warm autoimmune hemolytic anemia. 27

Erythrocyte Disorders severe symptomatic anemia, previous acute chest syndrome pain is exacerbated by emotional stress, anxiety, insomnia, (ACS), or stroke. Managing SCD requires a multidisciplinary and depression and is perhaps best treated with a holistic approach, considering preventive, acute, and chronic treat- approach emphasizing nonopioid options such as NSAIDS, ment goals (Table 15). relaxation techniques, massage, and biofeedback. A few Painful vaso occlusive events are the hallmark of SCD. patients develop opioid dependence, although the prevalence The frequency and severity of acute painful events varies con is no greater than in a comparable age- and illness matched siderably among patients, the reasons for which remain poorly population. understood. In most communities, a few patients with recur- Additional approved agents for the treatment and preven- rent acute painful events account for most hospitalizations. tion of painful events include L-glutamine and the P-selectin Research has shown that many physicians do not properly inhibitor crizanlizumab. Oral L glutamine, a precursor of assess and manage pain in this population, often leaving pain nicotinamide adenine dinucleotide (NAD), is necessary to undertreated. Painful events are associated with morbidity form the antioxidant NADH. It is believed that sickle cell crises and mortality in patients with SCD, and the number of painful are partially related to oxidant stress. A randomized trial events is inversely related to life expectancy. For these reasons, showed benefit with reduction in the number of sickle cell painful events should be recognized and treated immediately. crises with L-glutamine. Crizanlizumab reduces painful crises Opioids are the preferred analgesic, except for meperidine, by preventing cellular adhesion. which can cause seizures. The pathophysiologr ofchronic pain Pulmonary complications are the primary cause of mor is poorly understood, and it is more difficult to treat. Chronic bidity and mortality in patients with SCD. ACS is a clinical

severe symptomatic anemia, previous acute chest syndrome pain is exacerbated by emotional stress, anxiety, insomnia, (ACS), or stroke. Managing SCD requires a multidisciplinary and depression and is perhaps best treated with a holistic approach, considering preventive, acute, and chronic treat- approach emphasizing nonopioid options such as NSAIDS, ment goals (Table 15). relaxation techniques, massage, and biofeedback. A few Painful vaso occlusive events are the hallmark of SCD. patients develop opioid dependence, although the prevalence The frequency and severity of acute painful events varies con is no greater than in a comparable age- and illness matched siderably among patients, the reasons for which remain poorly population. understood. In most communities, a few patients with recur- Additional approved agents for the treatment and preven- rent acute painful events account for most hospitalizations. tion of painful events include L-glutamine and the P-selectin Research has shown that many physicians do not properly inhibitor crizanlizumab. Oral L glutamine, a precursor of assess and manage pain in this population, often leaving pain nicotinamide adenine dinucleotide (NAD), is necessary to undertreated. Painful events are associated with morbidity form the antioxidant NADH. It is believed that sickle cell crises and mortality in patients with SCD, and the number of painful are partially related to oxidant stress. A randomized trial events is inversely related to life expectancy. For these reasons, showed benefit with reduction in the number of sickle cell painful events should be recognized and treated immediately. crises with L-glutamine. Crizanlizumab reduces painful crises Opioids are the preferred analgesic, except for meperidine, by preventing cellular adhesion. which can cause seizures. The pathophysiologr ofchronic pain Pulmonary complications are the primary cause of mor is poorly understood, and it is more difficult to treat. Chronic bidity and mortality in patients with SCD. ACS is a clinical TABLE 15. Common Complications and Treatments in Adults With Sickle Cell Disease Complications Treatment Vaso-occlusive pain episode Acute: rest, relaxation, warmth, NSA|Ds, oral and lV hydration, opioid analgesia Recurring: HU for more than three episodes/yea1 pain that interferes with daily activities; avoidance of triggers; nonopioid (preferred) or opioid analgesia Acute chest syndrome Acute: oxygen, incentive spirometry, analgesics, empiric antibiotics, lVfluids, simple or erythrocyte exchange transfusions Preventive: HU for recurrent acute chest syndrome, incentive spirometry in hospitalized patients Aplastic crisis Acute: supportive care, blood transfusions as needed lnfection Acute: appropriate and immediate antibiotic management (particular concern for encapsulated bacteria) Prevention: influenza, pneumococcal, and meningococcal vaccines Hyperhemolytic crisis Acute: supportive care, avoid further blood transfusions, immunosuppression might be helpful Preventive: avoid blood transfusions if possible, extended antibody screen can lessen but not eliminate recurrence Multiorgan failure Acute: erythrocyte exchange transfusions lschemic stroke Acute: eryth rocyte exchan ge tra nsfusions, aspi ri n Preventive: chronic simple transfusions or erythrocyte exchange transfusions (target Hb S <30%-50%) Hepatic crisis Acute: supportive, transfusion or exchange transfusion if anemia is symptomatic Cholelithiasis Acute: if symptomatic, cholecystectomy with preoperative transfusions to hemoglobin of 10 g/dL (1 00 g/L)

TABLE 15. Common Complications and Treatments in Adults With Sickle Cell Disease Complications Treatment Vaso-occlusive pain episode Acute: rest, relaxation, warmth, NSA|Ds, oral and lV hydration, opioid analgesia Recurring: HU for more than three episodes/yea1 pain that interferes with daily activities; avoidance of triggers; nonopioid (preferred) or opioid analgesia Acute chest syndrome Acute: oxygen, incentive spirometry, analgesics, empiric antibiotics, lVfluids, simple or erythrocyte exchange transfusions Preventive: HU for recurrent acute chest syndrome, incentive spirometry in hospitalized patients Aplastic crisis Acute: supportive care, blood transfusions as needed lnfection Acute: appropriate and immediate antibiotic management (particular concern for encapsulated bacteria) Prevention: influenza, pneumococcal, and meningococcal vaccines Hyperhemolytic crisis Acute: supportive care, avoid further blood transfusions, immunosuppression might be helpful Preventive: avoid blood transfusions if possible, extended antibody screen can lessen but not eliminate recurrence Multiorgan failure Acute: erythrocyte exchange transfusions lschemic stroke Acute: eryth rocyte exchan ge tra nsfusions, aspi ri n Preventive: chronic simple transfusions or erythrocyte exchange transfusions (target Hb S <30%-50%) Hepatic crisis Acute: supportive, transfusion or exchange transfusion if anemia is symptomatic Cholelithiasis Acute: if symptomatic, cholecystectomy with preoperative transfusions to hemoglobin of 10 g/dL (1 00 g/L) Chronic kidney disease/ Preventive: blood pressure control to <130/80 mm Hg proteinu ria Secondary preventive: ACE inhibitor or ARB in patients with microalbuminuria Priapism Acute: relaxation, hydration, opioid analgesics, aspiration of blood from corpora cavernosa and irrigation with dilute epinephrine, transfusions, shunt procedure Preventive: oral cr-adrenergic agonists, HU. The role of leuprolide and sildenafil is not clear. Pulmonary hypertension No proven therapy established for prevention or treatment Retinopathy Annual ophthalmologic examination, laser phototherapy for retinopathy Osteope nialosteoporosis Supplementation with calcium and vitamin D, bone mineral density measurements Avascular necrosis Analgesics a nd physica I therapy, a rthroplasty Foot and leg ulcers Acute: early aggressive treatment, debridement, compression Preventive: proper footwear to prevent pressure points . ARB = angiotensin receptor blocker; Hb S = hemoglobin 5; HU = hydroxyurea; lV = intravenous.

Chronic kidney disease/ Preventive: blood pressure control to <130/80 mm Hg proteinu ria Secondary preventive: ACE inhibitor or ARB in patients with microalbuminuria Priapism Acute: relaxation, hydration, opioid analgesics, aspiration of blood from corpora cavernosa and irrigation with dilute epinephrine, transfusions, shunt procedure Preventive: oral cr-adrenergic agonists, HU. The role of leuprolide and sildenafil is not clear. Pulmonary hypertension No proven therapy established for prevention or treatment Retinopathy Annual ophthalmologic examination, laser phototherapy for retinopathy Osteope nialosteoporosis Supplementation with calcium and vitamin D, bone mineral density measurements Avascular necrosis Analgesics a nd physica I therapy, a rthroplasty Foot and leg ulcers Acute: early aggressive treatment, debridement, compression Preventive: proper footwear to prevent pressure points . ARB = angiotensin receptor blocker; Hb S = hemoglobin 5; HU = hydroxyurea; lV = intravenous. 30

Erythrocyte Disorders diagnosis based on the constellation of fever (>38.6 "C Erythrocyte Trons/usions in Sickle Cell Disectse [101.5 "F]), tachypnea, hypoxia, cough, shortness of breath, Transfusion management is complicated. Inappropriate transfu and new pulmonary infiltrate. ACS can be the result of infec sion can lead to alloimmunization, iron overload, and infectious tion, in situ thrombosis, thromboembolism. fat or bone mar complications. Antibody fbrmation can lead to hyperhemolysis, row embolism, or a combination of these factors. patients with a presumed immune response leading to hemolysis of nearly all ACS should receive empiric antibiotics (infection triggers are transfused blood in addition to native blood. Simple transfusions not uncommon) in addition to adequate hydration and sup with PRBCs are used to increase oxygen delivery and should not plemental oxygen as determined by pulse oximetry. Incentive be used for uncomplicated pain crises or to treat chronic anemia. spirometry should be encouraged and adequate analgesia pro Patients undergoing surgical procedures requiring general anes. vided. These patients also require erythrocyte transfusion, thesia should receive PRBC transfusion targeting a hemoglobin either with packed red blood cells (PRBCs) or as exchange level of 10 g/dl (100 g/L) to avoid surgical complications. Monthly transfusion. Pulmonary hypertension also occurs in up to 30,U, transfusions reduce stroke risk in those at risk based on cranial of patients with SCD and is associated with increased mortal- Doppler arterial velocity and reduce recurrent stroke risk. ity. Patients Szpically present with worsening right heart fail Exchange transfusion is often used in the treatment of acute ure. The appropriate management of pulmonary hypertension stroke, complicated ACS, and acute retinal artery occlusion. With in SCD has not been determined. Phosphodiesterase inhibi any transfusion, care should be taken to keep hemoglobin con tors, including sildenafil, have been associated with increased centrations less than 10 g/dl (100 g/L) to avoid problems with painful crises. blood hlperviscosity. Stroke and other central nervous system disease remain t(EY POIXIS major complications of SCD. Approximately 30'[, of patients with Hb SS, Hb SC, or SB* thalassemia can have silent or . Acute painful events should be recognized and treated symptomatic strokes. Monthly transf'usion begun after a stroke immediately, generally with opioid analgesics, in patients can reduce the incidence ofsubsequent stroke by 50'/" but car with sickle cell disease. ries the risk of iron overload necessitating iron chelation. . Patients with sickle cell disease and chronic pain should Hydroxyurea may also help in stroke prevention. In addition to avoid opioids, relying instead on NSAIDs, relaxation thrombotic stroke, patients with SCD can have moyamoya techniques, massage, and biofeedback. disease (irregular perforating vascular networks near occluded . Hydroxyurea decreases pain events, reduces the risk of or stenotic vessels in the region corresponding to lenticulostri acute chest syndrome or stroke, and prolongs survival ate and thalamoperforating arteries) predisposing to cerebral in patients with sickle cell disease; newer options that bleeding in the third and fourth decade of life. Adults with reduce the frequency of acute pain episodes are SCD have lower cognitive function than healthy adults, per L-glutamine and crizanlizumab. haps secondary to silent ischemia or chronic anemia. It is . Erythrocyte transfusions should be used judiciously in unclear whether such cognitive decline can be prevented. sickle cell disease to avoid risks of alloimmunization. Strong recommendations from expert guidelines for the iron overload, and transfusion transmitted infections. treatment of SCD are Iisted in Table 16. r Transfusion in patients with sickle cell disease is indi- TABLE 16, Strong Recommendations from the National cated for symptomatic, worsening anemia; simple or lnstitutes of Health/U.S. Department of Health and Human exchange transfusion is indicated in acute chest syn Services Guidelines for the Management of Sickle Cell Disease drome, stroke, and before surgical procedures to a target Rapid initiation of opioids for vaso-occlusive crisis hemoglobin level of approximately 10 g/dl (100 g/L). Use of incentive spirometry in hospitalized patients

diagnosis based on the constellation of fever (>38.6 "C Erythrocyte Trons/usions in Sickle Cell Disectse [101.5 "F]), tachypnea, hypoxia, cough, shortness of breath, Transfusion management is complicated. Inappropriate transfu and new pulmonary infiltrate. ACS can be the result of infec sion can lead to alloimmunization, iron overload, and infectious tion, in situ thrombosis, thromboembolism. fat or bone mar complications. Antibody fbrmation can lead to hyperhemolysis, row embolism, or a combination of these factors. patients with a presumed immune response leading to hemolysis of nearly all ACS should receive empiric antibiotics (infection triggers are transfused blood in addition to native blood. Simple transfusions not uncommon) in addition to adequate hydration and sup with PRBCs are used to increase oxygen delivery and should not plemental oxygen as determined by pulse oximetry. Incentive be used for uncomplicated pain crises or to treat chronic anemia. spirometry should be encouraged and adequate analgesia pro Patients undergoing surgical procedures requiring general anes. vided. These patients also require erythrocyte transfusion, thesia should receive PRBC transfusion targeting a hemoglobin either with packed red blood cells (PRBCs) or as exchange level of 10 g/dl (100 g/L) to avoid surgical complications. Monthly transfusion. Pulmonary hypertension also occurs in up to 30,U, transfusions reduce stroke risk in those at risk based on cranial of patients with SCD and is associated with increased mortal- Doppler arterial velocity and reduce recurrent stroke risk. ity. Patients Szpically present with worsening right heart fail Exchange transfusion is often used in the treatment of acute ure. The appropriate management of pulmonary hypertension stroke, complicated ACS, and acute retinal artery occlusion. With in SCD has not been determined. Phosphodiesterase inhibi any transfusion, care should be taken to keep hemoglobin con tors, including sildenafil, have been associated with increased centrations less than 10 g/dl (100 g/L) to avoid problems with painful crises. blood hlperviscosity. Stroke and other central nervous system disease remain t(EY POIXIS major complications of SCD. Approximately 30'[, of patients with Hb SS, Hb SC, or SB* thalassemia can have silent or . Acute painful events should be recognized and treated symptomatic strokes. Monthly transf'usion begun after a stroke immediately, generally with opioid analgesics, in patients can reduce the incidence ofsubsequent stroke by 50'/" but car with sickle cell disease. ries the risk of iron overload necessitating iron chelation. . Patients with sickle cell disease and chronic pain should Hydroxyurea may also help in stroke prevention. In addition to avoid opioids, relying instead on NSAIDs, relaxation thrombotic stroke, patients with SCD can have moyamoya techniques, massage, and biofeedback. disease (irregular perforating vascular networks near occluded . Hydroxyurea decreases pain events, reduces the risk of or stenotic vessels in the region corresponding to lenticulostri acute chest syndrome or stroke, and prolongs survival ate and thalamoperforating arteries) predisposing to cerebral in patients with sickle cell disease; newer options that bleeding in the third and fourth decade of life. Adults with reduce the frequency of acute pain episodes are SCD have lower cognitive function than healthy adults, per L-glutamine and crizanlizumab. haps secondary to silent ischemia or chronic anemia. It is . Erythrocyte transfusions should be used judiciously in unclear whether such cognitive decline can be prevented. sickle cell disease to avoid risks of alloimmunization. Strong recommendations from expert guidelines for the iron overload, and transfusion transmitted infections. treatment of SCD are Iisted in Table 16. r Transfusion in patients with sickle cell disease is indi- TABLE 16, Strong Recommendations from the National cated for symptomatic, worsening anemia; simple or lnstitutes of Health/U.S. Department of Health and Human exchange transfusion is indicated in acute chest syn Services Guidelines for the Management of Sickle Cell Disease drome, stroke, and before surgical procedures to a target Rapid initiation of opioids for vaso-occlusive crisis hemoglobin level of approximately 10 g/dl (100 g/L). Use of incentive spirometry in hospitalized patients Use of analgesics and physical therapy for treatment of Other Hemoglobinopathies avascular necrosis More than 1000 mutations have been identified in the o or Use of ACE inhibitors in patients with microalbuminuria B globin gene, including hemoglobin C, hemoglobin D, and hemoglobin E. Most of these are only clinically relevant if coin Regular ophthalmologic examinations and referral for laser photocoagulation for retinopathy herited with Hb S. Use of echocardiographyto evaluate signs of pulmonary hypertension Paroxysmal Nocturnal Hemoglobinuria Hydroxyurea for patients with more than three vaso-occlusive Paroxysmal noctumal hemoglobinuria (PNH) is an acquired, crises per year, for those with pain or chronic anemia intrinsic erythrocy.te defect arising from somatic mutations in interfering with daily activities, or those with recurrent acute the PIGA gene, resulting in deficiency of glycophosphatidylin<-r chest syndrome sitol anchored proteins on the erythrocfie surface. These pro Preoperative transfusion to serum hemoglobin level of 10 g/dL teins include complement decay accelerating factor, CD55, and (1 00 g/L) {or surgeries requiring general anesthesia the complement inhibitor CD59. Loss of these proteins allows Assess for iron overload and begin oral iron chelation if necessary for abnormal complement deposition, causing intravascular

Use of analgesics and physical therapy for treatment of Other Hemoglobinopathies avascular necrosis More than 1000 mutations have been identified in the o or Use of ACE inhibitors in patients with microalbuminuria B globin gene, including hemoglobin C, hemoglobin D, and hemoglobin E. Most of these are only clinically relevant if coin Regular ophthalmologic examinations and referral for laser photocoagulation for retinopathy herited with Hb S. Use of echocardiographyto evaluate signs of pulmonary hypertension Paroxysmal Nocturnal Hemoglobinuria Hydroxyurea for patients with more than three vaso-occlusive Paroxysmal noctumal hemoglobinuria (PNH) is an acquired, crises per year, for those with pain or chronic anemia intrinsic erythrocy.te defect arising from somatic mutations in interfering with daily activities, or those with recurrent acute the PIGA gene, resulting in deficiency of glycophosphatidylin<-r chest syndrome sitol anchored proteins on the erythrocfie surface. These pro Preoperative transfusion to serum hemoglobin level of 10 g/dL teins include complement decay accelerating factor, CD55, and (1 00 g/L) {or surgeries requiring general anesthesia the complement inhibitor CD59. Loss of these proteins allows Assess for iron overload and begin oral iron chelation if necessary for abnormal complement deposition, causing intravascular 31

Erythrocyte Disorders hemolysis. Patients are also at risk for venous and arterial complement (C3). or both on the erythrocyte surface' thrombosis, although the mechanism is unclear. PNH can Characteristics of immune mediated hemolysis are shown in be isolated, or associated with other bone marrow diseases, Table 17. Drugs can also cause immune-mediated hemolysis including myelodysplastic syndrome and aplastic anemia. Flow through different mechanisms. cytometry demonstrates loss of CD55 and CD59 to confirm the diagnosis. Eculizumab and ravulizumab are monoclonal Werm Autoimmune HemolYtic Anemia antibodies that bind C5 and inhibit activation of the terminal In WAIHA, pathogenic lgG antibodies recognize Rh llpe anti- complement cascade. They have been shown to decrease gens on the erythrocyte surf'ace. These antibodies may or may hemolysis and reduce thrombotic risk in PNH. Patients should not fix complement. IgG-coated erythrocytes can be com receive meningococcal vaccination before their use because of pletely phagocytized by macrophages, mainly in the spleen an increased risk of Neisserio inf'ections. through the Fc receptor. and cleared from the circulation. Partial phagocytosis of the erythrclcyte surface area results in rEY POII'T spherocytes seen on PBS. Although WAIHA can be a primary . Eculizumab and ravulizumab decrease hemolysis and disorder, it can also occur secondary to other conditions (see reduce thrombotic risk in patients with paroxysmal Table 17). nocturnal hemoglobi nuria. Treatment involves addressing symptomatic anemia and decreasing antibody production to alleviate erythrocyte Extrinsic Erythrocyte Abnormalities destruction. Patients who are asymptomatic and without sig- Immune-Mediated Hemolysis nificant cardiovascular afl'ects from anemia do not require Immune mediated hemolysis is characterized by antibody transfusion. However, transfusion may be required for those binding to erlthroc)'tes causing complement and phagocyte with severe anemia, symptoms, or significant comorbidities. mediated destruction. The broad classifications for autoim- The autoantibody obscures detection of alloantibodies, compli mune hemolytic anemia are related to the optimal temperature cating identification of serocompatible donors. Additionally, the at which the antibodies bind to erythrocytes. Warm antibodies, transfused blood will also be subject to hemolysis, shortening typically lgG, bind at body temperature (37 'C [98.6 'F]) and the duration of benefit. Glucocorticoids are first line treatment comprise most autoimmune hemolytic anemia. Cold autoanti- aimed at eliminating antibody production, with an estimated bodies, also termed cold agglutinins (usually IgM) bind opti- two thirds of adults responding to treatment. Rituximab is also mally at temperatures less than 37 "C (98.6 "F), but they can be effective. Nearly 70'l. of patients respond to splenectomy, which active at body temperature as well. Warm autoimmune hemo is reserved for those who do not respond to, or do not tolerate, lytic anemia (WAIHA) and cold agglutinin disease can be pri glucocorticoids or other immunosuppressive therapies. mary or idiopathic, or secondary induced by other underlying conditions, including infections, rheumatologic processes, or Cold Agglutinin Disease malignancies, especially lymphoproliferative disorders. The In cold agglutinin disease, pathogenic IgM antibodies are laboratory hallmark of immune mediated hemolysis is a posi- directed against erythrocyte glycoprotein antigens (l or i anti- tive direct antiglobulin (Coombs) test result that detects IgG, gen). The potential for clinical implications depends on the

hemolysis. Patients are also at risk for venous and arterial complement (C3). or both on the erythrocyte surface' thrombosis, although the mechanism is unclear. PNH can Characteristics of immune mediated hemolysis are shown in be isolated, or associated with other bone marrow diseases, Table 17. Drugs can also cause immune-mediated hemolysis including myelodysplastic syndrome and aplastic anemia. Flow through different mechanisms. cytometry demonstrates loss of CD55 and CD59 to confirm the diagnosis. Eculizumab and ravulizumab are monoclonal Werm Autoimmune HemolYtic Anemia antibodies that bind C5 and inhibit activation of the terminal In WAIHA, pathogenic lgG antibodies recognize Rh llpe anti- complement cascade. They have been shown to decrease gens on the erythrocyte surf'ace. These antibodies may or may hemolysis and reduce thrombotic risk in PNH. Patients should not fix complement. IgG-coated erythrocytes can be com receive meningococcal vaccination before their use because of pletely phagocytized by macrophages, mainly in the spleen an increased risk of Neisserio inf'ections. through the Fc receptor. and cleared from the circulation. Partial phagocytosis of the erythrclcyte surface area results in rEY POII'T spherocytes seen on PBS. Although WAIHA can be a primary . Eculizumab and ravulizumab decrease hemolysis and disorder, it can also occur secondary to other conditions (see reduce thrombotic risk in patients with paroxysmal Table 17). nocturnal hemoglobi nuria. Treatment involves addressing symptomatic anemia and decreasing antibody production to alleviate erythrocyte Extrinsic Erythrocyte Abnormalities destruction. Patients who are asymptomatic and without sig- Immune-Mediated Hemolysis nificant cardiovascular afl'ects from anemia do not require Immune mediated hemolysis is characterized by antibody transfusion. However, transfusion may be required for those binding to erlthroc)'tes causing complement and phagocyte with severe anemia, symptoms, or significant comorbidities. mediated destruction. The broad classifications for autoim- The autoantibody obscures detection of alloantibodies, compli mune hemolytic anemia are related to the optimal temperature cating identification of serocompatible donors. Additionally, the at which the antibodies bind to erythrocytes. Warm antibodies, transfused blood will also be subject to hemolysis, shortening typically lgG, bind at body temperature (37 'C [98.6 'F]) and the duration of benefit. Glucocorticoids are first line treatment comprise most autoimmune hemolytic anemia. Cold autoanti- aimed at eliminating antibody production, with an estimated bodies, also termed cold agglutinins (usually IgM) bind opti- two thirds of adults responding to treatment. Rituximab is also mally at temperatures less than 37 "C (98.6 "F), but they can be effective. Nearly 70'l. of patients respond to splenectomy, which active at body temperature as well. Warm autoimmune hemo is reserved for those who do not respond to, or do not tolerate, lytic anemia (WAIHA) and cold agglutinin disease can be pri glucocorticoids or other immunosuppressive therapies. mary or idiopathic, or secondary induced by other underlying conditions, including infections, rheumatologic processes, or Cold Agglutinin Disease malignancies, especially lymphoproliferative disorders. The In cold agglutinin disease, pathogenic IgM antibodies are laboratory hallmark of immune mediated hemolysis is a posi- directed against erythrocyte glycoprotein antigens (l or i anti- tive direct antiglobulin (Coombs) test result that detects IgG, gen). The potential for clinical implications depends on the TABL[ 1 7. Characteristics of Warm Autoimmune Hemolytic Anemia and Cold Agglutinin Disease Characeristic Warm Autoimmune HemolyticAnemia Cold Agglutinin Disease Temperature for optimal antibody 37.0 "C (98.6 "F) <37.0 .C (98.6.F) binding to erythrocytes lmmunoglobulin class lgG lgM TypicalAGT pattern lgG positive, C3 positive or negative lgG negative, C3 positive Peripheral blood smear findings Spherocytes Erythrocyte agglutination Clinical manifestationsa Anemia, fatigue, dyspnea, jaundice, Anemia, fatigue, dyspnea, jaundice, splenomegaly acrocyanosis, splenomegaly Associated conditions Autoimmune, lym phoproliferative disorders lnfectious (Myc o plasm a and Epstein-Barr (chronic lymphocytic leukemia, B-cell non- vi rus), lymphoproliferative disorders (lgM Hodgkin lymphomas), drug-inducedb MGUS, Waldenstrom macroglobulinemia, other B'cell non-Hodgkin lymphomas) Treatment Glucocorticoids, splenectomy, immunosup- Cold avoidance, rituximab, plasmapheresis, pression, treatment of underlying condition treatment of underlying condition AGT = antiglobulin (Coombs)test; MGUS = monoclonal gammopathy of undetermined significance.

TABL[ 1 7. Characteristics of Warm Autoimmune Hemolytic Anemia and Cold Agglutinin Disease Characeristic Warm Autoimmune HemolyticAnemia Cold Agglutinin Disease Temperature for optimal antibody 37.0 "C (98.6 "F) <37.0 .C (98.6.F) binding to erythrocytes lmmunoglobulin class lgG lgM TypicalAGT pattern lgG positive, C3 positive or negative lgG negative, C3 positive Peripheral blood smear findings Spherocytes Erythrocyte agglutination Clinical manifestationsa Anemia, fatigue, dyspnea, jaundice, Anemia, fatigue, dyspnea, jaundice, splenomegaly acrocyanosis, splenomegaly Associated conditions Autoimmune, lym phoproliferative disorders lnfectious (Myc o plasm a and Epstein-Barr (chronic lymphocytic leukemia, B-cell non- vi rus), lymphoproliferative disorders (lgM Hodgkin lymphomas), drug-inducedb MGUS, Waldenstrom macroglobulinemia, other B'cell non-Hodgkin lymphomas) Treatment Glucocorticoids, splenectomy, immunosup- Cold avoidance, rituximab, plasmapheresis, pression, treatment of underlying condition treatment of underlying condition AGT = antiglobulin (Coombs)test; MGUS = monoclonal gammopathy of undetermined significance. 'Manifestations in cold agglutinin disease are worse upon exposure to the cold. Lymphadenopathy in either entity should raise suspicion of a lymphoprolilerative disorder. r'Cephalosporins, penicillins, NSAlDs, isoniazid, procainamide, methyldopa, levodopa.

TABL[ 1 7. Characteristics of Warm Autoimmune Hemolytic Anemia and Cold Agglutinin Disease Characeristic Warm Autoimmune HemolyticAnemia Cold Agglutinin Disease Temperature for optimal antibody 37.0 "C (98.6 "F) <37.0 .C (98.6.F) binding to erythrocytes lmmunoglobulin class lgG lgM TypicalAGT pattern lgG positive, C3 positive or negative lgG negative, C3 positive Peripheral blood smear findings Spherocytes Erythrocyte agglutination Clinical manifestationsa Anemia, fatigue, dyspnea, jaundice, Anemia, fatigue, dyspnea, jaundice, splenomegaly acrocyanosis, splenomegaly Associated conditions Autoimmune, lym phoproliferative disorders lnfectious (Myc o plasm a and Epstein-Barr (chronic lymphocytic leukemia, B-cell non- vi rus), lymphoproliferative disorders (lgM Hodgkin lymphomas), drug-inducedb MGUS, Waldenstrom macroglobulinemia, other B'cell non-Hodgkin lymphomas) Treatment Glucocorticoids, splenectomy, immunosup- Cold avoidance, rituximab, plasmapheresis, pression, treatment of underlying condition treatment of underlying condition AGT = antiglobulin (Coombs)test; MGUS = monoclonal gammopathy of undetermined significance. 'Manifestations in cold agglutinin disease are worse upon exposure to the cold. Lymphadenopathy in either entity should raise suspicion of a lymphoprolilerative disorder. r'Cephalosporins, penicillins, NSAlDs, isoniazid, procainamide, methyldopa, levodopa. 32

Erythrocyte Disorders maximunr temperature at lvhich the antibocly ltincls (thern.rirl process is often refbrred to as nric'nrongiopathic henrolyfic amplitucle) ilnd the abilitl' of thc IgM to fix irncl tctivate conl onentia, although not irll causes (Table 18) are related to isslles plement tl.rat rnediates henroh,sis. A cold ag3lutirlin that onh. ir-r the microcirculatior-r. per se. l.ragnrentecl er)'throc!'tes binds at 0'(l (32 "F) u,ould not lte clinically signilicant. u,hereils (scl.ristocytes) .lrc notcd on the ['}BS (Figure 21). T]re nrecha one that bincls at or close to bo(ly tenlperitturc ntrty have greater nisrn by which crythrocytes becon'rc sheared, leircling to consequences. lf complenrent flxatior-r occllrs, (l:l coated cells her-r-rolysis. varies. Several causes are also associirtccl with are cleared by l-repatic Kuplle r cells and destroyccl in circula th ror-r-rbocytopcn i a.'l'reatment is cli rected toward aclclressing tion. The autoantibod),can spiln en,throcytes lncl crrusc apgln the underlying cluse. tination. lcircling to an elevatecl MC\,' on lallorxtor) testiltg (Figure 20). Rarellt lrarked ;rgqlr-rtination in vivo results ir.r lnfections vascular occlusior-r and orgxll ischemia in severe cirses. lnlections can clirectly cause lysis through production of' Trealnlent is primarily clirccted itt:lvoiddncc ol'colcl expo toxins or through premature removal of erythrocytcs by sure, incluclir-rg rtarming of all irrf r.rsates. Glucocorticoids ancl rracrophages after parasitic invrsion. Clo.stridiunr perlrin splenecton'ry ;tre seldom eflective. Rituximab. combined r,r'ith .qens produces phospholipase C. r,r,l'tich damages the er1-thro fludarabine or bendamllstine. has demonstruterl eflicaq' in c1,te lipid bila1,er. Sepsis fronr clostriclia can caLlse a ltrisk, case series. lift threater-ring intravascular henrolysis that is severe enough to interf'ere with laboratory assirys including biochcruicnl Drug induced Immune llentolytic Anentio anirlyses and cross matching arrcl cirn lead to severe kidney Drugs may crluse immune nrecliirted erythrocytc destructioll injur)'1 Streptococcll and staphylococcitl sepsis hiive rtlso bcen through cliflerent mechanisr.ns, including inducing autoanti rtrsorirtled r,r il lt ltt'tttol\ sis. body iornration or through a hapten or drr:g a(lsorption pro cess. The lrtter occurs when the drug adheres to erythrocyte TABTE 18, Differential Diagnosis of Fragmentation membranc proteins and an lg(i antibocly is clirectcd ag:linst Hemolytic Anemia the drug. I)enicillin and cephalosporins are known to cause Thrombotic th rom bocytopenic purpura hapten nrecliitted hemolytic itnemia. lntravenous inttttunc- Hemolytic uremic syndrome globulin can crllse hen.rolysis througl-r the tr:rnsfer of itntibod Atypical hemolytic uremic syndrome ies that intcract rtith erythrocyte intigens in soue cases. The list ot nrerlicltions knowr-r to ciluse immune llledilrted hemo Disseminated intravascular coagulation

maximunr temperature at lvhich the antibocly ltincls (thern.rirl process is often refbrred to as nric'nrongiopathic henrolyfic amplitucle) ilnd the abilitl' of thc IgM to fix irncl tctivate conl onentia, although not irll causes (Table 18) are related to isslles plement tl.rat rnediates henroh,sis. A cold ag3lutirlin that onh. ir-r the microcirculatior-r. per se. l.ragnrentecl er)'throc!'tes binds at 0'(l (32 "F) u,ould not lte clinically signilicant. u,hereils (scl.ristocytes) .lrc notcd on the ['}BS (Figure 21). T]re nrecha one that bincls at or close to bo(ly tenlperitturc ntrty have greater nisrn by which crythrocytes becon'rc sheared, leircling to consequences. lf complenrent flxatior-r occllrs, (l:l coated cells her-r-rolysis. varies. Several causes are also associirtccl with are cleared by l-repatic Kuplle r cells and destroyccl in circula th ror-r-rbocytopcn i a.'l'reatment is cli rected toward aclclressing tion. The autoantibod),can spiln en,throcytes lncl crrusc apgln the underlying cluse. tination. lcircling to an elevatecl MC\,' on lallorxtor) testiltg (Figure 20). Rarellt lrarked ;rgqlr-rtination in vivo results ir.r lnfections vascular occlusior-r and orgxll ischemia in severe cirses. lnlections can clirectly cause lysis through production of' Trealnlent is primarily clirccted itt:lvoiddncc ol'colcl expo toxins or through premature removal of erythrocytcs by sure, incluclir-rg rtarming of all irrf r.rsates. Glucocorticoids ancl rracrophages after parasitic invrsion. Clo.stridiunr perlrin splenecton'ry ;tre seldom eflective. Rituximab. combined r,r'ith .qens produces phospholipase C. r,r,l'tich damages the er1-thro fludarabine or bendamllstine. has demonstruterl eflicaq' in c1,te lipid bila1,er. Sepsis fronr clostriclia can caLlse a ltrisk, case series. lift threater-ring intravascular henrolysis that is severe enough to interf'ere with laboratory assirys including biochcruicnl Drug induced Immune llentolytic Anentio anirlyses and cross matching arrcl cirn lead to severe kidney Drugs may crluse immune nrecliirted erythrocytc destructioll injur)'1 Streptococcll and staphylococcitl sepsis hiive rtlso bcen through cliflerent mechanisr.ns, including inducing autoanti rtrsorirtled r,r il lt ltt'tttol\ sis. body iornration or through a hapten or drr:g a(lsorption pro cess. The lrtter occurs when the drug adheres to erythrocyte TABTE 18, Differential Diagnosis of Fragmentation membranc proteins and an lg(i antibocly is clirectcd ag:linst Hemolytic Anemia the drug. I)enicillin and cephalosporins are known to cause Thrombotic th rom bocytopenic purpura hapten nrecliitted hemolytic itnemia. lntravenous inttttunc- Hemolytic uremic syndrome globulin can crllse hen.rolysis througl-r the tr:rnsfer of itntibod Atypical hemolytic uremic syndrome ies that intcract rtith erythrocyte intigens in soue cases. The list ot nrerlicltions knowr-r to ciluse immune llledilrted hemo Disseminated intravascular coagulation lytic anenria is extensive, irncl a carelul history ol recent expo Malignant hypertension sures is helptul. Many cascs of clrr-rg mediated atttoimmune Drugs (calcineurin inhibitors, clopidogrel, chemotherapeutics hemolysis are mild and resolvc withir-r dirys ttl several rteeks Ie.g., mitomycin, gemcitabine]) after rernovir.rg tl.re olfencling agent. Foreign mechanical devices (cardiac valve, left ventricular assist device, intra-aortic balloon pump)

lytic anenria is extensive, irncl a carelul history ol recent expo Malignant hypertension sures is helptul. Many cascs of clrr-rg mediated atttoimmune Drugs (calcineurin inhibitors, clopidogrel, chemotherapeutics hemolysis are mild and resolvc withir-r dirys ttl several rteeks Ie.g., mitomycin, gemcitabine]) after rernovir.rg tl.re olfencling agent. Foreign mechanical devices (cardiac valve, left ventricular assist device, intra-aortic balloon pump) Fragmentation Hemolysis Anatomic issues (severe aortic stenosis, large hemangiomas/ Kasabach l\rlerritt syndrome) Hemolysis can arise trom nrcchirnical shearirtg antl destruc HELLP syndrome tion of erythrocytes as they circulate in the vasculature. This Vasculitis 1& ffi HELLP = hemolys s e cvated iver enzymes, low Pidt. ets 0 @ I ],] iji o # o o o T & * $e & I ^ F I G U R E 2 0. Cold agglutinin disease. Notice the erythrocyte agglutination on

o # o o o T & * $e & I ^ F I G U R E 2 0. Cold agglutinin disease. Notice the erythrocyte agglutination on the slide, which can lead to a spuriously high mean corpuscular v0lurle on automated t I G U R E 2 1 . Peripheral blood smear showing schistocytes, or fragmented tou nters. erythrocytes (arrows). 33

lron Overload Syndromes Hemolysis results from parasitic infestation of erythro Patients are often identified at asymptomatic stages cytes from malaria, babesiosis, and bartonellosis (see MKSAP through laboratory evaluation of iron studies. A transferrin 19 Infectious Disease). Plasmodium falciparum is associated saturation greater than 45'1, with an elevated serum ferritin with the most severe hemolysis of the malarial infections and level raises suspicion for HH (Figure 22). Ferritin is an acute has been called blackwater flever because of the associated phase reactant, however, and elevations can be seen with hemoglobinuria. The parasite can be seen on thick Wright acute or chronic inflammatory conditions, infections, and Giemsa stained blood smears. Babesiosis is transmitted by the malignancies. Ixodes tick, and patients without a spleen are more likely to Other patients may present late in the disease course, have symptomatic disease, which can include fever, fatigue, with cirrhosis and cardiomyopathy as major morbidities. Liver and evidence of intravascular hemolysis. A thin blood smear and cardiac damage are largely irreversible. Other findings can shows parasites in the erythrocytes in a characteristic Maltese include small joint arthritis and endocrinopathies. Pituitary cross pattern. Bartonellosis, common in South America, injury leads to androgen insufficiency and excess melatonin causes rapid and severe hemolytic anemia and, if left untreated, excretion, the latter causing skin hyperpigmentation and the can be fatal. In each of these parasitic infections, effective term "bronze diabetes" in persons with diabetes mellitus. treatments produce resolution of the hemolysis with eradica Diagnosis is confirmed through genetic testing and ruling tion of the infection. out secondary causes of elevated serum ferritin. Specialized MRI (MRl T2-) can quantiSr the degree of, iron overload in the liver t(EY P0l1{IS and heart, and generally eliminates the need for organ biopsy. . Treatment of symptomatic warm autoimmune hemo The 2019 American College of Gastroenterologr guideline lytic anemia involves glucocorticoids, rituximab, or recommends treatment in patients who are homozygous for other immunosuppression; splenectomy is also effective C2B2Y with a serum ferritin level greater than 300 ng/ml in nearly 70% of patients. (300 pg/L) in men and >200 ng/ml (200 pg/L) in women o Treatment of cold agglutinin disease is primarily directed along with a transferrin saturation of 45"/,, or greater. Other at avoidance of cold exposure, including warming of all sources recommend observation for serum ferritin levels infusates; symptomatic patients with signiflcant anemia less than 500 ng/ml (SOO pg/L) regardless of genotype. respond to rituximab-based regimens. Symptomatic patients with evidence of end-organ injury and . Hemolysis can result from Clostridioides toxins or other those with a more significantly elevated serum ferritin level intraerythrocy.tic parasitic infections such as malaria, (>1000 ng/ml [1OOO pg/Ll) should undergo aggressive thera- babesiosis, and bartonellosis. peutic phlebotomy. One unit of blood (450-500 mL) contains 200 to 250 mg of iron, and repeated treatments unload paren- chymal iron deposition. Phlebotomy frequency depends on lron Overload Syndromes the individual serum ferritin level, degree of organ involve ment, and hematocrit level. Treatment occurs as often as once PrimarylHereditary or twice weekly initially, tapering to maintain a target serum f'erritin level of 50 to 100 nglml (50-100 pg/L). When patients Hemochromatosis reach this goal, maintenance phlebotomy may be performed Hemochromatosis is tissue damage resulting from abnormal two to six times annually. Ferritin levels should be monitored iron deposition. Hemochromatosis can arise from iron hyper at 3- to 6-month intervals. Avoiding supplemental iron and absorption from hereditary causes or, secondarily, from chronic alcohol is recommended. Patients without hepatic fibrosis or transfusion therapy. cardiomyopathy have a normal life expectancy with regular Mutations in the HFE gene comprise the most prevalent monitoring. First degree relatives of affected patients should form of hereditary hemochromatosis (HH), with a prevalence be screened. Screening for hepatocellular carcinoma is recom of 1 in 250 persons of northern European descent. Increased mended for patients with cirrhosis but is likely unnecessary iron absorption results from reduced hepcidin and increased for those who have stage 3 fibrosis or less on liver biopsy. ferroportin expression on the duodenal enterocytes. The C282Y H63D, and S65C mutations are the three most com- I(EY POITTS mon, and homozygosity for C282Y accounts for 80% to 90,2, of . HFEgene mutations (CzszY H63D, and S65C) are the patients with hemochromatosis who have a genetic mutation. most common cause of hereditary hemochromatosis. Emerging evidence suggests that persons with isolated H63D . Elevated transferrin saturation and serum ferritin level or S65C mutations (without the C282Y mutation) are not at are typical findings on laboratory testing. risk of iron overload injury. Phenotypic penetrance of HFE o Phlebotomy is the mainstay of treatment and is indicated mutations is relatively low, particularly in women. It is esti- in qrmptomatic patients with evidence of end-organ injury mated that up to 30% of persons with HH in the United States and in asymptomatic patients with an elevated serum do not have an HFEgene abnormality, particularly non-White persons. ferritin level.

Hemolysis results from parasitic infestation of erythro Patients are often identified at asymptomatic stages cytes from malaria, babesiosis, and bartonellosis (see MKSAP through laboratory evaluation of iron studies. A transferrin 19 Infectious Disease). Plasmodium falciparum is associated saturation greater than 45'1, with an elevated serum ferritin with the most severe hemolysis of the malarial infections and level raises suspicion for HH (Figure 22). Ferritin is an acute has been called blackwater flever because of the associated phase reactant, however, and elevations can be seen with hemoglobinuria. The parasite can be seen on thick Wright acute or chronic inflammatory conditions, infections, and Giemsa stained blood smears. Babesiosis is transmitted by the malignancies. Ixodes tick, and patients without a spleen are more likely to Other patients may present late in the disease course, have symptomatic disease, which can include fever, fatigue, with cirrhosis and cardiomyopathy as major morbidities. Liver and evidence of intravascular hemolysis. A thin blood smear and cardiac damage are largely irreversible. Other findings can shows parasites in the erythrocytes in a characteristic Maltese include small joint arthritis and endocrinopathies. Pituitary cross pattern. Bartonellosis, common in South America, injury leads to androgen insufficiency and excess melatonin causes rapid and severe hemolytic anemia and, if left untreated, excretion, the latter causing skin hyperpigmentation and the can be fatal. In each of these parasitic infections, effective term "bronze diabetes" in persons with diabetes mellitus. treatments produce resolution of the hemolysis with eradica Diagnosis is confirmed through genetic testing and ruling tion of the infection. out secondary causes of elevated serum ferritin. Specialized MRI (MRl T2-) can quantiSr the degree of, iron overload in the liver t(EY P0l1{IS and heart, and generally eliminates the need for organ biopsy. . Treatment of symptomatic warm autoimmune hemo The 2019 American College of Gastroenterologr guideline lytic anemia involves glucocorticoids, rituximab, or recommends treatment in patients who are homozygous for other immunosuppression; splenectomy is also effective C2B2Y with a serum ferritin level greater than 300 ng/ml in nearly 70% of patients. (300 pg/L) in men and >200 ng/ml (200 pg/L) in women o Treatment of cold agglutinin disease is primarily directed along with a transferrin saturation of 45"/,, or greater. Other at avoidance of cold exposure, including warming of all sources recommend observation for serum ferritin levels infusates; symptomatic patients with signiflcant anemia less than 500 ng/ml (SOO pg/L) regardless of genotype. respond to rituximab-based regimens. Symptomatic patients with evidence of end-organ injury and . Hemolysis can result from Clostridioides toxins or other those with a more significantly elevated serum ferritin level intraerythrocy.tic parasitic infections such as malaria, (>1000 ng/ml [1OOO pg/Ll) should undergo aggressive thera- babesiosis, and bartonellosis. peutic phlebotomy. One unit of blood (450-500 mL) contains 200 to 250 mg of iron, and repeated treatments unload paren- chymal iron deposition. Phlebotomy frequency depends on lron Overload Syndromes the individual serum ferritin level, degree of organ involve ment, and hematocrit level. Treatment occurs as often as once PrimarylHereditary or twice weekly initially, tapering to maintain a target serum f'erritin level of 50 to 100 nglml (50-100 pg/L). When patients Hemochromatosis reach this goal, maintenance phlebotomy may be performed Hemochromatosis is tissue damage resulting from abnormal two to six times annually. Ferritin levels should be monitored iron deposition. Hemochromatosis can arise from iron hyper at 3- to 6-month intervals. Avoiding supplemental iron and absorption from hereditary causes or, secondarily, from chronic alcohol is recommended. Patients without hepatic fibrosis or transfusion therapy. cardiomyopathy have a normal life expectancy with regular Mutations in the HFE gene comprise the most prevalent monitoring. First degree relatives of affected patients should form of hereditary hemochromatosis (HH), with a prevalence be screened. Screening for hepatocellular carcinoma is recom of 1 in 250 persons of northern European descent. Increased mended for patients with cirrhosis but is likely unnecessary iron absorption results from reduced hepcidin and increased for those who have stage 3 fibrosis or less on liver biopsy. ferroportin expression on the duodenal enterocytes. The C282Y H63D, and S65C mutations are the three most com- I(EY POITTS mon, and homozygosity for C282Y accounts for 80% to 90,2, of . HFEgene mutations (CzszY H63D, and S65C) are the patients with hemochromatosis who have a genetic mutation. most common cause of hereditary hemochromatosis. Emerging evidence suggests that persons with isolated H63D . Elevated transferrin saturation and serum ferritin level or S65C mutations (without the C282Y mutation) are not at are typical findings on laboratory testing. risk of iron overload injury. Phenotypic penetrance of HFE o Phlebotomy is the mainstay of treatment and is indicated mutations is relatively low, particularly in women. It is esti- in qrmptomatic patients with evidence of end-organ injury mated that up to 30% of persons with HH in the United States and in asymptomatic patients with an elevated serum do not have an HFEgene abnormality, particularly non-White persons. ferritin level. 34

Platelet Disorders Target population Asymptomatic Adult first-degree Symptomatic ALT/AST >35 U/L relative of HH Step 1 Serum transferrin saturation (TS) and serum fenitin (SF) TS <45olo and TS >45% and/or normal SF elevated SF Step 2 No further evaluation HFE genotype c282Y/C282Y c282Y/H63D homozygote compound heteroyzgote, C282Y heteroyzgote, or non-C282Y

c282Y/C282Y c282Y/H63D homozygote compound heteroyzgote, C282Y heteroyzgote, or non-C282Y SF >1 000 ng/ml (1 000 pgll) SF <1000 ng/mL (1000 trglL) or elevated liver enzymes and normal liver enzymes Evaluate other liver/ hematologic disorders * liver biopsy/MRl Liver biopsy for Step 3 fibrosis staging and Therapeutic Elevated HIC+ to rule out concurrent phlebotomy SF >1 000 nglml liver disease (1 000 rrglL) FIGURE 22.Algorithmregardingthediagnosisandtreatmentof HH.Stepl:lnpatientswithsuspectedHHbasedonsymptoms,elevatedliverenzymes,orlamilyhistory, the sugge(ed initial screening tests should beTS and SF level. Step 2: lfIS <45% and SF is normal, further evaluation is unnecessary. lfTS >45% and SF is elevated, HFE gene testing should be performed. Step 3: All patienr homozygous for C2B2Y should proceed to phlebotomy. lf SF >1000 ng/mL(1000 pg/t), liver biopsy is suggested for fibrosis and hematologic disorders. lfothercauses of iron overload have been ruled out, HIC should be assessed by liver biopsy or MRl. Patients with elevated HIC and SF >1000 ng/mL

FIGURE 22.Algorithmregardingthediagnosisandtreatmentof HH.Stepl:lnpatientswithsuspectedHHbasedonsymptoms,elevatedliverenzymes,orlamilyhistory, the sugge(ed initial screening tests should beTS and SF level. Step 2: lfIS <45% and SF is normal, further evaluation is unnecessary. lfTS >45% and SF is elevated, HFE gene testing should be performed. Step 3: All patienr homozygous for C2B2Y should proceed to phlebotomy. lf SF >1000 ng/mL(1000 pg/t), liver biopsy is suggested for fibrosis and hematologic disorders. lfothercauses of iron overload have been ruled out, HIC should be assessed by liver biopsy or MRl. Patients with elevated HIC and SF >1000 ng/mL concentration; SF = serum ferritin; TS = transferrin saturation.

FIGURE 22.Algorithmregardingthediagnosisandtreatmentof HH.Stepl:lnpatientswithsuspectedHHbasedonsymptoms,elevatedliverenzymes,orlamilyhistory, the sugge(ed initial screening tests should beTS and SF level. Step 2: lfIS <45% and SF is normal, further evaluation is unnecessary. lfTS >45% and SF is elevated, HFE gene testing should be performed. Step 3: All patienr homozygous for C2B2Y should proceed to phlebotomy. lf SF >1000 ng/mL(1000 pg/t), liver biopsy is suggested for fibrosis and hematologic disorders. lfothercauses of iron overload have been ruled out, HIC should be assessed by liver biopsy or MRl. Patients with elevated HIC and SF >1000 ng/mL concentration; SF = serum ferritin; TS = transferrin saturation. Secondary lron Overload hands) and hypertrichosis are characteristic. Patients respond well to phlebotomy. Secondary iron overload can occur in persons requiring chronic transfusions, as in those with hemoglobinopathies I(EY POI]IT (thalassemias, sickle cell disease), bone marrow failure, and r Iron chelation is recommended in most cases of secondary hematologic malignancies (e.g., myelodysplastic syndrome). iron overload because phlebotomy is contraindicated with End-organ involvement in these patients can be similar to that anemia. seen with HH, particularly hepatic deposition. Therapeutic phlebotomy is not recommended because of anemia in these patients. Iron chelation therapy is the main- stay of treatment; iron chelators include parenteral deferox- Platelet Disorders amine or oral alternatives, deferasirox and deferiprone. Secondary iron overload is uncommonly caused by por- Normal Platelet Physiology phyria cutanea tarda, which is associated with acquired Platelets are megakaryocyte fragments circulating in an inac abnormalities in porphyrin metabolism and underlying liver tive state for B to 10 days, with 30'7, sequestered in the spleen disease, especially hepatitis C. Cutaneous blisters (often on the (released in response to stress). Activation is a three-stage

Secondary lron Overload hands) and hypertrichosis are characteristic. Patients respond well to phlebotomy. Secondary iron overload can occur in persons requiring chronic transfusions, as in those with hemoglobinopathies I(EY POI]IT (thalassemias, sickle cell disease), bone marrow failure, and r Iron chelation is recommended in most cases of secondary hematologic malignancies (e.g., myelodysplastic syndrome). iron overload because phlebotomy is contraindicated with End-organ involvement in these patients can be similar to that anemia. seen with HH, particularly hepatic deposition. Therapeutic phlebotomy is not recommended because of anemia in these patients. Iron chelation therapy is the main- stay of treatment; iron chelators include parenteral deferox- Platelet Disorders amine or oral alternatives, deferasirox and deferiprone. Secondary iron overload is uncommonly caused by por- Normal Platelet Physiology phyria cutanea tarda, which is associated with acquired Platelets are megakaryocyte fragments circulating in an inac abnormalities in porphyrin metabolism and underlying liver tive state for B to 10 days, with 30'7, sequestered in the spleen disease, especially hepatitis C. Cutaneous blisters (often on the (released in response to stress). Activation is a three-stage 35

Platelet Disorders process: adherence (mediated by von Willebrand factor Symptoms include nlucocutaneous bleeding (epistaxis, [vWF]), activation with shape change (resulting in the release gum bleeding. menorrhagia, hematuria. melena. or hema of clotting and inflammatory substances). and aggregation. tochezia) and easy bruising. A thorough review of medic:r Platelet aggregation is reversible lollowing fibrinogen binding tions and supplements is requircd. Drug ar.rd alcohol exposure but irreversible after released arachidonic acid is converted must be documented and dietary restrictions noted (vegans into thromboxane Ar. Aspirin irreversibly acetylates and inac may be deficient in vitamin B,r). Related disorders, such as tivates thromboxane Ar, and clopidogrel irreversibly binds to HIV infection, hepatitis C inf'ection, or thyroid diseases must the P2Y12 adenosine diphosphate receptor. blocking platelet be evaluated. activation and aggregation. Intravenous agents such as abcixi- The physical examination nray reveal blood blisters in mab, eptifibatide, and tirofiban inhibit fibrinogen binding. the mouth (wet purpura), petechiae or ecchymoses. or Platelets also provide the phospholipid membrane for the splenomegallr coagulation cascade (see Bleeding Disorders).

process: adherence (mediated by von Willebrand factor Symptoms include nlucocutaneous bleeding (epistaxis, [vWF]), activation with shape change (resulting in the release gum bleeding. menorrhagia, hematuria. melena. or hema of clotting and inflammatory substances). and aggregation. tochezia) and easy bruising. A thorough review of medic:r Platelet aggregation is reversible lollowing fibrinogen binding tions and supplements is requircd. Drug ar.rd alcohol exposure but irreversible after released arachidonic acid is converted must be documented and dietary restrictions noted (vegans into thromboxane Ar. Aspirin irreversibly acetylates and inac may be deficient in vitamin B,r). Related disorders, such as tivates thromboxane Ar, and clopidogrel irreversibly binds to HIV infection, hepatitis C inf'ection, or thyroid diseases must the P2Y12 adenosine diphosphate receptor. blocking platelet be evaluated. activation and aggregation. Intravenous agents such as abcixi- The physical examination nray reveal blood blisters in mab, eptifibatide, and tirofiban inhibit fibrinogen binding. the mouth (wet purpura), petechiae or ecchymoses. or Platelets also provide the phospholipid membrane for the splenomegallr coagulation cascade (see Bleeding Disorders). Th rom boclrtopen ic Disorders Approach to the Patient With Decreased Production Thromboclrtopenia Disorders associated with bone marrow infiltration (myelofi Thrombocltopenia must be evaluatecl according to the platelet brosis. metastatic tumors, granulomatous diseases) can count and the ciinical setting. Platelet counts greater than decrease platelet production, as can nutritional deficier.rcies 100.000/pL (100 x 10ei L) are safb. Counts greater than 50.000rpl (vitamin B,, or folate) or abnormalities in stem cell maturation (50 x 10'/L) do not require treatment and are adequate for surgi (aplastic anemia and myelodysplasia). Other cl.topenias often cal procedures, although 100,000rpl (100 x 10erL) is desirable for accompany the low platelet count. neurosurgery Counts less than 50.000/pL (50 x 10ei L) should be corrected before surgeries with significant bleeding risk, and lncreased Destruction counts less than 10,000/pL (10 x 10')/L) are associated with risk of Non - Immune-Mediated Thrombocytopenia spontaneous bleeding. Concomitant use of drugs that impair Splenomegaly is a common n.redical problem that causes platelet function increase bleeding risk from thrombocy.topenia. thrombocytopenia through increased sequestration without Evaluation begins with a revier,r, ot the peripheral blood actual platelet destruction. The thrombocytopenia is usually smear to confirm the count. Pseuclothrombocytopenia occurs associated with anemia and leukopenia. if patients have antibodies to ethylenediaminetetraacetic acid. Unlike sequestration, nonimntune platelet destruction causing platelets to clump together in vitro (Figure 23). An may be caused by abnormal platelet aggregation occurring in accurate count can be obtained from blood drar.r,n in citrate or the setting of disseminated intravascular coagulation or heparin. Inaccurate machine counts may occur if the platelets microangiopathic hemolytic anemia (MAHA). are exceptionally large (mistaken fbr erythrocytes, which falsely lowers the count) or if erythrocyte fragments (schisto Immune Thrombocytopenic Purpura cytes) are counted as platelets (falsely elevated counts). Immune thrombocytopenic purpura (lTP) is caused by autoantibodies to platelet surface membranes. Diagnosis requires a platelet count of less than 100,000/pL (100 x 10"/L). ITP can be a primary diagnosis or occur secondary to other disorders such as systemic lupus erythematosus. chronic lymphocytic leukemia. HIV hepatitis C. and I lelicobacter pylori infection. Drugs can also induce imntune platelet destruction. * Acute, persistent, and chronic ITP are defined as lasting a t\ . i'!il:'!1., less than 3 months, 3 to 12 months, and more than 12 months. i:'ii respectively. Many patients are asymptomatic until the platelet count decreases to less than 10,000/prL (10 x loe/L). Petechiae and ecchymoses without splenomegaly are nota ble physical signs. Laboratory findings are limited to a low platelet count. Testing for HIV and hepatitis C should be *t!r' perfbrmed. Bone marrow evaluation is not necessarl,unless a I clinical findings suggest an alternate diagnosis. Platelet F IG UR E 2 3. A peripheral blood smear showing platelet clumps suggesting pseudothrombocytopenia. Pseudothrombocytopenia autoantibodl,testing is not recommended because the test is is a laboratory artifact in which platelets drawn int0 an ethylenediaminetetraacetic acid-anticoagulated test neither sensitive nor specific enough to play a major role in tube clump and fail to be counted accurately by the aut0mated counter, resulting establishing the diagnosis, and results do not correlate with in a spuriously low platelet count. clinical outcomes.

Th rom boclrtopen ic Disorders Approach to the Patient With Decreased Production Thromboclrtopenia Disorders associated with bone marrow infiltration (myelofi Thrombocltopenia must be evaluatecl according to the platelet brosis. metastatic tumors, granulomatous diseases) can count and the ciinical setting. Platelet counts greater than decrease platelet production, as can nutritional deficier.rcies 100.000/pL (100 x 10ei L) are safb. Counts greater than 50.000rpl (vitamin B,, or folate) or abnormalities in stem cell maturation (50 x 10'/L) do not require treatment and are adequate for surgi (aplastic anemia and myelodysplasia). Other cl.topenias often cal procedures, although 100,000rpl (100 x 10erL) is desirable for accompany the low platelet count. neurosurgery Counts less than 50.000/pL (50 x 10ei L) should be corrected before surgeries with significant bleeding risk, and lncreased Destruction counts less than 10,000/pL (10 x 10')/L) are associated with risk of Non - Immune-Mediated Thrombocytopenia spontaneous bleeding. Concomitant use of drugs that impair Splenomegaly is a common n.redical problem that causes platelet function increase bleeding risk from thrombocy.topenia. thrombocytopenia through increased sequestration without Evaluation begins with a revier,r, ot the peripheral blood actual platelet destruction. The thrombocytopenia is usually smear to confirm the count. Pseuclothrombocytopenia occurs associated with anemia and leukopenia. if patients have antibodies to ethylenediaminetetraacetic acid. Unlike sequestration, nonimntune platelet destruction causing platelets to clump together in vitro (Figure 23). An may be caused by abnormal platelet aggregation occurring in accurate count can be obtained from blood drar.r,n in citrate or the setting of disseminated intravascular coagulation or heparin. Inaccurate machine counts may occur if the platelets microangiopathic hemolytic anemia (MAHA). are exceptionally large (mistaken fbr erythrocytes, which falsely lowers the count) or if erythrocyte fragments (schisto Immune Thrombocytopenic Purpura cytes) are counted as platelets (falsely elevated counts). Immune thrombocytopenic purpura (lTP) is caused by autoantibodies to platelet surface membranes. Diagnosis requires a platelet count of less than 100,000/pL (100 x 10"/L). ITP can be a primary diagnosis or occur secondary to other disorders such as systemic lupus erythematosus. chronic lymphocytic leukemia. HIV hepatitis C. and I lelicobacter pylori infection. Drugs can also induce imntune platelet destruction. * Acute, persistent, and chronic ITP are defined as lasting a t\ . i'!il:'!1., less than 3 months, 3 to 12 months, and more than 12 months. i:'ii respectively. Many patients are asymptomatic until the platelet count decreases to less than 10,000/prL (10 x loe/L). Petechiae and ecchymoses without splenomegaly are nota ble physical signs. Laboratory findings are limited to a low platelet count. Testing for HIV and hepatitis C should be *t!r' perfbrmed. Bone marrow evaluation is not necessarl,unless a I clinical findings suggest an alternate diagnosis. Platelet F IG UR E 2 3. A peripheral blood smear showing platelet clumps suggesting pseudothrombocytopenia. Pseudothrombocytopenia autoantibodl,testing is not recommended because the test is is a laboratory artifact in which platelets drawn int0 an ethylenediaminetetraacetic acid-anticoagulated test neither sensitive nor specific enough to play a major role in tube clump and fail to be counted accurately by the aut0mated counter, resulting establishing the diagnosis, and results do not correlate with in a spuriously low platelet count. clinical outcomes. 36

Platelet Disorders In adults with newly diagnosed ITP who are asympto- l(lY P0lllTS (oainued) matic or have minor mucocutaneous bleeding and also have a o Treatment for acute immune thrombocytopenic pur- platelet count less than 30,000/pL (30 x 10e/L), treatment with pura is instituted with glucocorticoids or intravenous glucocorticoids is recommended. Asymptomatic patients or immune globulin when patients become symptomatic those with minor mucocutaneous bleeding with a platelet or ifthe platelet count decreases to less than 30,000/pL count greater than 20,000/trrl (20 x 10"/L) may be managed as (30 x 10e/L); asymptomatic patients with higher platelet outpatients. Recommended initial therapy includes a short counts can be managed with careful observation. course (<6 weeks) of prednisone or dexamethasone. The response to intravenous immune globulin is faster and may be indicated in patients with more severe thrombocy.topenia and Heparin-Induced Thrombocytopenia life threatening bleeding. Complications from glucocorticoids Type I heparin induced thrombocytopenia (HIT) refers to a include mood disorders, insomnia. fluid retention, hypergly non immune mediated decrease in platelets occurring cemia, and hypertension. Complications from intravenous within the first few days of exposure to heparin. No interven immune globulin include infusion reactions (headache, chills, tion is needed. Type II HIT is an immune mediated thrombo anaphylaxis), kidney disease, and thrombosis. Patients who cytopenia occurring 5 to l0 days after exposure. lt is caused by relapse or have ITP refractory to these treatments require sec antibodies against platelet factor 4 (complexed to heparin). ond Iine treatments, such as splenectomy, rituximab, and Associated thrombosis, which includes deep venous throm thrombopoietin receptor agonists. bosis, pulmonary embolism, or more unusual acute arterial Thrombopoietin receptor agonists (e.g., daily oral eltrom occlusions, can be life threatening. The risk is highest with bopag or avatrombopag; weekly subcutaneous romiplostim) unfractionated heparin compared with low molecular may be beneficial but must be taken continuously to prevent weight heparin. Most patients with HIT develop platelet relapse. Splenectomy is advised for patients who are unre counts less than 150,000/pl, (150 x 10"/L), but severe throm sponsive to or intolerant of medical management but should bocytopenia is unusual. In patients with high baseline platelet be delayed for 1 year after diagnosis because of the possibility counts, a decrease ofgreater than 50'2, warrants concern. Skin of delayed remission. necrosis at the site of heparin injection or progressive throm Because patients with chronic ITP may be asymptomatic, boembolic events in patients receiving heparin are signs ol treatment decisions must balance the risk of bleeding against possible HIT, even if the platelet count remains normal. The treatment related toxicities. 4T scoring system (Table f9) is useful for estimating the likeli hood of HIT and the need for discontinuing heparin while XEY POIXTS definitive tests are pending. HVC o Antiplatelet antibody testing is neither sensitive nor The enzyme linked immunosorbent assay for platelet specific enough to establish the diagnosis of immune factor 4 antibodies is a very sensitive screening test for HIT (a thrombocytopenic purpura and should not be per- negative test result rules out the diagnosis) but is not specific. formed' (continued) Confirmation requires either the serotonin release assay or the heparin induced platelet aggregation assay (Figure 24).

In adults with newly diagnosed ITP who are asympto- l(lY P0lllTS (oainued) matic or have minor mucocutaneous bleeding and also have a o Treatment for acute immune thrombocytopenic pur- platelet count less than 30,000/pL (30 x 10e/L), treatment with pura is instituted with glucocorticoids or intravenous glucocorticoids is recommended. Asymptomatic patients or immune globulin when patients become symptomatic those with minor mucocutaneous bleeding with a platelet or ifthe platelet count decreases to less than 30,000/pL count greater than 20,000/trrl (20 x 10"/L) may be managed as (30 x 10e/L); asymptomatic patients with higher platelet outpatients. Recommended initial therapy includes a short counts can be managed with careful observation. course (<6 weeks) of prednisone or dexamethasone. The response to intravenous immune globulin is faster and may be indicated in patients with more severe thrombocy.topenia and Heparin-Induced Thrombocytopenia life threatening bleeding. Complications from glucocorticoids Type I heparin induced thrombocytopenia (HIT) refers to a include mood disorders, insomnia. fluid retention, hypergly non immune mediated decrease in platelets occurring cemia, and hypertension. Complications from intravenous within the first few days of exposure to heparin. No interven immune globulin include infusion reactions (headache, chills, tion is needed. Type II HIT is an immune mediated thrombo anaphylaxis), kidney disease, and thrombosis. Patients who cytopenia occurring 5 to l0 days after exposure. lt is caused by relapse or have ITP refractory to these treatments require sec antibodies against platelet factor 4 (complexed to heparin). ond Iine treatments, such as splenectomy, rituximab, and Associated thrombosis, which includes deep venous throm thrombopoietin receptor agonists. bosis, pulmonary embolism, or more unusual acute arterial Thrombopoietin receptor agonists (e.g., daily oral eltrom occlusions, can be life threatening. The risk is highest with bopag or avatrombopag; weekly subcutaneous romiplostim) unfractionated heparin compared with low molecular may be beneficial but must be taken continuously to prevent weight heparin. Most patients with HIT develop platelet relapse. Splenectomy is advised for patients who are unre counts less than 150,000/pl, (150 x 10"/L), but severe throm sponsive to or intolerant of medical management but should bocytopenia is unusual. In patients with high baseline platelet be delayed for 1 year after diagnosis because of the possibility counts, a decrease ofgreater than 50'2, warrants concern. Skin of delayed remission. necrosis at the site of heparin injection or progressive throm Because patients with chronic ITP may be asymptomatic, boembolic events in patients receiving heparin are signs ol treatment decisions must balance the risk of bleeding against possible HIT, even if the platelet count remains normal. The treatment related toxicities. 4T scoring system (Table f9) is useful for estimating the likeli hood of HIT and the need for discontinuing heparin while XEY POIXTS definitive tests are pending. HVC o Antiplatelet antibody testing is neither sensitive nor The enzyme linked immunosorbent assay for platelet specific enough to establish the diagnosis of immune factor 4 antibodies is a very sensitive screening test for HIT (a thrombocytopenic purpura and should not be per- negative test result rules out the diagnosis) but is not specific. formed' (continued) Confirmation requires either the serotonin release assay or the heparin induced platelet aggregation assay (Figure 24). TABLE 19. The 4T Scoring System for Predicting Heparin-lnduced Thrombocytopenia and Thrombosis 4Ts 2 Points 1 Point O Points

In adults with newly diagnosed ITP who are asympto- l(lY P0lllTS (oainued) matic or have minor mucocutaneous bleeding and also have a o Treatment for acute immune thrombocytopenic pur- platelet count less than 30,000/pL (30 x 10e/L), treatment with pura is instituted with glucocorticoids or intravenous glucocorticoids is recommended. Asymptomatic patients or immune globulin when patients become symptomatic those with minor mucocutaneous bleeding with a platelet or ifthe platelet count decreases to less than 30,000/pL count greater than 20,000/trrl (20 x 10"/L) may be managed as (30 x 10e/L); asymptomatic patients with higher platelet outpatients. Recommended initial therapy includes a short counts can be managed with careful observation. course (<6 weeks) of prednisone or dexamethasone. The response to intravenous immune globulin is faster and may be indicated in patients with more severe thrombocy.topenia and Heparin-Induced Thrombocytopenia life threatening bleeding. Complications from glucocorticoids Type I heparin induced thrombocytopenia (HIT) refers to a include mood disorders, insomnia. fluid retention, hypergly non immune mediated decrease in platelets occurring cemia, and hypertension. Complications from intravenous within the first few days of exposure to heparin. No interven immune globulin include infusion reactions (headache, chills, tion is needed. Type II HIT is an immune mediated thrombo anaphylaxis), kidney disease, and thrombosis. Patients who cytopenia occurring 5 to l0 days after exposure. lt is caused by relapse or have ITP refractory to these treatments require sec antibodies against platelet factor 4 (complexed to heparin). ond Iine treatments, such as splenectomy, rituximab, and Associated thrombosis, which includes deep venous throm thrombopoietin receptor agonists. bosis, pulmonary embolism, or more unusual acute arterial Thrombopoietin receptor agonists (e.g., daily oral eltrom occlusions, can be life threatening. The risk is highest with bopag or avatrombopag; weekly subcutaneous romiplostim) unfractionated heparin compared with low molecular may be beneficial but must be taken continuously to prevent weight heparin. Most patients with HIT develop platelet relapse. Splenectomy is advised for patients who are unre counts less than 150,000/pl, (150 x 10"/L), but severe throm sponsive to or intolerant of medical management but should bocytopenia is unusual. In patients with high baseline platelet be delayed for 1 year after diagnosis because of the possibility counts, a decrease ofgreater than 50'2, warrants concern. Skin of delayed remission. necrosis at the site of heparin injection or progressive throm Because patients with chronic ITP may be asymptomatic, boembolic events in patients receiving heparin are signs ol treatment decisions must balance the risk of bleeding against possible HIT, even if the platelet count remains normal. The treatment related toxicities. 4T scoring system (Table f9) is useful for estimating the likeli hood of HIT and the need for discontinuing heparin while XEY POIXTS definitive tests are pending. HVC o Antiplatelet antibody testing is neither sensitive nor The enzyme linked immunosorbent assay for platelet specific enough to establish the diagnosis of immune factor 4 antibodies is a very sensitive screening test for HIT (a thrombocytopenic purpura and should not be per- negative test result rules out the diagnosis) but is not specific. formed' (continued) Confirmation requires either the serotonin release assay or the heparin induced platelet aggregation assay (Figure 24). TABLE 19. The 4T Scoring System for Predicting Heparin-lnduced Thrombocytopenia and Thrombosis 4Ts 2 Points 1 Point O Points Thrombocytopenia Platelet count decrease >50o/" Platelet count decrease 30"/"-50"/" Platelet count decrease <30% or and platelet nadir >20,000/pL or platelet nadir 1 0,000-1 9,000/pL platelet nadir <1 0,000/pL (20 x 1 0elL) (10-19x1Oe/L) (10x 1oell) Timing of platelet Clear onset between days 5-10 or Consistent with platelet count Platelet count decrease <4 days count decrease platelet count decrease <1 day (with decrease between days 5-1 0, but without recent exposure heparin exposure within 30 days) unclear (e.g., missing platelet counts); onset after day 1 0; or decrease <1 day (heparin exposure 30-1 00 days ago)

Thrombocytopenia Platelet count decrease >50o/" Platelet count decrease 30"/"-50"/" Platelet count decrease <30% or and platelet nadir >20,000/pL or platelet nadir 1 0,000-1 9,000/pL platelet nadir <1 0,000/pL (20 x 1 0elL) (10-19x1Oe/L) (10x 1oell) Timing of platelet Clear onset between days 5-10 or Consistent with platelet count Platelet count decrease <4 days count decrease platelet count decrease <1 day (with decrease between days 5-1 0, but without recent exposure heparin exposure within 30 days) unclear (e.g., missing platelet counts); onset after day 1 0; or decrease <1 day (heparin exposure 30-1 00 days ago) Thrombosis or other New thrombosis (confirmed); skin Progressive or recurrent clot; None sequelae necrosis; acute systemic reaction nonnecrotizing (e.9., erythematous) after intravenous unfractionated skin lesions; suspected thrombosis heparin bolus (not proved) Other causes for None apparent Possible Definite thrombocytopen ia High prob,ability: 6 8 points. lntermediate probab,ility: 4 5 points. Low probability:0 3 points. 37