ISSUES IN HEMATOLOGY
| MICROCYTIC ANEMIAS —Richard S. Eisenstaedt, MD, Chairman, Department of Medicine, Abington Memorial Hospital,
Abington, Pennsylvania
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| Iron deficiency: anemia present in >10% of healthy, young women; iron deficiency most common etiology; typical dietary
intake of iron in United States, 10 to 15 mg daily (10%-20% absorbed in gastrointestinal [GI] tract); obligate loss
includes 1 mg per day in GI tract (nonpathologic) and ≈30 mg per month in menstrual blood loss; dietary deficiency unusual
in adults; malabsorption rare in young patients (typically associated with overt disorder of GI tract)
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| Iron deficiency anemia: does not require dietary inadequacy, excessive menstrual bleeding, or uterine pathology;
diagnosis—laboratory testing not necessary, but follow-up needed to ascertain response to empiric iron therapy; fecal
occult blood test acceptable, but invasive procedures (eg, colonoscopy) unnecessary in women of reproductive age
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| Iron therapy: compliance—most common reason for failure; adverse effects include abdominal discomfort and constipation,
especially if iron begun at high dose; absorption—primarily occurs in duodenum; decreases for enteric coated or
delayed-release preparations (increased tolerance likely results from decreased absorption); decreases with presence of
phosphates, phytates, and tannins in some foods; increases with acid environment (ascorbic acid increases absorption;
antacids, H2 blockers, and proton pump inhibitors [PPI] may decrease absorption); dosage—adverse effects related to
amount of elemental iron (depends on formulation and dosage); speaker recommends 1 tablet of iron sulfate daily, until
patient can tolerate higher dose; patient education about potential adverse effects important; other reasons for failure—
large, continuous loss of blood (patient may require parenteral iron); malabsorption (eg, patients with celiac sprue may
have subtle GI manifestations and may present with refractory iron deficiency anemia; appropriate therapy should relieve
GI symptoms and may improve anemia); factors inhibiting erythropoiesis (eg, chronic kidney disease or suppression of
bone marrow); incorrect diagnosis
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| Thalassemia: alpha thalassemia—production of α globin impaired; more common form; no diagnostic laboratory test
(ie, diagnosis of exclusion); beta thalassemia—production of β globin impaired; subtle increases in fetal hemoglobin (Hb)
and Hb A2; quantitative studies diagnostic (specify “thalassemia screen” or “quantitative fetal Hb”); patients often have longstanding
anemia, often without symptoms; management includes avoiding unnecessary iron therapy and genetic counseling
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| Lead intoxication: occupational hazards include exposure to batteries, radiators, and ammunition; reports of leaching
from radiographic film (potential exposure for workers in dental offices); other sources include ingestion of “moonshine”
and exposure to leaded gasoline and lead paint; clinical manifestations—neurologic (central and peripheral) symptoms include
difficulty concentrating and neuropathy; GI symptoms include vague abdominal pain; modest renal insufficiency; hypochromic
microcytic anemia; diagnosis—elevated level of lead in blood
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| Anemia of chronic disease: laboratory features—usually normocytic, but 25% to 35% of cases microcytic or hypochromic;
low iron; total iron-binding capacity (TIBC) typically low (as opposed to iron deficiency anemia); ferritin—
always elevated (important for diagnosis); >100 ng/mL indicates sufficient level of iron; <15 ng/mL indicates iron deficiency;
other clinical features useful for evaluating patients with intermediate levels (empiric iron therapy acceptable in
these patients); iron therapy not effective for patients with anemia of chronic disease; chronic diseases—cancer; chronic
infection; collagen vascular disorders; autoimmune diseases; congestive heart failure; diabetes; mechanism—decreased
production of erythropoietin, mediated by inflammatory cytokines (ie, anemia of chronic inflammation); occasionally,
overt chronic disease not present; condition may occur acutely with acute inflammation; erythropoietin therapy—
benefits seen in patients undergoing chemotherapy for treatment of cancer, patients with HIV infection, and those undergoing
orthopedic procedures (eg, hip replacement) when given perioperatively; benefits of therapy unclear in patients
with other chronic diseases
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| GI pathology: consider in men and in older women who present with classic iron deficiency anemia; additional
studies—colonoscopy recommended, esophagogastroduodenoscopy (EGD) in some cases
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| THROMBOCYTOPENIA —Dr. Eisenstaedt
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| Thrombocytopenia: increased destruction of platelets—in response, bone marrow increases production of platelets;
increased number of megakaryocytes in marrow and megathrombocytes (ie, large new platelets) in peripheral blood; decreased
production of platelets—decreased number of megakaryocytes in marrow; normal, small platelets; corresponding
decreases in other lines of blood cells (eg, erythrocytes, leukocytes)
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| Decreased production of platelets: injury to bone marrow—overall function of bone marrow suppressed; sources
of injury include toxins (eg, radiation, chemicals, drugs, alcohol), infections (eg, tuberculosis, HIV), metastatic cancer,
and disorders involving stem cells (eg, aplastic anemia, acute leukemia, and dysmyelopoietic syndrome); folate (vitamin
B12) deficiency—classically, causes megaloblastic anemia and broad suppression of hematopoiesis; may lead to leukopenia
and thrombocytopenia
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| Heparin-induced thrombocytopenia (HIT): occurs in 1% to 3% of patients after exposure to heparin (more common
with unfractionated than with low molecular weight heparin); typically begins 4 to 10 days after exposure (but early
and delayed onset may occur); causes modest thrombocytopenia, rarely resulting in bleeding; diagnosis—laboratory assays
useful, but history and clinical suspicion key; management—discontinuation of heparin; dramatic hypercoagulable
state increases risk for embolism and arterial occlusion and requires immediate anticoagulation with lepirudin or danaparoid;
consultation with hematologist recommended
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| Sepsis: thrombocytopenia most commonly associated with gram-negative bacteremia, but may occur with other bacteremia
and even viremia; disseminated intravascular coagulation (DIC)—risk increases with sepsis, cancer, obstetric catastrophe,
critical illness, multiorgan dysfunction, and liver failure; initial hypercoagulable state progresses to bleeding; thrombotic
manifestations may occur; prolonged prothrombin time (PT) and partial thromboplastin time (PTT) typical; other
features include decreased fibrinogen and elevated degradation products of fibrin; increased index of suspicion for any ill
patient who presents with thrombocytopenia
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| Hypersplenism: enlarged spleen may lead to excessive destruction of platelets; etiologies include liver disease with portal
hypertension, myeloproliferative diseases, and lymphoproliferative diseases; splenomegaly not always palpable, but
readily detected by ultrasonography; pancytopenia results
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| Immune thrombocytopenic purpura (ITP): seen in ambulatory patients; pathogenesis—autoimmune response
against platelets and megakaryocytes decreases production and increases destruction of platelets; increased number of
megakaryocytes produce fewer platelets (ie, ineffective megakaryopoiesis); etiology—drug-induced form may occur
with quinine and quinidine, rifampin, trimethoprim–sulfamethoxazole (TMP-SMZ), and others (note, many naturopathic
and homeopathic formulations contain quinine); condition sometimes associated with underlying immune disorder
(eg, lupus, HIV, or lymphoproliferative malignancy); idiopathic form also occurs; diagnosis—avoid assays for
platelet antibodies (ineffective and sometimes misleading); rule out other causes of thrombocytopenia; suspect ITP
when Hb and white blood cell (WBC) count normal and patient otherwise healthy; consider other diagnosis if patient
has symptoms other than thrombocytopenic bleeding
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 | Management: stop potential drug triggers; rule out underlying illness; manage idiopathic form with high-dose corticosteroids,
intravenous (IV) immunoglobulin, or both; in addition, begin immediate transfusion of platelets for patients with
emergent bleeding; note—relapse common among adults with ITP; decision to treat based on severity of thrombocytopenia;
splenectomy effective at increasing platelet count, but long-term problems include increased risk for sepsis;
chronic ITP—potential adverse effects of long-term treatment with steroids; stable hemostasis may render treatment
unnecessary
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| Thrombotic thrombocytopenic purpura (TTP): potentially fatal, multisystem disease that results in consumptive
thrombocytopenia, microangiopathic hemolysis, and problems associated with selective deposition or removal of platelets
from microvasculature; clinical features—reversible (or fluctuating) neurologic findings; fever; renal disease; others;
management—platelet transfusion may cause stroke, acute renal failure, or sudden death if begun before definitive
therapy (ie, plasma exchange and treatment with corticosteroids) has arrested TTP process
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| SICKLE CELL DISEASE —Patricia Adams-Graves, MD, Associate Professor of Medicine, University of Tennessee College
of Medicine, and Director, Diggs-Kraus Sickle Cell Center, Memphis
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| Disease overview: symptoms manifest at ≈6 mo of age, at onset of production of adult Hb; in children, 0 to 11 yr of age,
primary events include acute splenic sequestration crisis, dactylitis, anemia, and aplastic crisis in response to viral infection;
as patients age, pain often chief complaint; challenge to physicians—manage pain without promoting dependence
on pain medications (especially opiates)
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| Common complications that cause pain: avascular necrosis—deterioration of joint, often visible only with magnetic
resonance imaging (MRI); nonsteroidal anti-inflammatory drugs (NSAIDs) helpful for acute episodes; management
of chronic pain often necessary; patients with chronic pain may develop tolerance to medications and may require transdermal
fentanyl (Duragesic patch) or morphine (eg, MS Contin); prophylaxis required to manage adverse effects of opiates;
leg ulcers—contribute to daily pain in patients with sickle cell disease (SCD)
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| Sickle chest syndrome: in children, often caused by Haemophilus influenza, Chlamydia, or similar pathogen;
progression—patient with SCD who presents with hypoxia may have occluded vasculature in lungs (not always evident
on radiographs); occlusion of subsegmental vessels may not result in formation of infiltrate; if untreated, patients often
present with acute chest syndrome in ≈3 days; appropriate treatment includes plasma exchange; note—suspect impending
chest syndrome in any patient with SCD who presents with symptoms referable to chest (eg, cough, chest pain, shortness
of breath); consider hospitalization and daily monitoring of O2 saturation, especially for patients with fever;
etiology—fat emboli (≈50% of cases; ≈98% fatal within 72 hr); atypical pneumonias more common than typical pneumonias
(therefore, treat with macrolide, eg, levofloxacin [Levoquin]); viral infection; mixed infection; complications—
patients at risk for infarction; prevention—patients with chest pain tend to avoid taking deep breaths; expanding lungs
prevents atelectasis and pneumonia
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| Anemia: patients may appear jaundiced with scleral icterus or only mildly icteric; rigid cells adhere to vascular endothelium
and to macrophages, increasing viscosity of blood; hematocrit >30% in patients with Hb SS (“SS patients”) and
>38% in patients with Hb SC (“SC patients”) indicates hyperviscosity; transfusion may increase viscosity, worsen vascular
occlusion, and increase risk for stroke; hemolysis—intravascular hemolysis of abnormal cells occurs within 2 wk;
spleen and reticuloendothelial system selectively remove abnormal cells; laboratory features—Hb 6.5 to 8 g/dL in SS
patients; reticulocytosis often results in high mean corpuscular volume (MCV); mean corpuscular hemoglobin concentration
(MCHC) elevated; reticulocyte count typically elevated, but generally <10%; WBC and platelet counts elevated; low
erythrocyte sedimentation rate (ESR), except in patients with lupus or other autoimmune disease; erythrocytes unable to
form rouleaux; increased lactate dehydrogenase (LDH) and indirect bilirubin; decreased haptoglobin; low erythropoietin
(lowered further by O2 )
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| Recommendations for management of pain: for severe pain, start at 10 mg morphine, q 3 hr to q 4 hr, or 100 mg
of meperidine (Demerol) q 3 hr (maximum of 30 doses, then switch to Duragesic patch or morphine); note—important
to taper pain medication, especially in high utilizers; preventing painful episodes—maintain adequate hydration; avoid
salicylates and exposure to cold; intervene early in patients with fever; transfuse monthly (in selected patients); update
immunizations; treat herpes infections with acyclovir (given IV if outbreak involves central nervous system [CNS]), and
consider prophylaxis for 3 to 5 yr
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| Infection: increased risk due to loss of splenic function; pathogens—encapsulated organisms and atypical bacteria (consider
treatment with azithromycin); pneumococcal sepsis in children; Salmonella (uncommon)
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| Transfusions: acute anemia—transfuse patient when hematocrit decreases >20% from baseline, or when Hb <5 g/dL;
note—hematocrit of 30% prevents production of sickle cells, but increases risk for hyperviscosity syndrome; transfusion
not indicated—patients with customary level of Hb; uncomplicated painful episodes; uncomplicated pregnancy
(transfusion may increase risk); minor surgery with local anesthesia; indications for exchange transfusion—any CNS
event; acute chest syndrome; priapism; sickle hepatopathy; major surgery or eye surgery; goal—decrease sickle Hb to
20% to 30% and hematocrit to ≈30% (risk for hyperviscosity syndrome in SS patients when hematocrit >30%); indications
for long-term transfusion therapy—stroke; recurrent splenic sequestration in children; pregnancy, if history of fetal
loss; nonhealing ulcer on leg; note—long-term transfusion therapy not indicated for recurrent crises of acute pain
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Educational Objectives
| The goal of this activity is to provide the clinician with information about the evaluation and management of patients with
common hematologic disorders. After hearing and assimilating this program, the clinician will be better able to:
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| 1. Discuss the common causes of microcytic anemia.
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| 2. Diagnose patients with common microcytic anemias, and establish plans for their management.
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| 3. Discuss the etiologies of thrombocytopenia.
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| 4. Compare clinical features and management strategies for patients with immune thrombocytopenic purpura (ITP) to
those with thrombotic thrombocytopenic purpura (TTP).
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| 5. Recognize common complications of sickle cell disease (SCD) and plan for management of chronic pain in these
patients.
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Discussed on This Program
Azithromycin [Zithromax]
Danaparoid sodium [Orgaran]
Fentanyl transdermal system [Duragesic]
Heparin sodium injection
Lepirudin [Refludan]
Levofloxacin [Levaquin, Quixin]
Meperidine HCl [Demerol]
Morphine sulfate [Astramorph PF, Duramorph, Infumorph, Kadian, MSIR, MS Contin, Roxanol, RMS, UltraJect]
Quinidine (several formulations and trade names)
Quinine sulfate
Rifampin (rifampicin) [Rifadin, Rimactane]
Trimethoprim-sulfamethoxazole (co-trimoxazole; TMP-SMZ) [Bactrim, Bactrim DS, Bactrim IV, Bactrim Pediatric,
Cotrim, Cotrim D.S., Septra, Septra DS, Septra IV, Sulfatrim]
Suggested Reading
Ballas SK, Lusardi M: Hospital readmission for adult sickle cell painful episodes: frequency, etiology, and prognostic
significance. Am J Hematol 79:17, 2005; Bank A: Understanding globin regulation in beta-thalassemia: it’s as simple as
alpha, beta, gamma, delta. J Clin Invest 115:1470, 2005; Beyan C, et al: The platelet count/mean corpuscular hemoglobin
ratio distinguishes combined iron and vitamin B12 deficiency from uncomplicated iron deficiency. Int J Hematol
81:301, 2005; Gabrilove J: Anemia and the elderly: clinical considerations. Best Pract Res Clin Haematol 18:417,
2005; Gami AS, et al: Incidence and prognosis of acute heart failure in thrombotic microangiopathies. Am J Med
118:544, 2005; Gasbarrini A, Franceschi F: Does H. pylori infection play a role in idiopathic thrombocytopenic purpura
and in other autoimmune diseases? Am J Gstroenterol 100:1271, 2005; Hershko L, et al: Role of autoimmune
gastritis, Helicobacter pylori, and celiac disease in refractory or unexplained iron deficiency anemia. Haematologica
90:577A, 2005; Jang IK, Hursting MJ: When heparins promote thrombosis: review of heparin-induced thrombocytopenia.
Circulation 111:2671, 2005; Kaur N, et al: Potential role of the ventilation and perfusion (V/Q) lung scan in the
diagnosis of acute chest syndrome in adults with sickle cell disease. Am J Hematol 77:407, 2005; Kojouri K, George
JN: Recent advances in the treatment of chronic refractory immune thrombocytopenic purpura. Int J Hematol 81:119,
2005; Machado RF, Gladwin MT: Chronic sickle cell lung disease: new insights into the diagnosis, pathogenesis, and
treatment of pulmonary hypertension. Br J Haematol 129:449, 2005; Scholl TO: Iron status during pregnancy: setting
the stage for mother and infant. Am J Clin Nutr 81:1218S, 2005; Smith WR, et al: Understanding pain and improving
management of sickle cell disease: the PiSCES study. J Natl Med Assoc 97:183, 2005; Thomas C, Thomas L: Anemia
of chronic disease: pathophysiology and laboratory diagnosis. Lab Hematol 11:14, 2005.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue, the faculty reported
nothing to disclose.
Dr. Eisenstaedt was recorded in Philadelphia, at Family Practice Review, sponsored by Temple University School of
Medicine, and held March 13-18, 2005; Dr. Adams-Graves was recorded in Memphis, at 38th Annual Review Course
for the Family Physician, sponsored by University of Tennessee College of Medicine, and held March 14-18, 2005.
The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.
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