BLOOD ISSUES
From the 39th Annual Review Course for the Family Physician, sponsored by the University of Tennessee College of
Medicine, Memphis
| VENOUS THROMBOEMBOLISM —Gregg E. Mitchell, MD, Assistant Professor, University of Tennessee, College of
Medicine, Memphis, and Interim Director, Family Practice Residency Program, Health Science Center, Jackson
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| Epidemiology: incidence—2 million cases of deep venous thrombosis (DVT) and 600,000 cases of pulmonary embolism
(PE) diagnosed each year; postphlebitic syndrome common after resolution of DVT; some patients with PE develop pulmonary
hypertension and associated complications; ≈1 million cases of silent PE occur annually; mortality—50% of fatalities
from PE potentially curable; appropriate prophylaxis could save 80,000 lives each year; age as risk factor—
incidence of thromboembolic events increases with age; population aging, therefore, incidence increasing despite therapeutic
advances; PE mortality—death may occur within 1 to 2 hr; diagnosis often missed
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| Risk factors in hospitalized patients: age \>40 yr; history of nonhemorrhagic ischemic stroke, congestive heart failure, or
venous thromboembolism (VTE); thrombophilia; obesity; malignancy; admission to intensive care unit (ICU); chronic
lung disease or respiratory failure; pneumonia; infection; active collagen vascular disease; inflammatory disorders; presence
of central venous catheter; varicose veins; nephrotic syndrome; use of oral contraceptives (OCs) or estrogen replacement
therapy; treatment with tamoxifen or raloxifene; pregnancy
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| Thrombophilia: 50% of thrombotic events in patients with inherited thrombophilia associated with acquired risk factor
(eg, surgery, pregnancy, use of OCs); 25% of patients with DVT have hereditary thrombophilia (10% in general population)
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| Malignancy: VTE second leading cause of death in cancer patients; evidence-based evaluation for cancer appropriate in
patients with VTE
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| Diagnosis: 80% of cases clinically silent; edema, pain, and warmth associated with relatively low diagnostic accuracy;
Homan’s sign unreliable; initial laboratory tests—complete blood count (CBC); prothrombin time (PT) and partial
thromboplastin time (PTT; to ensure hematocrit and platelet count sufficient before initiating anticoagulation); comprehensive
metabolic panel (CMP; kidney function important for drug metabolism; elevations in liver enzymes may indicate
malignancy); urinalysis; prostate-specific antigen (PSA) in men \>50 yr of age; chest radiograph, especially in smokers;
pregnancy test; fecal occult blood test; other testing—factor V Leiden mutation and prothrombin gene 20210 A mutation
(2 most common inherited thrombophilias); homocysteine; antiphospholipid antibody and lupus anticoagulant; protein
C, protein S, and antithrombin III useful if above tests yield no positive findings
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| Timing of tests: thrombosis can reduce levels of antithrombin III, protein C, and protein S; heparin therapy may decrease
antithrombin III by 30%; warfarin markedly reduces protein C and protein S; recommendation—perform tests 2 wk after
completing warfarin (Coumadin) therapy
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| Testing for inherited thrombophilia: indications—family history positive for blood clots; age <50 yr; recurrent DVT;
DVT with use of OCs or pregnancy; unusual site of thrombus (eg, portal, mesenteric, hepatic, cerebral)
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| Objective testing for DVT: ultrasonography (US) preferred, but recent DVT may leave scarring and compromise accuracy;
impedance plethysmography sometimes used; contrast venography (CV) gold standard; magnetic resonance imaging
(MRI); diagnostic US—good test in symptomatic patients; low sensitivity (59%) but high specificity (98%) in
asymptomatic patients; benefits include noninvasiveness, portability, and capacity for imaging femoral and popliteal
veins; disadvantages include lower accuracy for thrombi in calf and iliac veins, need for experienced technician, and unknown
accuracy in patients with recurrent VTE
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| Diagnostic decision tree for patients with suspected DVT: treat patients with positive findings on US; assign risk to patients
with negative findings; low risk—D-dimer appropriate; negative findings indicate low probability of DVT (clinical
follow-up sufficient); moderate risk—consider treatment; repeat US in 5 to 7 days; high risk—perform
venography or MRI; note—clinical information alone inadequate to confirm or exclude diagnosis of DVT or PE; 2 cardinal
signs and symptoms of PE dyspnea and pleuritic chest pain; others include tachypnea, tachycardia, cough, hemoptysis,
and hypotension
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| Other diagnostic tools: spiral computed tomography (CT)—intravenous (IV) contrast required; sensitivity 90% for PE in
proximal pulmonary arteries; favored technique for patients with suspected cardiopulmonary disease, because of utility in
diagnosing other abnormalities; ventilation-perfusion (V/Q) scan—often nondiagnostic; most useful when patient has
normal or high probability; pulmonary arteriography—gold standard; D-dimer—appropriate only in patients with low
clinical probability of VTE; other imaging—if CT yields negative findings, consider US of legs to look for DVT
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| Prophylaxis: options—low-dose unfractionated heparin (UFH); low molecular weight heparin (LMWH); danaparoid or direct
thrombin inhibitors; fondaparinux; warfarin; elastic stockings; intermittent pneumatic compression (IPC) devices (if
used, initiate within first 3 days of hospitalization; use in patient who has DVT may provoke development of PE);
study----- subcutaneous administration of 40 mg enoxaparin (6-14 days) decreased mortality, reduced risk for VTE by
63%, and did not increase risk for hemorrhage or thrombocytopenia (compared to placebo and 20 mg/day enoxaparin);
recommendations—LMWH or low-dose UFH recommended (grade 1A) for prophylaxis in medical patients with risk
factors; contraindications—bleeding; hypersensitivity to heparin; uncontrolled hypertension; creatinine clearance <30
mL/min; coagulopathy; heparin-induced thrombocytopenia (HIT); recent intraocular or intracranial surgery; lumbar
puncture or epidural anesthesia within 24 hr
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| Risk for VTE after surgery: categorized as low, moderate, high, and highest; based on age, invasiveness of surgery, and
existence of risk factors or history of VTE; low risk—no specific recommendations for prophylaxis; aggressive mobilization
after surgery encouraged; moderate and high risk—prophylaxis options consist of LMWH, low-dose UFH, elastic
stockings (moderate risk only), or IPC; highest—prophylactic options consist of LMWH, oral anticoagulants, IPC or
elastic stockings plus low-dose UFH or LMWH or adjusted-dose UFH
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| Dosing: enoxaparin—30 mg q12h or 40 mg q24h, depending on setting; dose reduced in patients with creatinine clearance
<30 mL/min; fondaparinux—2.5 mg subcutaneously q24h, starting 6 to 8 hr after surgery (all indications); efficacy
somewhat better than enoxaparin, but more expensive; contraindications include low body weight and creatinine clearance
<30 mL/min (dosing unknown); adverse effects include hemorrhage (usually at surgical site) and local reactions at
injection site; no reports of thrombocytopenia
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| Outpatient treatment: pharmacokinetic properties of LMWH associated with more predictable response, longer half-life,
and reduced risk for HIT and osteopenia; studies compared outpatient treatment with enoxaparin to traditional treatment
with UFH in patients with documented proximal DVT without PE; rates of recurrence and major hemorrhage did
not differ significantly; treatment well tolerated, convenient, and reduces cost by ≈50%; contraindications—
concurrent symptomatic PE; active bleeding or familial bleeding disorder; marked renal insufficiency; severe liver disease;
weight \>120 kg; severe leg swelling or pain; concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs);
pregnancy; prolonged admission anticipated for other reasons
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 | Guidelines for outpatient treatment: 1 mg/kg enoxaparin q12h or 1.5 mg/kg q24h for 5 to 7 days; warfarin begun when
appropriate (usually within 72 hr; may begin within 24 hr); treatment continued until international normalized ratio
(INR) ≥2.0 (average treatment lasts 7 days; enoxaparin [Lovenox] tolerated up to 17 days)
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| Coumadin: duration of treatment—from 3 mo to lifetime, depending on risk for recurrence; lifetime treatment—
appropriate for patients with recurrent objectively diagnosed DVT or PE, patients with inherited thrombophilia who develop
DVT, patients with DVT or PE with no risk factors, and cancer patients who develop PE; efficacy—low-intensity
warfarin associated with 48% reduction in recurrent VTE, hemorrhage, and death, compared to placebo; conventional-intensity
warfarin further reduces risk for VTE; lifetime therapy may improve outcome in patients with DVT or PE
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| ANEMIA —William G. Byrd, MD, Instructor of Family Medicine, University of Tennessee, College of Medicine, and
Family Practice Residency Program, St. Francis Medical Center, Memphis
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| Work-up for suspected anemia: begin with CBC and peripheral blood smear
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| Red blood cell (RBC) count: above normal range—causes include medications (eg, thiazides), polycythemia vera, and
high altitude; below normal range—causes include alcohol abuse, chronic disease, renal failure, hemoglobinopathy,
hemolysis, hemorrhage, iron-deficiency anemia, and medications (eg, acetaminophen, acyclovir, amphetamines, antibiotics,
digoxin)
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| Mean corpuscular volume (MCV): <80 fL considered microcytic; \>100 fL considered macrocytic; MCV elevated in infants
<6 mo of age
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| Mean corpuscular hemoglobin concentration (MCHC): elevation suggests presence of large number of spherocytes
(seen in infancy, in patients with hemolysis, and with use of OCs or heparin); depression often indicates hypochromia
(associated with thalassemias and chronic disease); note—changes in erythrocyte indices often precede other abnormalities
in CBC
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| Red cell distribution width (RDW): elevated value suggests anisocytosis and warrants evaluation of blood smear (even if
CBC within normal limits); normal RDW in patients with microcytic anemia suggests thalassemia, whereas high RDW
suggests iron deficiency
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| Hemoglobin: decreased levels result in decreased capacity to transport O2 ; alterations—increased levels associated with
chronic hypoxia, dehydration, high altitude, polycythemia vera, and malignancy; decreased levels associated with ethanol
abuse, chronic disease, hemolysis, hemorrhage, iron deficiency, and megaloblastic and sideroblastic anemias
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| Anisocytosis: microcytic anemia—low MCV; etiologies include iron deficiency, chronic intravascular hemolytic anemia, severe
fragmentation hemolysis, chronic disease, hyperthyroidism, and antituberculosis medication; normocytic anemia—
associated with chronic disease, HIV, acute hemorrhage, endocrinopathy (eg, Addison’s disease, panhypopituitarism), liver
disease, uremia, hemoglobinopathy, and myelophthisic anemia (problem with bone marrow); macrocytic anemia—
etiologies include macrocytosis, alcohol abuse, vitamin B12 deficiency, folate deficiency, hemolysis, aplastic anemia, and
RBC aplasia (caused by drug, malignancy, or virus)
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| Reticulocyte count: measure of immature non-nucleated RBCs; provides estimate of RBC production by bone marrow;
corrected reticulocyte count (reticulocyte count x hematocrit ÷ 45 x 0.5) in anemic patients, gives clues to bone marrow
response; alterations—elevated in patients with hemolytic anemia, hemorrhage, pregnancy, and on certain medications
(eg, dapsone, epoetin); decreased with cancer, liver disease, alcoholism, nonhemolytic anemia, radiation therapy, chemotherapy,
and medications (eg, AZT, chloramphenicol)
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| Signs and symptoms of anemia: tachycardia or palpitations; angina; weakness; fatigue; congestive heart failure; hypertension;
symptom severity—reflects severity of anemia (degree of O2 insufficiency), rate of onset, adequacy of compensatory
mechanisms (eg, shift in O2 dissociation curve), and existence of comorbid conditions
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| Hemolysis: results in increased levels of indirect (unconjugated) bilirubin, urine urobilinogen, and serum lactate dehydrogenase,
increased reticulocyte count (compensatory erythropoiesis), and decreased haptoglobin; increased free hemoglobin
in plasma and urine indicates intravascular origin; hemosiderin evident in urine after several days
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| Iron-deficiency anemia: microcytic anemia; usually associated with milk-only diet (in infants), some parasitic infections,
and poor diet among elderly patients; other etiologies—insufficient absorption after gastric surgery or in patients with
sprue or celiac disease; insufficient iron transport caused by deficiency in transferrin (as seen in some inflammatory conditions);
abnormal loss of iron (eg, hemorrhage, menstruation, occult bowel carcinoma); increased iron requirements
(children and pregnant women)
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| Thalassemia: result of defect in synthesis of hemoglobin subunits; β-thalassemia becomes evident at 4 to 6 mo, when β-
subunit normally replaces fetal γ-subunit
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| Megaloblastic anemia: result of impaired synthesis of DNA; etiologies—alcoholism; vitamin B12 or folate deficiency;
medications that interfere with DNA synthesis; tropical sprue (Latin America); some parasites; myelodysplastic syndrome;
aplastic anemia
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| Sickle cell anemia: trait seen in 8% of black patients; 1 in 625 born with sickle cell disease; presentation—chronic
hemolytic anemia; painful infarctions; atrophic spleen (may lead to pancytopenia); increased risk for priapism, pulmonary
failure, cholelithiasis, hepatitis, and placental insufficiency; increased risk for osteomyelitis with infections (Staphylococcus
, Group A Streptococcus, or Salmonella); factors that initiate crisis—hypothermia; hypoxia; dehydration;
acidosis; infarction; infection; laboratory findings—sickle-shaped RBCs; nucleated RBCs; target cells; Howell-Jolly
bodies; positive test for sickling; increased reticulocyte count; positive hemoglobin electrophoresis; increased bilirubin;
decreased haptoglobin; life expectancy—50% of patients die before 50 yr of age; treatment—exchange transfusion; hydroxyurea;
bone marrow transplantation; pain control; anticoagulation; prophylactic penicillin; folate supplementation;
immunizations—pneumococcal and meningococcal vaccines; Haemophilus influenza vaccine
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Educational Objectives
| The goal of this activity is to review risk factors and treatment recommendations for patients with venous thromboembolism
(VTE) and review the etiologies of anemia. After hearing and assimilating this program, the clinician will be better
able to:
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| 1. Identify patients at risk for VTE and assess need for prophylaxis.
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| 2. Discuss the diagnostic certainty of deep venous thrombosis (DVT) and pulmonary embolism (PE).
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| 3. Summarize treatment recommendations for patients with DVT or PE.
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| 4. Review blood components and their functions.
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| 5. Compare the various forms of anemia and list the diagnostic criteria for each.
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Discussed on This Program
Acetaminophen (n-acetyl-p-aminophenol; APAP) [several formulations and trade names]
Acyclovir (acycloguanosine) [Zovirax]
Chloramphenicol [Chloramphenicol Sodium Succinate, Chloromycetin, Chloromycetin Sodium Succinate]
Colchicine
Danaparoid sodium [Orgaran]
Dapsone (DDS) [Aczone]
Digoxin [Digitek, Lanoxicaps, Lanoxin]
Enoxaparin sodium [Lovenox]
Epoetin alfa (erythropoietin; EPO) [Epogen, Procrit]
Epoetin beta [Marogen]
Fondaparinux sodium [Arixtra]
Heparin sodium injection
Nitrofurantoin macrocrystals [Macrobid, Macrodantin]
Warfarin sodium [Coumadin]
Zidovudine (azidothymidine; AZT; compound S; ZDV) [Retrovir]
Suggested Reading
Abetz L, et al: The impact of iron overload and its treatment on quality of life: results from a literature review. Health Qual
Life Outcomes 4:73, 2006; Beris P, Maniatis A: Role of intravenous iron therapy in anemia management: state of the art.
Semin Hematol 43:S1, 2006; Caprini JA, Hyers TM: Compliance with antithrombotic guidelines. Manag Care 15:49,
2006; Edelsberg J, et al: Risk of venous thromboembolism among hospitalized medically ill patients. Am J Health Syst
Pharm 63:S16, 2006; Elabbassi W, et al: Prevalence and clinical implications of anemia in congestive heart failure patients
followed at a specialized heart function clinic. Congest Heart Fail 12:258, 2006; Emmerich J, et al: Role of fibrinolysis
and interventional therapy for acute venous thromboembolism. Thromb Haemost 96:251, 2006; Galloway MF,
Smellie WS: Investigating iron status in microcytic anemia. BMJ 333:791, 2006; Monreal M, et al: Pulmonary embolism
in patients with chronic obstructive pulmonary disease or congestive heart failure. Am J Med 119:851, 2006; Natelson EA:
Pregnancy-induced pancytopenia with cellular bone marrow: distinctive hematologic features. Am J Med Sci 332:205,
2006; Piccioli A, et al: Cancer and venous thromboembolism. Semin Thromb Hemost 32:694, 2006; Schulman S, Ogren
M: New concepts in optimal management of anticoagulant therapy for extended treatment of venous thromboembolism.
Thromb Haemost 96:258, 2006; Semba RD, et al: Low serum selenium is associated with anemia among older women living
in the community: the Women’s Health and Aging Studies I and II. Biol Trace Elem Res 112:97, 2006; Simioni P, et al:
Inherited thrombophilia and venous thromboembolism. Semin Thromb Hemost 32:700, 2006; Spyropoulos AC, Merli G:
Management of venous thromboembolism in the elderly. Drugs Aging 23:651, 2006.
Faculty Disclosure
In adherence with 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.
Drs. Mitchell and Byrd were recorded in Memphis, TN, at the 39th Annual Review Course for the Family Physician,
held February 27 to March 3, 2006, and sponsored by the University of Tennessee, College of Medicine. The Audio-
Digest Foundation thanks the speakers and the University of Tennessee, College of Medicine for their cooperation in
the production of this program.
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