INTERNAL MEDICINE BOARDS - PART 6 docx

HEMATOLOGY TREATMENT No specific management of 2° erythrocytosis is necessary. The treatment of polycythemia vera is covered in a separate section. Thrombocytopenia Defined as a platelet count < 150 × 10 9 /L. Its causes are outlined in Table 9.11. DIAGNOSIS ■ Examine a peripheral smear. TABLE 9.10. Evaluation of Erythrocytosis LABS IMAGING Arterial O 2 saturation RBC mass Ferritin, B 12 , folate, creatinine, LFTs, uric acid Abdominal ultrasound or CT scan Serum erythropoietin JAK2 mutation TABLE 9.11. Causes of Thrombocytopenia CAUSE EXAMPLES ↑ destruction Immune thrombocytopenia: ■ 1°: Autoimmune (ITP). ■ 2°: Lymphoid malignancies, HIV, SLE, alloimmunization from prior platelet transfusions. ■ Drug induced: Gold, abciximab, ticlopidine, quinine, heparin. ■ Post-transfusion purpura. Microangiopathies: ■ TTP, HUS, eclampsia. ■ DIC, sepsis. ■ Severe hypertension. Mechanical: ■ Artificial heart valves. ■ Hemangiomas. ■ Central venous catheters. Hypersplenism ↓ production Essentially any cause of marrow suppression can produce thrombocytopenia in isolation. See the pancytopenia discussion below. Probably the most important is drug-induced thrombocytopenia. Other Dilutional: From massive blood transfusions and fluid resuscitation. Pseudothrombocytopenia: From platelet clumping. 358 HEMATOLOGY ■ Rule out platelet clumping. Ask for a count/smear done in citrate, as EDTA (the anticoagulant most often employed in tubes used to collect a CBC) can cause clumping of platelets not seen on smear. ■ Look for evidence of microangiopathy (i.e., schistocytes), marrow sup- pression (megaloblastic changes, dysplastic changes), and immature platelets (giant platelets) suggesting ↑ platelet turnover. ■ Take a careful drug history. ■ Acetaminophen, H 2 blockers, sulfa drugs, furosemide, captopril, digoxin, and β-lactam antibiotics are all associated with thrombocy- topenia. ■ Never forget heparin-induced thrombocytopenia (see the discussion of clotting disorders below). ■ Consider bone marrow biopsy if other findings suggest marrow dysfunc- tion. ■ Platelet-associated antibody tests are not useful. ■ ITP is a diagnosis of exclusion. TREATMENT ■ Treat the underlying cause. ■ Platelet transfusions in the absence of bleeding are usually unnecessary. Specific guidelines are given in the discussion of transfusion medicine be- low. Platelet transfusions are contraindicated in TTP/HUS and heparin- induced thrombocytopenia. Thrombocytosis Defined as a platelet count > 450 × 10 9 /L. The main distinction is reactive thrombocytosis vs. myeloproliferative disorder. The steps involved in the evaluation of thrombocytosis are outlined in Table 9.12. TABLE 9.12. Evaluation of Thrombocytosis STEPS IN EVALUATION COMMENTS Repeat CBC and examine peripheral smear Elevated platelet count may be spurious or transient. Clues to reactive thrombocytosis may be present. Stratify by degree of thrombocytosis A platelet count < 600k is unlikely to be essential thrombocythemia. A platelet count > 1000k is less likely to be reactive thrombocytosis, but many “platelet millionaires” still have reactive thrombocytosis. Identify causes of reactive thrombocytosis Iron deficiency anemia, RA, IBD, infection or inflammatory states, postsplenectomy, active malignancy, myelodysplasia with 5q-, sideroblastic anemia. Rule out other myeloproliferative syndromes Consider testing for the JAK2 mutation for essential thrombocythemia. BCR-ABL by PCR in CML. Elevated RBC mass in polycythemia. Characteristic peripheral smear and splenomegaly in myelofibrosis. Consider a bone marrow biopsy Megakaryocyte morphology can suggest essential thrombocythemia. Examination for myelodysplasia, sideroblasts. 359 HEMATOLOGY Neutrophilia ■ Defined as an absolute neutrophil count > 10 × 109/L. The main distinc- tion is between myeloproliferative disorder (typically CML) and reactive neutrophilia. ■ Reactive neutrophilia is readily apparent from the history (inflammation, infection, severe burns, glucocorticoid, epinephrine) and from examina- tion of a peripheral smear (Döhle bodies, toxic granulations). Eosinophilia ■ Defined as an absolute eosinophil count > 0.5 × 10 9 /L. May be 1° (idio- pathic) or 2°. ■ Idiopathic hypereosinophilia syndrome: ■ Extremely rare and heterogeneous. ■ A prolonged eosinophilia of unknown cause with the potential to affect multiple organs by eosinophil infiltration. ■ Almost all cases have bone marrow infiltration, but heart, lung, and CNS involvement predicts a worse outcome. ■ Some cases are treatable with imatinib mesylate (Gleevec). ■ 2° eosinophilia: Remember the mnemonic NAACP. ■ Note that several drugs (nitrofurantoin, penicillin, phenytoin, ranitidine, sulfonamides) and toxins (Spanish toxic oil, tryptophan) have been re- ported to cause eosinophilia. Neutropenia ■ Defined as an absolute neutrophil count (ANC) < 1.5 × 10 9 /L (< 1.2 in blacks). Causes are outlined in Table 9.13. ■ Gram-ᮍ organisms account for 60–70% of cases of neutropenic fever. ■ See the discussion of neutropenic fever in the Oncology chapter. Pancytopenia ■ Almost always represents ↓ or ineffective bone marrow activity. Differenti- ated as follows: ■ Intrinsic bone marrow failure: Aplastic anemia, myelodysplasia, acute leukemia, myeloma, drugs (chemotherapy, chloramphenicol, sulfon- amides, antibiotics). ■ Infectious: HIV, post-hepatitis, parvovirus B19. ■ Marrow infiltration: TB, disseminated fungal infection (especially coc- cidioidomycosis and histoplasmosis), metastatic malignancy. Causes of 2° eosinophilia— NAACP Neoplastic Asthma/Allergic Addison’s Collagen-vascular disease Parasites TABLE 9.13. Causes of Neutropenia IMPAIRED PRODUCTION ↑ DESTRUCTION Cytotoxic chemotherapy and other drugs Autoimmune neutropenia Aplastic anemia and other causes of Felty’s syndrome marrow failure Sepsis Congenital HIV Cyclic neutropenia Acute viral illness 360 HEMATOLOGY ■ Peripheral smear morphology is often helpful in diagnosis (see Tables 9.14 and 9.15). BONE MARROW FAILURE SYNDROMES Aplastic Anemia Marrow failure with hypocellular bone marrow and no dysplasia. Typically seen in young adults or the elderly. Subtypes are as follows: ■ Autoimmune (1°) aplastic anemia: The most common type. Assumed when 2° causes have been ruled out. ■ 2° aplastic anemia: Can be caused by multiple factors. ■ Toxins: Benzene, toluene, insecticides. ■ Drugs: Gold, chloramphenicol, clozapine, sulfonamides, tolbutamide, phenytoin, carbamazepine, and many others. ■ Post-chemotherapy or radiation. ■ Viral: Post-hepatitis, parvovirus B19, HIV, CMV, EBV. ■ Other: PNH, pregnancy. SYMPTOMS/EXAM ■ Presents with symptoms of pancytopenia (fatigue, bleeding, infections). ■ Adenopathy and splenomegaly are not generally seen. DIAGNOSIS ■ Labs: Pancytopenia and markedly ↓ reticulocytes are classically seen. ■ Peripheral smear: Pancytopenia without dysplastic changes. ■ Bone marrow: Hypocellular without dysplasia. TREATMENT ■ Supportive care as necessary (transfusions, antibiotics). ■ 1° aplastic anemia: ■ Definitive treatment is allogeneic bone marrow transplant. TABLE 9.14. Summary of Peripheral Smear Morphology—RBCs RBC FORM ASSOCIATED CONDITIONS Schistocytes Microangiopathy, intravascular hemolysis. Spherocytes Extravascular hemolysis, hereditary spherocytosis. Target cell Liver disease, hemoglobinopathy. Teardrop cell Myelofibrosis, thalassemia. Burr cell (echinocyte) Uremia. Spur cell (acanthocyte) Liver disease. Howell-Jolly body Postsplenectomy, functional asplenia. 361 HEMATOLOGY 362 ■ Remissions can sometimes be induced with antithymocyte globulin and cyclosporine. ■ 2° aplastic anemia: Treat by correcting the underlying disorder. Pure Red Cell Aplasia (PRCA) Marrow failure in erythroid lineage only. SYMPTOMS/EXAM Symptoms are related to anemia. DIFFERENTIAL After other causes of isolated anemia have been excluded, distinguish autoim- mune PRCA from that stemming from abnormal erythropoiesis. ■ Autoimmune: Thymoma, lymphoma/CLL, HIV, SLE, parvovirus B19. ■ Abnormal erythropoiesis: Hereditary spherocytosis, sickle cell anemia, drugs (phenytoin, chloramphenicol). DIAGNOSIS ■ CBC: Presents with anemia that is often profound, but WBC and platelet counts are normal. Markedly ↓ reticulocytes. ■ Peripheral smear: No dysplastic changes. ■ Bone marrow biopsy: Abnormal erythroid maturation and characteristic giant pronormoblasts are seen in parvovirus B19 infection. ■ Obtain parvovirus B19 serology or PCR. TREATMENT ■ IVIG may be helpful in cases due to parvovirus. ■ Remove thymoma if present. ■ Immunosuppression with antithymocyte globulin and cyclosporine. Myelodysplastic Syndrome (MDS) A clonal stem cell disorder that is characterized by dysplasia resulting in inef- fective hematopoiesis, and that exists on a continuum with acute leukemia. Eighty percent of patients are > 60 years of age. MDS is associated with TABLE 9.15. Summary of Peripheral Smear Morphology—WBCs WBC FORM ASSOCIATED CONDITIONS Atypical lymphocyte Mononucleosis, toxoplasmosis, CMV, HIV. Döhle body, toxic granulations Infections, sepsis. Hypersegmented neutrophil B 12 deficiency. Auer rods AML. Pelger-Huët anomaly Myelodysplasia, congenital. HEMATOLOGY myelotoxic drugs and ionizing radiation and carries the risk of transforming to AML (but seldom to ALL). Its prognosis is related to the percentage of blasts, cytogenetics, and the number of cytopenias (see Table 9.16). SYMPTOMS/EXAM Symptoms are related to those of cytopenias. DIFFERENTIAL Dysplasia can occur with vitamin B 12 deficiency, viral infections (including HIV), and exposure to marrow toxins, so these factors must be ruled out be- fore a diagnosis of MDS can be made. DIAGNOSIS Peripheral smear shows dysplasia (see Figure 9.10). ■ RBCs: Macrocytosis, macro-ovalocytes. ■ WBCs: Hypogranularity; hypolobulation (pseudo–Pelger-Huët). ■ Platelets: Giant or hypogranular. ■ Bone marrow: Dysplasia; typically hypercellular. Cytogenetics can be nor- mal or abnormal. TREATMENT ■ Supportive care with transfusions and growth factors (generally associated with a poor response). ■ Chemotherapy and anticytokine agents (e.g., thalidomide and lenalido- mide). ■ Bone marrow transplantation is occasionally performed in younger pa- tients. TABLE 9.16. Classification of Myelodysplastic Syndromes SUBTYPE CYTOPENIA BLASTS OTHER Refractory anemia (RA) At least one lineage. < 1% in peripheral blood, < 5% in bone marrow. Refractory anemia with ringed At least one lineage. < 1% in peripheral blood, > 15% ringed sideroblasts in sideroblasts (RARS) < 5% in bone marrow. marrow. Refractory anemia with excess Two or more lineages. < 5% in peripheral blood, blasts (RAEB) 5–20% in bone marrow. Chronic myelomonocytic < 5% in peripheral blood, Peripheral blood monocytosis leukemia (CMML) < 20% in bone marrow. (> 1 × 10 9 /L). Refractory anemia with excess No longer used. blasts in transformation (RAEB-T) 363 5q− syndrome is a subset of MDS associated with a deletion of the long arm of chromosome 5. The disorder is associated with a better outcome as well as with a better response to treatment with lenalidomide. HEMATOLOGY 364 MYELOPROLIFERATIVE SYNDROMES A group of syndromes characterized by clonal ↑ of bone marrow RBCs, WBCs, platelets, or fibroblasts. Each is defined by the cell lineages predomi- nantly affected. Syndromes have considerable clinical overlap, and it is often difficult to distinguish them (see Table 9.17). Polycythemia Vera Defined as an abnormal ↑ in all blood cells, predominantly RBCs. The most common of the myeloproliferative disorders, it shows no clear age predomi- nance. SYMPTOMS/EXAM ■ Splenomegaly is common. ■ Symptoms are related to higher blood viscosity and expanded blood vol- ume and include dizziness, headache, tinnitus, blurred vision, and plethora. ■ Erythromelalgia is frequently associated with polycythemia vera and is characterized by erythema, warmth, and pain in the distal extremities. May progress to digital ischemia. ■ Other findings include generalized pruritus, epistaxis, hyperuricemia, and iron deficiency from chronic GI bleeding. DIAGNOSIS ■ Exclude 2° erythrocytosis. ■ Bone marrow aspirate and biopsy with cytogenetics. ■ A mutation of JAK2, a tyrosine kinase, is found in 65–95% of patients. Al- though not yet part of the diagnostic criteria, it can be used to help distin- FIGURE 9.10. Myelodysplasia. Both neutrophils in this slide demonstrate hypogranulation and hypolobation (pseudo–Pelger- Huët anomaly), suggesting myelodysplasia. (Courtesy of Lloyd Damon, MD.) Erythromelalgia = erythema, warmth, and pain in the distal extremities. It is often associated with polycythemia vera. HEMATOLOGY guish polycythemia vera from 2° erythrocytosis in unclear cases (but note that JAK2 is mutated in other myeloproliferative disorders and is not diag- nostic for polycythemia vera). ■ Diagnostic criteria from the Polycythemia Vera Study Group are out- lined in Table 9.18. TREATMENT ■ No treatment clearly affects the natural history of the disease, so treat- ment should be aimed at controlling symptoms. ■ Phlebotomy to keep hematocrit < 45% treats viscosity symptoms. ■ Helpful medications include the following: ■ Hydroxyurea or anagrelide to keep platelet count < 400,000; both med- ications have been shown to prevent thromboses. ■ Allopurinol if uric acid is elevated. ■ The current standard is to recommend low-dose aspirin in patients with erythromelalgia or other microvascular manifestations. Avoid as- pirin in patients with a history of GI bleeding or platelets greater than 1 × 10 9 /μL (except in the setting of erythromelalgia or microvas- cular symptoms). COMPLICATIONS Predisposes to both clotting and bleeding; may progress to myelofibrosis or acute leukemia. TABLE 9.17. Differentiation of Myeloproliferative Disorders WBC HEMATOCRIT PLATELETS RBC MORPHOLOGY COMMENTS Polycythemia Normal or ↑↑ Normal or ↑ Normal JAK2 ᮍ in about 90% of cases. vera CML ↑ Normal or ↓ Normal Normal Philadelphia chromosome or BCR- ABL ᮍ in > 95% of cases. Myelofibrosis Variable Usually ↓ Variable Abnormal JAK2 ᮍ in 40—60% of cases. Essential Normal or ↑ Normal ↑ Normal JAK2 ᮍ in 50–60% of cases. thrombocythemia TABLE 9.18. Polycythemia Vera Study Group Criteria a “A” CRITERIA “B” CRITERIA A1: Raised RBC mass or hematocrit ≥ B1: Platelet count > 400,000. 60% in males, 56% in females. B2: Neutrophil count > 10,000 (> 12,500 A2: Absence of cause of 2° in smokers). erythrocytosis. B3: Splenomegaly by imaging. A3: Palpable splenomegaly. B4: Characteristic bone marrow colony A4: Abnormal marrow karyotype. growth (almost never used) or low serum erythropoietin. a A1 + A2 + A3 or A4 = polycythemia vera; A1 + A2 + any two B = polycythemia vera. 365 HEMATOLOGY Chronic Myelogenous Leukemia (CML) An excessive accumulation of neutrophils that can transform to an acute process. It is defined by chromosomal translocation t(9;22), the Philadelphia chromosome. SYMPTOMS/EXAM ■ Hepatosplenomegaly is variable. ■ Pruritus, flushing, diarrhea, fatigue, and night sweats are commonly seen. ■ Leukostasis symptoms (visual disturbances, headache, dyspnea, MI, TIA/CVA, priapism) typically occur when the WBC count is > 300,000. DIAGNOSIS ■ Labs reveal a markedly elevated neutrophil count. ■ Basophilia, eosinophilia, and thrombocytosis may also be seen (see Figure 9.11). ■ Leukocyte alkaline phosphatase (LAP) is low but rarely needed. ■ The Philadelphia chromosome is present in 90–95% of cases. De- tectable by cytogenetics or by PCR for the BCR-ABL fusion gene, per- formed on peripheral WBCs. ■ Bone marrow biopsy is not necessary for diagnosis but is often done to de- termine the prognosis. ■ The disease has three phases based on the percentage of blasts in periph- eral blood: ■ Chronic phase: Bone marrow and circulating blasts < 10%. ■ Accelerated phase: Bone marrow or circulating blasts 10–20%. ■ Blast crisis: Bone marrow or circulating blasts ≥ 20%. CML is associated with the Philadelphia chromosome, t(9;22), in 90–95% of cases. First-line treatment is generally a tyrosine kinase inhibitor called imatinib that targets the unique gene product of the Philadelphia chromosome, BCR-ABL. FIGURE 9.11. Chronic myelogenous leukemia. Note the large number of immature myeloid forms in the peripheral blood, including metamyelocytes, myelocytes, and promyelocytes, as well as a large number of eosinophils and basophils. (Courtesy of Lloyd Damon, MD.) 366 [...]... with PTT Guidelines for INR: Range and Duration of Anticoagulation CONDITION INR Provoked DVT/PE DURATION 2–3 6 18 weeks after offending condition is resolved Non-life-threatening DVT/PE 2–3 3 6 months Life-threatening or severe DVT/PE 2–3 6 12 months vs indefinite Hereditary thrombophilia 2–3 6 12 months vs indefinite Atrial fibrillation 2–3 Indefinite Mitral stenosis with evidence of thrombosis or atrial... with patient-controlled anesthesia (PCA) or regularly scheduled nurse-administered medication 394 TA B L E 10 8 Initial Dosing of Opioids ORAL STARTING DOSE 0.5–1.5 mg q 3–4 h 6 mg q 3–4 h Hydrocodone — 10 mg q 3–4 h Oxycodone — 10 mg q 3–4 h Methadone — 5 mg q 6 8 h Morphine 5–10 mg q 3–4 h 30 mg q 3–4 h Meperidine 50–100 mg q 3 h — — 60 mg q 3–4 h Hydromorphone Codeine In chronically opioid-dependent... disorder, in which antibodies form against the heparin-platelet factor 4 (PF4) complex 380 Types of Heparin-Induced Thrombocytopenia DOSE- SEVERITY OF TIMING OF CLINICALLY TYPE DEPENDENT THROMBOCYTOPENIA THROMBOCYTOPENIA SIGNIFICANT I Yes Mild Immediate No Heparin-induced platelet clumping II No Moderate/severe 4–7 days after exposure Yes Antibody against heparin-platelet ETIOLOGY complex SYMPTOMS/EXAM Type... in severe forced diuresis donor RBCs cases with mannitol and (typically ABO) urinary alkalinization HBV 1 in 66 ,000 HCV 1 in 103,000 HIV 1 in 67 6,000 382 ■ ■ ■ ■ H E MATOLOGY Management of Transfusion Reactions Stop the transfusion immediately Contact the blood bank immediately to start double-checking paperwork Draw CBC, direct antiglobulin test, LDH, haptoglobin, indirect bilirubin, free hemoglobin,... 10.2 B Lung scan for a 63 -year-old woman who presented with idiopathic pulmonary embolism The lung scan showed normal ventilation (A) and multiple segmental perfusion defects (B), indicating a V/Q mismatch and a high probability of pulmonary embolism (Reproduced, with permission, from Crawford MH Current Diagnosis & Treatment in Cardiology, 2nd ed New York: McGraw-Hill, 2003: 369 .) 390 ■ Rarely, phlegmasia... short-lived Used for acute day × 2 rate bleeding risk Splenectomy N/A 70% remission rate May require looking for accessory spleen Danazol 60 0 mg/day 10–80% response Usually second line IVIG rate Rituximab 80–90% response 50 μg/kg × 1 375 mg/m2 q wk × 4 doses Induces hemolytic anemia; works only with Rh-ᮍ rate Anti-RhD patients 30% response rate Can cause allergic reactions in chronic refractory ITP 3 76. .. RBC and plasma USE Provides oxygen-carrying capacity and plasma volume expansion For patients with massive blood loss (e.g., trauma) Packed RBCs RBC concentrated from donor unit Standard RBC product Each unit raises hemoglobin 1 g/dL Washed RBCs RBCs with plasma removed Prevent allergic reactions Irradiated RBCs Irradiation Prevent graft-versus-host disease Leukocyte-depleted RBCs Deplete donor leukocytes... Vitamin Deficiencies Table 9. 36 outlines common vitamin deficiencies and their associated disorders TA B L E 9 36 Common Vitamin Deficiencies VITAMIN DEFICIENCY A (retinol) CLINICAL SYMPTOMS Night blindness, conjunctival xerosis, Bitot’s spots (white spots on conjunctiva), keratomalacia B1 (thiamine) Dry beriberi, Peripheral neuropathy, Wernicke-Korsakoff syndrome; high-output CHF, vascular leak wet... ophthalmoplegia, ↓ proprioception 385 H E MATOLOGY Porphyrias H E MATOLOGY NOTES 3 86 CHAPTER 10 Hospital Medicine Jesse Liu, MD Robert Trowbridge, MD Venous Thromboembolic Disease 388 PULMONARY EMBOLISM 388 DEEP VENOUS THROMBOSIS 391 Acute Pain Management 393 Delirium 3 96 GI Prophylaxis in the Hospitalized Patient 3 96 Perioperative Management 397 PREOPERATIVE CARDIAC EVALUATION 397 PREOPERATIVE PULMONARY... ■ ■ ■ ■ ■ TA B L E 9 26 Treatment of ITP TREATMENT Prednisone An unprovoked clot occurring in a young person (< 50 years of age) A clot in an unusual location (e.g., mesenteric vein, sagittal sinus) An unusually extensive clot Arterial and venous clots A strong family history DOSE 1 mg/kg/day × 4 6 weeks EFFICACY 60 % response rate NOTES Time to remission is 1–3 weeks First-line treatment, but 90% . mutation of JAK2, a tyrosine kinase, is found in 65 –95% of patients. Al- though not yet part of the diagnostic criteria, it can be used to help distin- FIGURE 9.10. Myelodysplasia. Both neutrophils. cases. De- tectable by cytogenetics or by PCR for the BCR-ABL fusion gene, per- formed on peripheral WBCs. ■ Bone marrow biopsy is not necessary for diagnosis but is often done to de- termine. mutation is not part of the diagnostic criteria and not specific but strongly suggests the diagnosis. 367 HEMATOLOGY 368 ■ Bone marrow aspirate is frequently a dry tap (no aspirate can be ob- tained);