key: cord-0034728-o0kwuo3g
authors: Hui, David
title: Hematology
date: 2010-08-13
journal: Approach to Internal Medicine
DOI: 10.1007/978-1-4419-6505-9_6
sha: c6a76c131591f6987a25745fc5987a6d203790fd
doc_id: 34728
cord_uid: o0kwuo3g

SPURIOUS—stress (Geisböck’s syndrome), decrease intravascular volume PRIMARY—polycythemia rubra vera

LABS-CBCD, lytes, urea, Cr, LAP, vitamin B12, RBC mass (total blood volume  Hct, to rule out spurious causes), carboxyhemoglobin level, cortisol level, peripheral blood smear 

DISTINGUISHING FEATURES BETWEEN IRON DEFICIENCY AND THALASSEMIA RDW-red cells in thalassemia tend to have a narrower distribution than in iron deficiency MCV-red cells in thalassemia tend to be smaller than in iron deficiency RBC-RBC high or normal if thalassemia but tend to decrease proportionally to Hb in iron deficiency THALASSEMIA INDEX-MCV/RBC. Suggests thalassemia if <13 and iron deficiency if >13 MORPHOLOGY-thalassemia causes microcytic target cells DISTINGUISHING FEATURES BETWEEN IRON DEFI-CIENCY AND ANEMIA OF CHRONIC DISEASE-ferritin is indicative of marrow iron stores and is key to the diagnosis of iron deficiency anemia as serum iron and TIBC levels may change with other diseases <30 ng/ml-iron deficiency anemia (PPV 92-98%) 30-100 ng/ml-combination of anemia of chronic disease and true iron deficiency if (sTfR/ log ferritin)>2. Anemia of chronic disease alone if (sTfR/log ferritin) <1 100 ng/ml-anemia of chronic disease MANAGEMENT SYMPTOM CONTROL-transfusion 2 U PRBC IV over 2 h TREAT UNDERLYING CAUSE-iron deficiency (iron gluconate 300 mg PO TID, iron sulfate 325 mg PO TID, sodium ferric gluconate complex in sucrose 125 mg IV, ferumoxytol 510 mg IV). It may take up to 6 weeks to correct anemia and 6 months to replete iron stores

PLUMMER-VINSON SYNDROME-iron deficiency anemia, atrophic glossitis and esophageal web. Increased risk of esophageal squamous cell carcinoma

MCHC-" MCHC suggests spherocytosis MCV-a rise in MCV suggests reticulocytosis; """ MCV indicates the presence of cold agglutinins causing agglutination in the laboratory specimen before blood is run through the analyzer COOMBS TEST DIRECT COOMBS TEST (DAT)-patient's washed RBC incubated with anti-IgG and anti-C3. A positive result (i.e. agglutination) indicates that IgG and/ or C3 have bound to RBC surface in vivo. DAT positivity suggests immune rather than nonimmune causes of hemolysis IMMUNE HEMOLYTIC ANEMIA (DAT positive)autoimmune hemolytic anemia, drug-induced hemolytic anemia, alloimmune hemolytic anemia (acute hemolytic reaction) NON-IMMUNE HEMOLYTIC ANEMIA (DAT negative)-TTP/HUS, DIC, hemoglobinopathies, hereditary spherocytosis INDIRECT COOMBS TEST-normal RBC incubated with patient's serum. It is mainly used to detect low concentrations of antibodies in a patient's serum prior to blood transfusion RETICULOCYTE PRODUCTION INDEX (RPI, corrected reticulocyte count)-more accurate than raw reticulocyte count to evaluate if bone marrow response to anemia is appropriate or hypoproliferative RPI = [retic count  (hematocrit in %/45)]/ maturation factor w ABCDEFGH PAIN w ANEMIA CHRONIC HEMOLYSIS-normo or macrocytic due to reticulocytosis, elevated bilirubin, LDH, low haptoglobin). There may be associated folate/iron deficiency from increased utilization ACUTE ANEMIA-may be due to splenic sequestration crisis (venoocclusion of spleen leading to RBC pooling), aplastic crisis (transient arrest of erythropoiesis), and hyperhemolytic crisis (sudden onset of severe hemolysis). All of these may be triggered by viral infections such as parvovirus B19

BONES-bone infarction (pancytopenia), avascular necrosis, fat embolism, orbital compression syndrome CARDIAC-myocardial infarction (due to increased oxygen demand from cardiac output) ACUTE CHEST SYNDROME (chest pain, pulmonary infiltrates, cough, progressive anemia, hypoxemia, with or without fever)-treat precipitating factor, fluids, pain control, transfusions (simple or exchange) PRIAPISM-hydration, analgesics, transfusions, urology consultation PREOPERATIVELY-transfuse to Hb 100 g/L [10 g/dL] CHRONIC-interprofessional team, immunizations (Streptococcus pneumoniae, Haemophilus influenzae, Niesseria meningitidis, hepatitis B virus, and influenza), exchange transfusion (goal HbS < 30%), hydroxyurea (increase levels of fetal Hb, decrease incidence of vasoocclusive pain), folic acid 1 mg PO daily ASPLENIC PATIENTS-particularly susceptible to encapsulated bacteria (S. pneumoniae, H. influenzae, and N. meningitidis), Capnocytophaga canimorsus, Gram-negative enteric organisms, and babesiosis VACCINATIONS-all patients should receive vaccinations against H. influenzae, pneumococcus, and meningococcus. Flu shot should be given annually and other immunizations repeated every 5 years

ANTIBIOTICS WITH FEVER-any fever in an asplenic patient should prompt self-administration of preprescribed antibiotics (levofloxacin 750 mg PO daily, moxifloxacin 400 mg PO daily, or cefuroxime 1 g PO daily 

MANAGEMENT SYMPTOM CONTROL-in under-production thrombocytopenia, transfuse 5 U platelets if platelets <50Â10 3 /mL and severe bleeding, platelets <10Â10 3 /mL in afebrile non-bleeding patient, <20Â10 3 /mL in febrile non-bleeding patient, and prior to certain procedures (expect platelet rise of $5/unit). Note that platelet transfusions are not effective in ITP and may worsen TTP/HUS and HITT TREAT UNDERLYING CAUSE-discontinue medications that may cause thrombocytopenia (platelets may return to normal in 14-21 days). Please refer to specific disorders below for details regarding treatment of each disease

HEMOLYTIC ANEMIA (MAHA)-also called fragmentation hemolysis. Characterized by non-immune hemolytic anemia and schistocytes. Causes include DIC, HELLP, TTP, HUS, malignancy, malignant hypertension, artificial heart valve, insertion of foreign bodies, and medications 

PATHOPHYSIOLOGY-antibody against phospholipids or cell surface proteins bound to anionic phospholipids. These include lupus anticoagulants, anticardiolipin antibody (false-positive VDRL), and anti-b2GP1 (b2-glycoprotein 1) antibody ! may lead to hypercoagulable state and may rarely inhibit coagulation CAUSES-primary APS, secondary APS (various rheumatic diseases such as SLE and infections such as HIV and drugs) CLINICAL FEATURES-venous and arterial thrombosis and rarely hemorrhage affecting the lungs, heart, CNS, GI, kidneys, skin, and eyes. Also recurrent fetal

losses (recurrent first trimester or single late term), thrombocytopenia, and livedo reticularis DIAGNOSIS-clinical criteria include thrombosis (!1 arterial, venous, or small-vessel thrombosis in any organ) or pregnancy complications (!1 unexplained deaths of morphologically normal fetus at or after the 10 th week of gestation, !1 premature births of morphologically normal neonate at or before the 34 th week of gestation, or !3 unexplained consecutive spontaneous abortions before the 10 th week of gestation TARGET CELLS-liver disease (especially obstructive jaundice, hepatitis), thalassemia, post-splenectomy, hemoglobinopathies (hemoglobin C and E), lecithin-cholesterol acyltransferase deficiency FRAGMENTED CELLS (schistocytes, helmet cells)microangiopathic hemolytic anemia (DIC, TTP, HUS), aortic valve prosthesis TEAR DROP CELLS-myelophthisis, myelofibrosis with myeloid metaplasia (MMM), severe iron deficiency, thalassemia major. Disappear after splenectomy BURR CELLS (echinocytes)-uremia, artifact SPUR CELLS (acanthocytes)-chronic liver disease, abetalipoproteinemia, malabsorption, anorexia nervosa SPHEROCYTES-due to loss of membrane surface area. Associated with autoimmune hemolytic anemia (microspherocytes), hereditary spherocytosis, and Clostridium infections ELLIPTOCYTOSIS (ovalocytosis)-hereditary elliptocytosis, megaloblastosis STOMATOCYTES-acute alcoholism, chronic liver disease, artifact ROULEAUX-stacking of RBC suggestive of high ESR or hypergammaglobulinemia. Causes include malignancies (myeloma), infections, and connective tissue disease Spleen has a notch 3. Spleen moves inferomedially on inspiration while the kidney moves inferiorly 4. Spleen is not usually ballotable unless gross ascites are present, but the kidney is because of its retroperitoneal position 5. The percussion note is dull over the spleen but is usually resonant over the kidney 6. A friction rub may occasionally be heard over the spleen, but never over the kidney because it is too posterior Traube's space (percuss space 6 th rib superiorly, mid-axillary line laterally and costal margin inferiorly; dullness suggests splenomegaly 62% 72%

Palpation Two-handed palpation with patient in right lateral decubitus position 71% 90% One-handed palpation with patient supine --APPROACH-''given the low sensitivity of the clinical examination, routine examination for splenomegaly cannot definitively rule in or rule out splenomegaly in normal, asymptomatic patients where the prevalence is < 10% and additional imaging tests will be required. Rather, the examination for splenomegaly is most useful to rule in the diagnosis of splenomegaly among patients in whom there is a clinical suspicion of at least 10%. The examination should always start with percussion. If no dullness is detected on percussion, there is no need to palpate as the results of palpation will not effectively rule in or rule out splenic enlargement. If the possibility of missing splenic enlargement remains an important clinical concern, then ultrasound or scintigraphy is indicated. In the presence of percussion dullness, palpation should follow. If both tests are positive, the diagnosis of splenomegaly is established (providing the clinical suspicion of splenomegaly was at least 10% before examination). If palpation is negative, diagnostic imaging will be required to confidently rule in or rule out splenomegaly''

JAMA 1993 t(15;17) (q22;q21), which results in fusion of PML gene and retinoic acid receptor a gene. This gene product plays a key role in leukemogenesis. Other combinations include t(11;17) with fusion of PLZF gene, t(5;17) with fusion of NPM gene, or t(11;17) with fusion of NuMA gene. Note that all except PLZF-RARA are susceptible to retinoic acid treatment CLINICAL FEATURES-similar to AML. DIC commonly occurs in PML and should be monitored closely TREATMENTS-induction with all-trans-retinoic acid plus idarubicin, then consolidation with anthracycline and cytarabine, and then maintenance with all-trans-retinoic acid for 1 year. Retinoic acid exerts its effect via (1) degradation of PML-RAR protein, (2) transformation of PML-RAR from transcription repressor to activator, and (3) differentiation. Retinoic acid syndrome may occur with fever, respiratory distress, interstitial pulmonary infiltrates, pleural and pericardial effusion, episodic hypotension, acute renal failure, and weight gain. Arsenic trioxide can be used for recurrent disease but is associated with QT prolongation and sudden death PROGNOSTIC FACTORS-while childhood ALL is curable in 85% of cases, adult ALL has a worse prognosis, with a 5-year survival of 35%. Factors associated with poorer survival include the following: CLINICAL-lack of response to induction therapy (most important), old age, leukocyte count, CNS involvement CYTOGENETICS-BCR-ABL fusion or t(9;22) (also known as the Philadelphia chromosome, in 20-50% of adults), MLL-AF4 fusion or t(4;11) (in 5-6% of adults), t(8;14), t(1;19), hypodiploidy ( < 45 chromosomes/cell), del (7), trisomy FAVORABLE PROGNOSIS-hyperdiploidy, del(9), TEL-AML1 fusion or t(12;21) (in 10% of adults) RISK CATEGORIES HIGH RISK-any of age >60, t(9;22) or bcr-abl, t(4;11), t(1;19); WBC >30Â10 3 /mL in B-ALL or >100Â10 3 /mL in T-ALL or pro-B ALL STANDARD RISK-none of high-risk features RISK FACTORS FOR CNS RELAPSE-high-risk genetic features, T-ALL, large tumor burden, CSF positivity MANAGEMENT REMISSION INDUCTION THERAPY-combination chemotherapy with prednisone, vincristine, an anthracycline AE asparaginase, and cyclophosphamide. Complete response 80-90%. Management of specific subgroups include PH+ ALL-add imatinib B-CELL ALL-treat as aggressive non-Hodgkin's lymphoma T-CELL ALL-treat with cyclophosphamide-containing regimens CNS PROPHYLAXIS-to start after remission with intrathecal methotrexate with high-dose systemic methotrexate. Consider cranial radiation for patients at high risk of CNS relapse INTENSIFICATION/CONSOLIDATION THERAPY STANDARD RISK-consolidation chemotherapy with various combinations of cyclophosphamide, 6mercaptopurine, cytarabine, vincristine, and doxorubicin HIGH RISK-allogeneic SCT if HLA-matched donor available and eligible for transplant; otherwise, consolidation chemotherapy MAINTENANCE THERAPY-POMP (6-mercaptopurine daily, methotrexate weekly, vincristine and prednisone monthly) or dexamethasone for 2-3 years, except for patients who received allogeneic SCT . Secondline therapy includes mainly alkylating agents (chlorambucil, cyclophosphamide, CVP). Alemtuzumab (anti-CD52 antibody) is useful for fludarabine-refractory disease (i.e. lack of CR/PR, or response but <6 months). Indications for treatment include symptoms (weakness, painful lymphadenopathy, B symptoms, symptomatic splenomegaly), anemia (Hb <110 g/L [<11 g/ dL]), thrombocytopenia (platelets <100Â10 3 /mL), autoimmune hemolytic anemia/thrombocytopenia that failed steroids, progressive disease (increasing lymphocytosis with doubling time <6 months AE rapidly enlarging lymph nodes, spleen, and liver). If evidence of

Richter's transformation, treat as aggressive lymphoma with CHOPR NOTE-while traditionally SLL has been managed as a low-grade non-Hodgkin's lymphoma, it is identical to CLL and should be treated as such

NCI WORKING GROUP DIAGNOSTIC CRITERIA FOR TREATMENT RESPONSE COMPLETE RESPONSE-normal physical examination and no symptoms. Lymphocytes 4 Â10 3 /mL, neutrophils !1.5Â10 3 /mL, platelets >100Â10 3 / mL, Hb >110 g/L [>11 g/dL], and bone marrow lymphocytes < 30% with no nodules. Duration of at least 2 months PARTIAL RESPONSE-nodes/liver/spleen !50% decrease PLUS one of neutrophils !1.5Â10 3 /mL, platelets >100Â10 3 /mL, or Hb >110 g/L [>11 g/dL] or 50% improvement. Duration of at least 2 months STABLE DISEASE-between PR and PD PROGRESSIVE DISEASE-any one of nodes/liver/ spleen !50% increase or new lesions, lymphocytes !50% increase, or Richter's syndrome

HAIRY CELL LEUKEMIA PATHOPHYSIOLOGY-rare indolent non-Hodgkin's lymphoma with mononuclear cells displaying cytoplasmic projections giving a hairy appearance. Secretes fibronectin, cytokines, and TNF-causing bone marrow fibrosis CLINICAL FEATURES-splenomegaly (90%), cytopenia (fatigue, recurrent infections, thrombocytopenia), and leukocytosis. Lymphadenopathy is uncommon TREATMENTS-treat only if symptomatic (cytopenia, splenomegaly, B symptoms). Cladribine (2Cda) is first-line treatment and may be repeated. Other treatments include pentostatin, interferon, splenectomy, rituximab, and BL22 (CD22 antibodies) II Two or more node regions on the same side of diaphragm. All nodal disease within the mediastinum is considered to be a single lymph node region and hilar involvement constitutes an additional site of involvement.

The number of anatomic regions should be indicated by a subscript (e.g. II-2)

III Involvement on both sides of diaphragm. BURKITT'S LYMPHOMA 14) host disease, graft failure, or death. Note that transplant is not affected by differences in ABO blood groups HLA CLASS I-HLA-A, HLA-B, HLA-C HLA CLASS II-HLA-DR, HLA-DQ, HLA-DP MATCHING PROCESS-need to ensure good match of the following loci: HLA-A, HLA-B, HLA-C, DRB1, and DQB1. The chance of finding a sibling match is 1-0.75 n , where n=number of siblings. The chance of finding a matched unrelated donor is >60%, higher for Caucasians and lower for other races. Search for a match typically takes 3-4 months CONDITIONING-goal is to eradicate malignancy and suppress recipient's immune system to minimize rejection of donor's stem cells. Myeloablative regimens include cyclophosphamide plus total body irradiation (TBI) or high-dose busulfan. Reduced intensity regimens include fludarabine plus busulfan. Reduced intensity (also known as non-myeloablative or ''mini'' transplant) regimens use a milder conditioning regimen more tolerable for older patients (e.g.

fludarabine plus cyclophosphamide, melphalan). Monitor toxicities closely during this time HEMATOLOGIC-pancytopenia, febrile neutropenia EARLY NON-HEMATOLOGIC-alopecia, N&V, oropharyngeal mucositis, diarrhea, sinusoidal obstruction syndrome (previously known as hepatic venoocclusive disease with tender hepatomegaly, jaundicem and ascites), seizures, parotitis, pericarditis, cardiomyopathy, interstitial pneumonitis, hemorrhagic cystitis, rash LATE NON-HEMATOLOGIC-hypothyroidism, sterility or premature menopause, growth impairment, dry eyes or mouth, cataracts, osteopenia, or osteoporosis FERTILITY-infertility is almost certain in both men and women after TBI regimens, but not definite with non-TBI regimens SECOND MALIGNANCIES-increased incidence of solid tumors (bone, oropharynx, connective tissue, CNS, thyroid, melanoma), myelodysplastic syndrome, acute myelogenous leukemia, and lymphoproliferative disorders. Highest risks in patients with TBI TRANSPLANTATION-infusion of stem cells over 30 min to 2 h ENGRAFTMENT-typically happens between days +10 and +20. Defined as ANC >0.5Â10 3 /mL, with platelet and RBC engraftment following. GCSF may be used in non-leukemic patients to accelerate engraftment by up to 1 week. Patient is supported with blood products and antimicrobial prophylaxis (e.g. ciprofloxacin for Gram negatives, trimethoprimsulfamethoxazole for PCP, acyclovir for HSV, fluconazole for fungal agents) until engraftment occurs. Failure to engraft (primary graft failure) and irreversible decline of blood counts (secondary graft failure) are serious complications ( <5%). For non-myeloablative transplant, perform chimerism analysis and consider either donor leukocyte infusion (DLI) or reducing immunosuppression to improve disease control IMMUNORECONSTITUTION-restoration of T-cell and B-cell immunity takes up to 12 months. Immunosuppressive treatment can usually be stopped within 1-3 years post-allogeneic transplant. Graft vs. host disease (GVHD) is a donor T-cell-mediated process. Overall transplant-related mortality is approximately 20-25% GRAFT VS. HOST DISEASE ACUTE GVHD ( <100 days)-occurs in 40% of matched sibling and 80% of unrelated donor transplant. Symptoms include rash, hepatic dysfunction, diarrhea, vomiting. Mortality up to 80% in grade III and IV acute GVHD. Prophylaxis consisting of methotrexate and cyclosporine is usually used for anyone other than identical twins. Treatments include corticosteroids, cyclosporine, mycophenolate mofetil, tacrolimus, and antithymocyte globulin

IgA <30 g/L [ <3 g/dL], and urinary l or k chains <4 g/day. Median survival $60 months STAGE II (intermediate burden, 0.6-1.2Â10 12 / m 2 )-between stages I and III. Median survival $30 months STAGE III (high tumor burden, >1.2Â10 12 /m 2 )-any of Hb <85 g/L

The international staging system for multiple myeloma is particularly useful STAGE I-b2 microglobulin < 3.5 mg/L, albumin !35 g/L [!3.5 g/dL]. Median survival 62 months STAGE II-neither stage I nor III. Median survival 44 months STAGE III-b2 microglobulin !5.5 mg/L. Median survival 29 months JCO

>100 days)-an autoimmune syndrome occurs in up to 50% of matched sibling and >50% of unrelated donor transplant. Symptoms include oral and ocular changes (sicca), alopecia, cholestatic hepatic dysfunction, polyserositis, cutaneous scleroderma, and bronchiolitis obliterans. Treatments include corticosteroids and cyclosporine or tacrolimus for at least 6 months INFECTIONS PRE-GRAFTMENT ( <30 days)-HSV, Gram-negative bacteria, Gram-positive Streptococcus, fungal, central line infections (S. epidermis) EARLY INFECTIONS (30-100 days)-CMV, some fungal, PCP, central line infections (S. epidermis) LATE INFECTIONS (>100 days)-VZV, encapsulated bacteria, PCP, Aspergillus AUTOLOGOUS TRANSPLANTATION MATCHING PROCESS-not applicable CONDITIONING-similar to allogeneic transplant

melphalan) TRANSPLANTATION-similar to allogeneic transplant, except stem cells obtained from patient pretransplant and cryopreserved ENGRAFTMENT-similar to allogeneic transplant IMMUNORECONSTITUTION-more rapid immune recovery and no GVHD. Overall transplant-related mortality is approximately 2% LATE EFFECTS-MDS and AML in at least 10% of patients 5-10 years after autologous transplant Related Topics Acute Leukemia (p. 166) Chemotherapy-Induced Diarrhea (p. 231) Non-Hodgkin's Lymphoma (p. 173) Febrile Neutropenia (p. 236) Fungal Infections (p. 265) Multiple Myeloma (p. 178) Oral Mucositis

 14) in 95%, cyclin D1 (bcl1) 18) in 85%, antiapoptotic protein (bcl2) DIFFUSE LARGE CELL 14) in 40%, zinc finger transcription factor (bcl6) 14) in < 5%, bcl10 BURKITT'S 14) AUTOLOGOUS TRANSPLANTATION (60%)-stem cells from self. The main advantage is lesser toxicity compared to allogeneic transplant, while the main disadvantage is possible contamination of the graft with malignant cells