Background (NEJM 1999;341:1986; 2005;352:1011; 353:1135; 2015;372:1832; 373:1649)
Definition: ↓ in RBC mass; threshold depends on age, sex, race: white
♂ Hgb <13.5 g/dL; African ancestry ♂ Hgb <12.8 g/dL; white ♀ Hgb
<12.2 g/dL; African ancestry ♀ Hgb <11.5 g/dL (Blood 2006;107:1747); other factors affecting RBC mass include high altitude, smoking, athletics, ACEI, volume status
| Causes of Anemia (AFP 2000;62:2255; 2009;79:203; 2010;82:1117; NEJM 2014;371:1324) |
| Microcytic: Iron/copper deficiency, anemia of chronic dz, lead poisoning, congenital/acquired sideroblastic anemias; thalassemias & hemoglobinopathies |
| Normocytic: Anemia of chronic dz, early iron deficiency, CKD, hypothyroidism, bleeding, hypersplenism, hemolysis (spherocytosis, sickle cell, G6PD, autoimmune, mechanical) |
| Macrocytic: B12/folate deficiency, ↑ reticulocytes, medications (dozens, inc hydroxyurea, AZT, chemotherapy), EtOH, liver dz, hypothyroidism, myelodysplastic/myeloproliferative dz |
Pathophysiology: Erythropoietin produced in kidney stimulates hematopoiesis in the bone marrow; Nl RBC life ∼120 d; hemolysis considered when life <120 d; in many pts iron deficiency is multifactorial
| Anemias with ↑ Erythrocyte Destruction (AFP 2004;69:2599) |
| DDx: Sickle cell, thalassemia major, hereditary spherocytosis, autoimmune, infectious (malaria, babesia, bartonella), G6PD deficiency, hypersplenism, medications (dapsone), liver dz, autoimmune hemolytic anemia, microangiopathy (i.e., aortic stenosis), pulmonary hemosiderosis. Hemolysis may be intravascular (mechanical trauma, paroxysmal nocturnal or cold hemoglobinurias, cold agglutin dz, infection, complement fixation) or extravascular in liver/spleen (antibody fixation, inability to deform) Autoimmune: ⊕ direct Coombs; cold agglutinins (IgM, found in mycoplasma PNA, mononucleosis) or warm (IgG, found in autoimmune dz, drug exposure (dozens reported, common culprits include penicillins, NSAIDs)) target RBC surface proteins → destruction; cold or warm agglutinins found in malignancy (CLL, lymphoma, Waldenstrom) Evan’s syndrome: Warm autoimmune hemolytic anemia + ITP
Fragmentation hemolysis: ↑ Schistocytes (>1%) found in disseminated intravascular coagulation, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, & HELLP syndrome (Am J Hematol 2004;75:18); fragmentation may also be seen w/ faulty prosthetic heart |
| valves, malignancy, severe HTN, hypersplenism, & after chemo Glucose 6-phosphate
dehydrogenase (G6PD) deficiency: NADPH produced by G6PD protects RBC from oxidative stress; X-linked; ↑ oxidants from physiologic stress, meds (i.e., acetaminophen, aspirin, chloroquine, colchicine, nitrofurantoin, phenazyopyridine, primaquine, sulfamethoxazole) → ↑ oxidative damage → RBC destruction (Blood 1994;84:3613); G6PD heterozygosity found in 20% & 12% of African-American ♂ & ♀, respectively (Mil Medicine 2006;171:905); degree of deficiency & consequences vary Thalassemia: ↓ or absent synthesis of α or β Hgb chains → ineffective erythropoiesis + hemolysis → microcytic, hypochromic anemia; classified into major (transfusion dependent) & minor (heterozygotes = trait, tend to be asx & mildly anemic); pts who are transfusion dependent susceptible to Yersinia infection 2° to ↑ iron |
| Anemias with Decreased Erythrocyte Production (Low Reticulocyte Count) |
| DDx: Iron, B12, folate deficiency (Chap X) due to malnutrition, malabsorption (celiac dz, H. pylori, atrophic gastritis, gastric bypass); marrow problems (MDS, tumor, aplastic anemia, medications, XRT); ↓ erythropoietin (renal failure), hypothyroidism, hypogonadism; chronic dz (↓ absorption, ↓ macrophage release) Iron deficiency: Iron deficiency anemia found in 1–2% of US adults; iron deficiency w/o anemia in 11% ♀, 4% ♂ (AFP 2007;75:671; JAMA 1997;277:973); nonanemic ♂ have ∼3–4 g in iron stores, ♀ have 2–3 g, most of which stored in Hgb; iron stores (mg) may be estimated by 8–10 × ferritin (ng/mL); inflammatory dz (i.e., RA), ↑ ferritin by ∼3-fold (Blood 2003;101:3359; Semin Hematol 1982;19:6); ↑ risk in pts with vegetarian/vegan diets & athletes (Fe loss via GIB & exercise-induced hemolysis); pts w/ obesity/CHF may be iron deficient due to subclinical inflammation (NEJM 2015;372:1832) Anemia of chronic disease: ↓ marrow RBC production 2/2 to chronic illness Elderly: 20–30% of pts have anemia of ? etiology, likely multifactorial & related to ↓ stem cells, hypogonadism, ↓ erythropoietin, & early MDS (AFP 2010;82:480; Blood 2004;104:2263) Sideroblastic anemia: Congenital or acquired (myelodysplasia, drugs [chloramphenicol, INH, linezolid]), EtOH, ↓ copper, lead/zinc poisoning) deficiency in synthesis of heme or Hgb → microchromic, typically microcytic anemia + iron overload EtOH abuse: ↓ heme synthesis, malnutrition, variceal bleeding; macrocytosis Acquired pure red cell aplasia: ↓ RBC production, absent retics, & absence of RBC precursors in marrow; most cases idiopathic; may be assoc w/ leukemia, MDS, thymoma, drugs (INH, valproic acid, mycophenolic acid), parvovirus, & autoimmune dz Aplastic anemia: Hematopoietic stem cell deficiency/failure → pancytopenia w/o splenomegaly → anemia + recurrent infections & bleeding. Congenital (Fanconi anemia), acquired (drugs – chloramphenicol, sulfonamides, phenytoin, carbamazepine, valproic acid, indomethacin; infection – parvovirus, EBV, hepatitis, HIV), & idiopathic (Lancet 1995;346:228).
Diagnosed by BmBx. Treated w/ removal of causative agent, supportive care (transfusions, abx), stem cell transplant, immunosuppression. |
| Anemias Due to Bleeding |
| GI, menorrhagia, blood donation, hemorrhage into thigh or retroperitoneum, iatrogenic (multiple blood draws), diverticular dz, malignancy |
Evaluation
History: Duration of sx; exertional dyspnea, fatigue, dizziness, HA, palpitations, ↓ concentration, syncope, menorrhagia, melena, hematochezia, bone pain, diet (vegetarian/vegan); signs of systemic dz
(fevers, night sweats, anorexia, wt loss, malaise); meds (esp NSAIDS, aspirin, PPI), EtOH, alternative meds; pica (craving items not suitable as food), geophagia (craving clay/dirt), pagophagia (craving ice); restless leg syndrome (Fe deficiency); ethnicity (i.e., Mediterranean) & FHx of hematologic dz/malignancy or bleeding d/o; blood transfusion/donation hx; sx on cold exposure (cold agglutinin hemolytic anemia); personal hx of H. pylori, PUD, sprue, IBD, bariatric surgery/gastrectomy, diverticular dz, hemorrhoids; compliance with oral iron therapy; Mediterranean/north African/south east Asian ancestry (thalassemia)
Abnormal menstrual bleeding: Changing pads >q3h. >21 pads/cycle, need to change pad at night (Am J Obstet Gynecol 2004;190:1216)
Exam: Pallor (skin, palmar creases, oral mucus membranes, nail beds, palpebral conjunctiva), tachycardia, orthostatic VS, systolic flow murmur (↑ CO), atrophic glossitis (Fe, folate, B12 def), angular cheilosis, jaundice (hemolysis), splenomegaly, koilonychia (spoon-like
fingernails seen in Fe deficiency); lymph node exam
Workup: CBC w/ differential & RBC indices, retic count, peripheral smear (NEJM 2005;353:498), Chem-12, stool guaiac. Further w/u based on clinical suspicion: Iron, TIBC, ferritin, folate, B12, Hgb electrophoresis, TSH, erythropoietin, SPEP, H. pylori, colonoscopy/EGD, ANA, TTG for
celiac dz (Chap X); referral to hematology for BmBx if Dx unclear
despite above w/u
Reticulocyte index: [reticulocyte count × (Pt’s HCT/nl HCT)]/maturation factor; maturation factors for given HCT: 45 = 1, 35 = 1.5, 25 = 2, 20 = 2.5. RI >2% = appropriate BM response; RI
<2 = inadequate BM response Screening: ✓ CBC in pregnant
women at first prenatal visit (USPSTF Ann Int Med 2015;163:529); CDC recommends ✓ CBC in premenopausal ♀ q5–10 y (MMWR Morb Mortal Wkly Rep 1998;47:1); consider CBC q5 y in asx pts >50 y & annually in pts w/ chronic dz (Curr Med Res Op 2006;22:385)
| Disease Test & Comments | |
| Iron deficiency | Microcytosis, ↓ Fe, ↓ ferritin, ↓ transferrin sat, ↑ TIBC, ± reactive ↑ PLT; ferritin <41 ng/mL 98% sensitive/specific; cutoff higher in CHF (300 ng/mL) due to inflammation (Blood 1997;89:1052);
transferrin sat <16% diagnostic (30% in pts w/ CKD) |
| Anemia of chronic dz |
Dx of exclusion; ↓ Fe, nl or ↓ TIBC, nl or ↑ ferritin, ↑ ESR or CRP, ↓ retic index, erythropoietin value not appropriately increased in pts w/ nl renal function (NEJM 2014;371:1324) |
| α-or β-thalassemia minor | Hgb electrophoresis; FHx anemia, nl or ↑ ferritin, Fe |
| B12 or folate deficiency | Macrocytosis + neutrophil hypersegmentation (Chap X) |
| Hemolysis | ↑ LDH, ↓ haptoglobin, ↑ indirect bilirubin, ± ↑ retic; ↑ urine & plasma Hgb & ↑ urine hemosiderin in intravascular hemolysis; Nl LDH + haptoglobin >25 mg/dL 92% sensitive in r/o hemolysis (JAMA 1980;243:1909) |
| Hypersplenism/bleeding | ↑ retic count, retic index >2% w/o e/o hemolysis |
| Autoimmune hemolytic anemia | ⊕ Direct Coombs: Detects offending Ab bound to pt RBC; washed pt RBCs mixed w/ antiserum or Abs specific to immunoglobulins (Indirect Coombs: Pt serum mixed w/ nl RBC; primarily used to test for transfusion compatibility) |
Treatment (AFP 2009;80:339; 2013;87:98; Am J Med 2008;121:943)
Transfusion: Consider if Hgb <8 g/dL or if pt symptomatic (Ann Intern Med 2012;157:49); 1 U packed RBC contains 200 mg iron, ↑ Hgb by 1 g/dL & HCT by 3–4% (Ann Intern Med 1994;121:278)
Iron deficiency anemia: Typical Rx is ferrous sulfate 325 mg PO QD; if not tolerated then ferrous gluconate 325 mg PO QD; co- administration of oral iron w/ ascorbic acid, orange juice or meat ↑ Fe absorption & tolerability; Ca supplements/antacids, tea, & soy protein ↓ Fe absorption. Goal: Daily dose of elemental iron 150–200 mg/d; IV iron may be used for pts unable to absorb or tolerate oral iron (i.e., IBD, s/p gastric bypass, celiac dz, H. pylori, HD, profound deficiency); treatment may continue until Hgb normalizes, unless profoundly deficient & iron stores need repletion; reticulocytosis ∼1 wk & ↑ Hgb
∼2 wks after beginning PO iron repletion suggests response; PO iron
produces dark stools but does not produce false positives on stool guaiac tests
Prevention: Pregnant pts should take a 30 mg/d iron supplement; if Fe deficiency found then Rx a 60–120 mg supplement Failure to respond: May be due to comorbid dz (i.e., anemia of chronic dz, MDS, RA), B12/folate deficiency, malignancy, thalassemia,
compliance issues, ↓ absorption (antacids, s/p bypass), bleeding
| Iron Repletion (Lancet 2007;369:1502; NEJM 2007;357:93; 2014;371:1324; 2015;372:1832) | |||
| Form | Elemental Fe | Comments | |
|
Oral |
Ferrous fumarate | 106 mg/tablet | Highest “concentration” of iron/tablet |
| Ferrous sulfate | 65 mg/tablet | Least expensive; first line treatment | |
| Ferrous gluconate | 28–38 mg/tablet | ↑ GI tolerance due to ↓ Fe, but more pills/day | |
| Ferrous sulfate elixir | 44 mg/5 mL | Better GI tolerance than sulfate tablet | |
| Carbonyl iron | 45–60 mg/tablet | Elemental iron in microscopic spheres → ↑ GI tolerance | |
| Heme iron polypeptide | 28 mg/tablet | May be combined w/ iron polysaccharide (Feosol Complete w/ Bifera); unlike elemental iron, heme iron may be taken w/ or w/o food; ↑ GI tolerance | |
| Goal dose (mg): Weight in kg × 2.3 × (target Hgb – pt Hgb) + 500–1000 mg to replete iron stores; various calculators available online, i.e., globalrph.com/iron.htm; General s/e: Nausea, pruritus, headache, myalgia/arthralgia | |||
| Iron sucrose | 200 mg per 2–90′ infusion | Equal in safety (Nephrol Dial | |
| Transplant 2006;21:378); test | |||
|
Intravenous |
dose not necessary unless pt has reacted previously to iron dextran; pts may require multiple infusions to replete | ||
| Ferric gluconate | 125 mg/10–60′ infusion | ||
| Ferric carboxymaltose | 750 mg/15–30′ | Doses must be given 1 wk apart | |
| Ferumoxytol | 510 mg (max) | Rapidly given (30 mg/sec); used in HD | |
| Iron dextran | 50 mg/mL | Highest rate of local or systemic s/e (4.7%), & anaphylactic rxns (1%) (Am J Kid Dis 1999;33:464); | |
| requires 25 mg test dose & 4–6 h infusion | |||
Anemia of chronic disease: Treat underlying condition; may coincide w/ iron deficiency anemia, which should be treated; consider use of an erythropoiesis-stimulating agent; see Chap X for management in CKD Hemolytic anemias: Co-management w/ hematology recommended
Immune: D/c culprit drug; Warm agglutinins: Steroids; immunosuppression, cytotoxic meds, IvIg; splenectomy in sev cases (Am J Hematol 2002;69:258); Cold agglutinins: Avoidance of cold, cytotoxic agents, rituximab, plasmaphresis in severe cases (Br J Haematol 2011;153:309) G6PD deficiency: D/c culprit drug; folate supplementation
Hereditary spherocytosis: Folate; transfusion w/ iron overload PPx; splenectomy Thalassemia major: Transfusion w/ iron overload PPx & folate; manage endocrinopathies, osteopenia; Minor: Preconception genetic counseling
Patient information: AFP 2000;62:2265; JAMA 2012;307:2448
Background (Ann Intern Med 2010;152:300; Blood 2007;110:1092; NEJM 2007;356:444;
459)
Definition: ↑ RBC mass (Hgb >18.5 g/dL ♂, >16.5 g/dL ♀, or HCT
>52% ♂, 48% ♀). Pts w/ thalassemia trait may have ↑ RBC # w/ a nl or
↓ Hgb/HCT &/or ↓ MCV.
Pathophysiology: Relative polycythemia is due to ↓ plasma volume; usually asx. Secondary polycythemia: ↑ RBC mass in response to ↓ oxygen (COPD, high altitude, smoking, OSA, chronic CO exposure, R
→ L shunt). May also be due to erythropoietin secretion secondary to renal-vascular dz, renal/uterine/ovarian/cerebellar/hepatocellular CA, fibroids, renal transplant, or testosterone/anabolic steroid use.
Polycythemia vera (PCV): ↑ in RBC mass due to clonal expansion ±
↑ granulocytes & PLTs in absence of physiologic stimulus; chronic myeloproliferative disorder due to JAK2 gain of function mutation V617F (95–97% pts) or exon 12 mutation. JAK2 V617F is found in
∼50% of pts w/ essential thrombocytosis & myelofibrosis.
Evaluation and Prognosis (AFP 2004;69:2139; Br J Haematol 2013;160:251)
History: H/o thrombosis, erythromelalgia (burning pain, erythema, & swelling in extremities); hyperviscosity (HA, dizziness, tinnitus, blurred vision); bleeding (easy bruising, epistaxis, GI bleed, hemoptysis); pruritus after bathing, gout; smoking Hx; occupational/home CO exposures; daytime somnolence.
Exam: Plethora, splenomegaly, HTN, purpura, engorged retinal veins, cyanosis, normal O2 sat at rest & w/ activity (i.e., walking).
Workup: CBC w/ diff (repeat testing to confirm ↑ RBC mass), pulse ox; Epo level (↑ in 2° polycythemia; ↓↓ in PCV). Carboxyhemoglobin level (↑ in 2° polycythemia due to CO). JAK2 mutation analysis (V617F most common, exon 12 mutations rare). CXR if pulm dz suspected.
Urinalysis (microscopic hematuria may be seen in Epo-secreting RCC). Other Epo-secreting tumors include HCC, hemangioblastoma, pheochromocytoma, & uterine fibroids.
Prognosis: Relative survival (mortality assoc w/ PCV) 72% at 10 y, 46% at 20 y from Dx; various prognostic indexes proposed. ↑ risk of AML, MDS, CV death, CVA, arterial/venous thrombosis.
Treatment (Blood 2012;120:275)
Secondary polycythemia: Treat underlying cause (smoking cessation, COPD (Chap X)).
Polycythemia vera: Hematology referral for phlebotomy (goal HCT
<45%) (NEJM 2013;368:22) & hydroxyurea if ↑ risk thrombosis (age >60 y, h/o thrombosis) or severe sx (pruritus, bone pain, weight loss, splenomegaly) (Br J Haematol 2005;130:174); first phlebotomy should remove
½ unit (250 cc) & replace volume lost w/ saline; avoid iron supplementation; allopurinol if ↑ UA; pruritus may be treated w/ antihistamines, avoiding hot showers & starch baths.
All pts: Consider low-dose ASA (75–100 mg/d) unless contraindicated.
Patient information: AFP 2004;69:2146
Evaluation (AFP 2012;86:913; Blood 2002;99:3102; NEJM 2003;349:1227; 2008;358:1037;
2010;363:266)
DDx of DVT: Varicose veins, superficial thrombophlebitis, muscle strain, cellulitis, lymphedema, Baker cyst. See “Chest Pain” (Chap X) for DDx of PE.
History: Edema, calf/thigh pain, venous distention, dyspnea, pleuritic chest pain, cough, hemoptysis, syncope, orthopnea or asx; PE found in 1 in 6 pts hospitalized for first episode of syncope (NEJM 2016;375:1524); H/o previous thrombosis; OCP or tamoxifen use; fetal losses; cancer hx, incl compliance w/ CA screening; pregnancy; FHx DVT/PE, cancer
(Am J Med 2007;120:871).
Risk factors: H/o immobility, surgery, obesity, h/o VTE, LE trauma, malignancy, OCP use, pregnancy, stroke
Exam: DVT: Edema, redness, warmth, palpable cord, ⊕ Homans’ sign (calf pain w/ passive foot dorsiflexion), difference in calf diameter; distal DVT → deep calf below the knee; proximal DVT → popliteal, femoral, or iliac veins. PE: Tachypnea, tachycardia, ↓ O2, rales, pleural rub, ↑
JVP, fever; stool guaiac prior to anticoagulation
Workup: Se of LE U/S 94% (proximal DVT), 63% (distal DVT), Sp 94% (both); if clinical suspicion for DVT is high & LE U/S negative, repeat in 5–7 d; ✓ ECG, coags, CBC w/ diff, Chem-12, UA (nephrotic syndrome); V:Q scan in pts who are morbidly obese, have CKD, or cannot undergo PE-CT
D-dimer: 96–99% NPV in pts w/ low/intermediate pretest probability; age-adjusted cut-off of 10 ng/mL × age should be used in pts >50 y (JAMA 2014;311:1117).
Hypercoagulability w/u: Controversial (JAMA 2005;293:2352); consider in idiopathic VTE, FHx VTE, recurrent pregnancy loss, recurrent VTE, unprovoked VTE in pt <50 y, thrombosis in unusual location; factor V Leiden & prothrombin gene mutations, antiphospholipid Ab, & UA (nephrotic syndrome) may be checked during anticoagulation; antithrombin, factor VIII, lupus anticoagulant, protein C/S affected by anticoagulation or acute thrombosis → check once DVT resolves & pt off anticoagulation; role of homocysteine screening unclear Malignancy w/u: Pts w/ unprovoked VTE should be current w/ routine cancer screening (Chap X), be carefully asked about FHx of CA, & be followed closely; consider CXR & screening for breast/cervical/prostate CA;
prevalence of occult CA 6% at time of VTE Dx & 10% 12 mos after (Ann Intern Med 2008;149:323); aggressive w/u not cost-effective & has ? effect on outcome (NEJM 1998;338:1169; NEJM 2015;373:697).
Dx of PE in pregnant pts: Consider LE U/S first then CXR to r/o other causes (NEJM 2008;359:2025); spiral CT has ↓ fetal radiation compared to V:Q scan (AFP 2008;77:1709).
| Wells Criteria for DVT (points) Dichotomized Wells Criteria for PE (points) | |
| Entire leg swollen (1) (JAMA 2006;295:199) | Clinical sx of DVT (3) (JAMA 2006;295:172) |
| Asymmetric swelling ≥3 cm (1) | Other dx less likely than PE (3) |
| Immobilization of leg (1) | HR >100 (1.5) |
| Bedridden >3 d or recent (1 mo) surgery (1) | Immobilization ≥ 3 d or surgery in previous 4 wks (1.5) |
| Tenderness along venous system (1) | H/o DVT/PE (1.5) |
| Pitting edema (1) | Hemoptysis (1) |
| Active malignancy (1) | Malignancy (1) |
| Collateral superficial vein (1) | PE unlikely (≤4 points): |
| Alternative dx more likely (subtract 2 points) | D-dimer negative or <500 ng/mL: PE ruled out D-dimer ⊕ or ≥500 ng/mL → ✓ PE-CT
PE likely (>4 points): ✓ PE-CT |
| Low (0 points) & mod (1–2 points) risk: D- dimer negative: DVT r/o; D-dimer ⊕ → ✓ LE U/S
High risk (≥3 points): ✓ LE U/S |
|
| PERC rule: Risk of testing for PE (D-dimer, imaging) outweighs potential benefit if pt meets all of following criteria: (1) Age <50 y, (2) HR <100, (3) Oxyhemoglobin ≥95%, (4) No hemoptysis, (5) No estrogen use, (6) No h/o DVT/PE, (7) No leg swelling, (8) No h/o hospitalization for trauma/surgery in previous 4 wks | |
| Risk for Recurrent DVT/PE (in pts w/o other risk factors, i.e. cancer, thrombophilia) | |
| Unprovoked: 1st episode: 10% 1st yr, then 5%/y; 2nd episode: 15% 1st yr, then 7.5%/y
Provoked: Surgery: 1% 1st yr, then 0.5%/y; nonsurgical factor: 5% 1st yr, then 2.5%/y |
|
| Estimating Bleeding Risk (Chest 2016;149:315) | |
| Risk factors (1 point each, unless noted): Age >65 y (+2 if >75 y), h/o bleeding, cancer (+2 if metastatic), liver or renal failure, stroke, DM2, anemia, ↓ PLT, anti-PLT or NSAID Rx, poor anticoagulant control, poor performance status, recent surgery, falls, EtOH abuse | |
| Bleeding risk (%/y): Increases with ↑ risk factors; low risk (1 factor): 0.8%; mod risk (1 factor): 1.6%; high risk (≥2 factors): ≥6.5% | |
Management (AFP 2011;83:293; 2013;87:556; 2017;95:295; Ann Intern Med 2007;146:204;
2008;149:ITC3-1; 2015;162:ITC-1; 2015;163:701; Blood 2014;123:1794; Chest 2016;149:315;
JAMA 2011;305:1336; 2014;311:717; 2015;314:72; Lancet 2010;375:500; Mayo Clin Proc
2013;88:495)
Outpatient management of PE/DVT: Consider in reliable pts w/ good social support, no O2 requirement, normal VS, no narcotic requirement, no h/o bleeding or serious comorbid disease (esp CKD); scoring systems available to guide pt selection for outpt PE treatment (Am J Med
2016;129:974; Lancet 2011;378:41)
Anticoagulation: Apixaban, dabigatran, edoxaban, or rivaroxaban recommended over warfarin in pts w/o malignancy. See Chap X for choice of specific agent.
Duration of venous thromboembolism (VTE) treatment: 1st episode of a provoked VTE (i.e., surgery, immobilization) or unprovoked distal DVT (i.e., calf): 3 mos; 1st episode of an unprovoked proximal DVT (i.e., popliteal, femoral, iliac) or PE & recurrent VTE: 3 mos then reassess risk/benefit of bleeding vs. recurrent VTE: Pts w/ low risk of bleeding → indefinite anticoagulation; mod risk → shared decision making; high → 3 mos total
Bleeding risk: Various scoring systems reported, but none more effective than physician subjective assessment (Am J Med 2012;125:1095) Cancer patients: Indefinite (metastatic) or until cancer resolves Compression stockings: 30–40 mmHg may prevent DVT postthrombotic syndrome.
D-dimer testing: Pts w/ 1st unprovoked PE or proximal DVT & an abnl D-dimer 1 mo after discontinuation of warfarin had ↑ risk of recurrent VTE (15% vs. 6%) compared to pts w/ a nl D-dimer (PROLONG, NEJM 2006;355:1780); D-dimer has poor NPV for predicting pts at low risk of recurrent VTE (JAMA 2015;313:1668) Aspirin: 100 mg PO QD ↓ risk of recurrent VTE in pts w/ a 1st unprovoked VTE who stopped anticoagulation (6% vs. 11%) compared to placebo w/o ↑ risk of major bleeding (WARFASA, NEJM 2012;366:1959); aspirin ↓ risk of recurrent VTE by ∼30% compared to ∼90% for warfarin (BMJ 2013;347:f5133) Repeat U/S: Pts w/ 1st proximal DVT & residual thrombus after 3 mos of anticoagulation who received continued anticoagulation had ↓ rate of recurrent VTE (12% vs. 17%) & ↑ major bleeding (1.5% vs.
0.7%) compared to pts who received fixed-duration anticoagulation (Ann Intern Med 2009;150:577)
| Anticoagulant | Dose & Monitoring | Reversal/Contraindications/Notes |
| Warfarin
(INR goal 2–3) ∼$7/mo Review pt med list for drugs that interfere w/ warfarin Diarrhea, fever may potentiate anticoagulation Preferred over NOAC in pts >120 kg |
Initial: 5 mg PO then dose by INR. Use lower starting doses in elderly
-Requires bridge for 5 d + INR 2–3 for >24–48 h in DVT/PE -Referral to anticoagulation monitoring service (↓ complications, ↑ time in therapeutic range) -Missed doses do not result in subtherapeutic anticoagulation |
↑ risk of bleeding, vascular, and all- cause mortality compared to NOAC in afib (JACC 2016;68:2508). ↑
risk of major bleeding compared to NOAC in mild renal insufficiency (CrCl 50–80 mL/min) (Chest 2016;149:1516) Preferred for CrCl <30 mL/min Reversal in asymptomatic pts (INR): -<4.5: ↓ or hold dose, ↑ freq of monitoring, resume at lower dose -4.5–10: Hold 1–2 dose(s), ↑ freq of monitoring, resume at lower dose ->10: Vitamin K ->20 or bleeding → ER |
| Dalteparin or
enoxaparin Superior to warfarin for VTE in cancer (Arch Intern Med 2002;162:1729; CLOT, NEJM 2003;349:146) |
DVT/PE dosing: Dalteparin: 100 U/kg q12h or 200 U/kg QD
Enoxaparin: 1 mg/kg q12h (preferred in CA, extensive clot, obese) or 1.5 mg/kg QD |
Protamine reverses. Anticoagulant of choice in liver disease
Contraindications: CrCl <30, HIT. Relative contraindications: Weight <50 kg or >150 kg (consider checking Xa levels) Preferred for outpt anticoagulation in pregnant pts. ↑ risk of osteoporosis if used for years |
| Fondaparinux
(synthetic Xa inhibitor) |
<50 kg → 5 mg QD
50–100 kg → 7.5 mg QD >100 kg → 10 mg QD; no monitoring required |
No antidote Contraindicated in bacterial
endocarditis (↑ risk ICH), weight <50 kg, CrCl <30. Safe in HIT |
| Apixaban
(factor Xa inhibitor) ∼$315/mo FDA approved for afib & VTE |
Afib: 5 mg BID
VTE: 10 mg BID × 10 d → 5 mg BID May be taken with or without food |
Safest direct oral anticoagulant in mild–moderate renal insufficiency (CrCl 30–80 mL/min) (Am J Cardiol 2015;115:323). No specific antidote
2.5 mg BID dose in pts w/ 2 of the following: Age ≥80 y, weight ≤60 kg, Cr ≥1.5 mg/dL |
| Dabigatran (direct | 150 mg BID (afib & VTE) | Reversed with idarucizumab (NEJM |
| thrombin inhibitor)
∼$315/mo FDA approved for afib & VTE |
Requires parenteral
bridging for VTE May be taken with or without food |
2015;373:511)
Afib: CrCl 15–30 mL/min: 75 mg BID Noninferior to warfarin for recurrent VTE with ↓ bleeding but ↑ risk of acute coronary syndrome (REMEDY, NEJM 2013;368:709) |
| Edoxaban
(factor Xa inhibitor) ∼$277/mo FDA approved for afib & VTE |
60 mg QD (afib & VTE)
Requires parenteral bridging for VTE May be taken with or without food |
Once-daily dosing
CrCl 15–50 mL/min or weight ≤60 kg: 30 mg QD Avoid if CrCl >95 mL/min No specific antidote |
| Rivaroxaban
(factor Xa inhibitor) ∼$315/mo FDA approved for afib & VTE |
Afib: 20 mg QD
VTE: 15 mg BID × 21d → 20 mg PO QD |
Once-daily dosing
Afib: CrCl 15–50 mL/min: 15 mg QD No specific antidote Must be taken with food. For afib, must be taken with the evening meal |
| Special Patient Populations (Chest 2016;149:315) | ||
| Coronary Artery Disease | Avoid dabigatran, which has ↑ risk of coronary events compared to warfarin, apixaban, edoxaban, or rivaroxaban | |
| Dyspepsia, GIB | Dabigatran ↑ risk of dyspepsia. Warfarin has ↓ risk of GIB vs.
NOACs |
|
| Poor Adherence | Warfarin. 1 missed dose of NOAC → subtherapeutic anticoagulation | |
| Renal Failure | Warfarin preferred for CrCl <30 | |
(JAMA 2014;311:731; 1150; 2015;314:76; 2016;315:2117)
Background (AFP 2009;80:1261; 2016;93:279; Mayo Clin Proc 2002;77:181; NEJM
2009;361:1887)
Cause: A bleeding disorder may be due to abnormalities in the coagulation cascade, platelets (Chap X), blood vessels, or fibrinolysis.
| Symptoms Platelet Disorders Coagulation Disorders | ||
| Location | Mucosal/cutaneous (oral, nasal, GI, GU) | Deep tissue (muscle & joints = hemarthroses) |
| Bleeding after trauma | Immediate | Delayed |
| Petechiae | Common | Rare |
| Ecchymoses | Small, superficial | Large subcutaneous/soft tissue |
von Willebrand disease (vWD): Most common inherited bleeding d/o (prevalence ∼1%, M:F 7:3) 2° to deficiency or dysfunction of VW factor (vWF) which binds platelets to endothelium → PLT & clotting defect; vWF binds factor VIII & protects it from proteolysis.
Type 1: Autosomal dominant (60–80% cases); mild to mod quantitative deficiency of vWF & factor VIII.
Type 2: Autosomal dominant or recessive (10–30% cases), 4 subtypes of qualitative vWF abnormalities.
Type 3: Severe (1–5% cases), autosomal recessive; severe or complete vWF deficiency & moderate to severe VIII deficiency Acquired: Rarely caused by Ab to or destruction of vWF in myeloma, lymphoma, CML, CLL, uremia, autoimmune dz (hypothyroidism, SLE), ET, valvular heart dz, drugs
Liver disease: ↑ bleeding risk (2° to ↓ coag factor synthesis, ↓ PLT (splenic sequestration, ↓ thrombopoietin) & ↑ clotting risk (↓ synthesis of protein C, S, antithrombin) (NEJM 2011;365:147)
Hemophilia: Factor VIII deficiency (A), factor IX deficiency (B, Christmas dz); X-linked recessive w/ bleeding in joints, muscles, GI tract with varying severity
Evaluation (AFP 2008;77:1117; NEJM 2008;359:938; 2016;375:76)
History: Bleeding after surgery, dental work, minor trauma, childbirth, h/o palpable lumps, epistaxis (>10 mins), menorrhagia, anemia, melena, BRBPR; how severe was the bleeding? FHx of bleeding; h/o transfusion; medications (esp abx, aspirin, NSAIDs, steroids, SSRIs + aspirin/clopidogrel, warfarin).
Exam: Purpura (purple or red patches/spots caused by bleeding, typically from broken/injured capillaries), petechiae (small purpura, typically 1–3 mm, may appear pinpoint), ecchymosis (large purpura = bruise); lymphadenopathy, splenomegaly
Workup: Peripheral smear (NEJM 2005;353:498); fibrinogen, factor VIII, vWF Ag, vWF activity (ristocetin cofactor activity); coags (below); referral to hematology for further classification testing if vWF Ag & activity suggest VWD
Prothrombin time (PT): Measures extrinsic (factor VII,
thromboplastin [tissue factor]) & common pathways (prothrombin [factor II], factors V, X, fibrinogen); INR = Patient PT ÷ control PT Activated partial thromboplastin time (aPTT): Measures intrinsic
(VIII, IX, XI, XII) & common pathways Mixing studies: Combine patient & normal plasma to identify factor deficiencies & inhibitors Thrombin time: Measures conversion of fibrinogen to fibrin & clot formation by thrombin
| Diagnosis PT aPTT [Platelet] | |||
| Prothrombin, fibrinogen, factor V or X deficiency, liver dz, severe vitamin K deficiency |
↑ |
↑ |
Nl |
| Factor VII or mild vitamin K deficiency, liver dz, warfarin |
↑ |
Nl | Nl |
| Hemophilia A or B, von Willebrand dz, factor XI, XII deficiency | Nl |
↑ |
Nl* |
| Vasculopathies, connective tissue dz, collagen d/o, PLT dysfunction, scurvy, steroid-induced purpura, vasculitis | Nl | Nl | Nl |
*Platelet count may be low in type 2B von Willebrand disease
Treatment (Blood 2009;114:1158; 2012;120:275; NEJM 2004;351:683)
von Willebrand disease: Hematology referral; aminocaproic acid or tranexamic acid may be used orally or topically for mild mucous membrane bleeding (dental work, menorrhagia); topical thrombin for epistaxis or gingival bleeding; desmopressin (dDAVP, promotes vWF release from endothelial cells), Factor VIII/vWF concentrate; combined OCPs or levonorgestrel IUD for pts w/ menorrhagia; consider family eval/screening
Hemophilia: Comprehensive care at a designated hemophilia center (cdc.gov/ncbddd/hemophilia/htc.html)
Patient information: AFP 2009;80:1269; JAMA 2012;308:1492
THROMBOCYTOPENIA (AFP 2012;85:612)
| PLT Count Bleeding Risk | |
| 149–50k | Asx, no increased bleeding risk even w/ major trauma |
| 40–20k | Minimal bleeding after trauma |
| 20–10k | Major bleeding after trauma, mild spontaneous bleeding |
| <10k | Spontaneous bleeding |
| <5k | Critical spontaneous bleeding |
| Bleeding risk also depends on PLT function (aspirin, uremia) & age | |
| PLT goals: >50k for surgery, endoscopy; >100k for neuro/ocular surgery/epidural interventions;
>30–50k for dental work; goal may need to be higher if pt febrile/septic; anticoagulation (ASA, clopidogrel, warfarin, etc.): Balance risk/benefit of anticoagulation vs. bleeding, generally >50k (Semin Thromb Hemost 2011;37:267) |
|
| Causes of Thrombocytopenia (JAMA 2004;292:2263) | ||
|
Destruction |
Immune-mediated
Drugs: Heparin (HIT-II), indomethacin, thiazides, sulfonamides, quinine (Tonic water), quinidine, (comprehensive listing at ouhsc.edu/platelets) ITP (dx of exclusion) Infxn: HIV, HCV, H. pylori Rheumatologic: SLE, APLS, RA, sarcoid Neoplasm: CML, Hodgkin, solid tumors Globulins: IgA-deficiency, hypogammaglobulinemia |
Nonimmune-mediated
Drugs Infection: Sepsis, mononucleosis, CMV, HSV, RMSF, ehrlichiosis, babesiosis MAHA: TTP, HUS, DIC, HELLP, vasculitis Others: HELLP, DIC, TTP- HUS, giant hemangioma |
|
↓ Production |
Drugs/toxins: EtOH, thiazides, estrogen, IFN, chemotherapy, many others;
XRT Infection: Sepsis, parvovirus, CMV, HSV, influenza, HIV, rubella, mononucleosis Cancer: Leukemia, lymphoma, myeloma, CLL, myelofibrosis, myelodysplasia, CML, aplastic anemia, paroxysmal nocturnal hemoglobinuria BM infiltration: Solid tumors, TB, osteopetrosis Nutritional deficits: B12 & Folate, rarely iron Hereditary: Wiskott–Aldrich syndrome, May–Hegglin anomaly |
|
|
Misc |
Hypersplenism: Portal HTN, hepatic/portal/splenic vein thrombosis, lymphoma, PE, myelofibrosis, sarcoidosis; Gestational; Pseudothrombocytopenia: Clotted specimen or EDTA-mediated PLT clumping (occurs in 0.1% healthy pts) | |
| Causes of Platelet dysfunction | ||
| ASA, NSAIDs, liver dz, uremia, multiple myeloma, Waldenström macroglobulinemia | ||
Immune (idiopathic) thrombocytopenic purpura (ITP): Dx of
exclusion for isolated ↓ PLT (NEJM 2002;346:995); incidence of 1 in 10,000/y; IgG against PLT membrane proteins or megakaryocytes → ↓ production, ↑ destruction
Thrombotic thrombocytopenic purpura–hemolytic uremic syndrome: ↓ PLT + microangiopathic hemolytic anemia (≥2 schistocytes on 100× HPF) of o/w unexplained etiology ± neurologic/renal dysfunction, fever (Blood 2010;116:4060; NEJM 2006;354:1927); urgent referral for plasmapheresis
Evaluation (NEJM 2007;357:580)
History: Mucosal bleeding (epistaxis, hematemesis, bleeding gums, hemoptysis, melena, BRBPR), menorrhagia, metrorrhagia; recent viral illnesses, diarrhea (esp bloody), new meds (including alternative therapies, supplements), nutrition, B-sx, FHx of bleeding/leukemia, cancer screening, HIV/TB risk factors, h/o DVT; h/o bleeding w/ minor trauma, dental work, easy bruising, blood transfusions
Exam: Splenomegaly, lymphadenopathy, petechiae, purpura, ecchymoses, stool guaiac
Workup: CBC w/ diff in citrate tube to avoid pseudothrombocytopenia; peripheral smear (NEJM 2005;353:498); PLT count of 50–100k w/o bleeding may be rechecked in 1–2 wks before further w/u; consider: Chem-12, CRP, retic, LDH, coags, ferritin, D-dimer, fibrinogen, ANA, H pylori testing, direct Coombs, B12/folate, HIV, HepC, AbdUS (splenomegaly); BmBx for severe unexplained ↓ PLT, age >60 y, multilineage involvement
Treatment (Blood 2011;117:4190; NEJM 2003;349:903; 2011;365:734)
General principles: Treat underlying disease (i.e., autoimmune, infectious)
Medication induced: D/c offending med; PLT typically recover after 1– 2 wks
ITP: Tx depends on bleeding risk/hx, typically Tx begun if PLT <30k or bleeding sx at dx; pts should avoid ASA/NSAIDs, dangerous activities if PLT <50; glucocorticoids 1st-line tx; IvIg & anti-Rh(D) are temporary tx; splenectomy or rituximab may induce remission while Tpo agonists require maintenance dosing
Patient information: AFP 2012;85:623
THROMBOCYTOSIS (JAMA 2015;314:1171; NEJM 2004;350:1211)
| Etiology of Thrombocytosis | |
|
Reactive (85%) |
Acute/chronic inflammation: Infectious (TB, osteomyelitis), Rheum (RA, vasculitis, sarcoid), IBD (UC, Crohn); Asplenia (Chap X), CKD/nephrotic synd; response to vigorous exercise |
| Nonmalignant hematologic conditions: Anemia (iron deficiency, bleeding, acute hemolysis), Rebound: Following Rx of ITP, B12 deficiency, chemo | |
| Malignancy: Metastatic disease, lymphoma | |
| Tissue damage: Surgery, trauma, burns, postexercise, acute pancreatitis, MI | |
| Drugs: ATRA, epinephrine, glucocorticoids, vincristine, interleukin 1-b | |
|
Primary (15%) |
Myeloproliferative neoplasms (MPN): Essential thrombocytopenia, polycythemia vera, CML, CMML, refractory anemia with ring-sideroblasts assoc w/ marked thrombocytosis (RARS), primary myelofibrosis (initial state), myelodysplasia (JAMA 2010;303:2513); Familial thrombocytopenia |
Essential thrombocythemia: Chronic ↑ PLT (>450k) not due to myeloproliferative d/o or reactive thrombocytosis (dx of exclusion); assoc w/ ↑ risk of CVA, PE, DVT, retinal artery thrombosis, bleeding, & acute myeloid leukemia; ∼50% of pts have a JAK2 V617F mutation (Blood 2007;110:1092); vasomotor sx may be treated w/ low dose ASA (81– 100 mg); PLT counts may be ↓ w/ hydroxyurea or anagrelide Rx (NEJM 2005;353:33); pts w/ high risk disease & a h/o arterial thrombosis should receive hydroxyurea + ASA 81 mg; pts w/ a h/o venous thrombosis should receive hydroxyurea + anticoagulation; pts aged >60 y should be treated with hydroxyurea + ASA 81 mg
Sx of thrombocytosis: HA, chest pain, sx assoc w/ thrombosis/bleeding, visual disturbances
LEUKOPENIA
| Causes of Neutropenia (Blood 2014;124:1251; Hematology ASH Educ 2004:63; 2012:174) |
| Infectious: Viral (HIV, HepB, HepC, EBV, CMV), bacterial (Shigella, Brucellosis, TB), parasitic, tick-borne (Ehrlicia, Rickettsial, RMSF) |
| Medications: Suppress BM or trigger autoimmune rxn; ACE inhibitors, acetaminophen, acyclovir, abx (ampicillin, bactrim, cephalosporins, macrolides, vancomycin), AZT, chemotherapy, clopidogrel, clozapine, digoxin, dipyridamole, fluoxetine, furosemide, ganciclovir, immunosuppressants, methimazole, NSAIDs, prednisone, propranolol, propylthiouracil, ranitidine, spironolactone, sulfasalazine, thiazides, tricyclic antidepressants, valproate, & many others (>125) (Ann Intern Med 2007;146:657); cocaine & heroin may be “cut” w/ levamisole (chemo drug) (Ann Intern Med 2009;150:287) |
| Autoimmune: Collagen vascular, aplastic anemia, Fanconi anemia, Felty synd (rheumatoid arthritis + splenomegaly + neutropenia), sarcoid |
| Malignancy: Leukemia, myelodysplasia, cancers that metastasize to bone, amyloidosis |
| Other: Vitamin B12, folate, copper deficiency, EtOH, common variable immune deficiency, pure white cell aplasia, hypersplenism; myeloperoxidase deficiency will result in artificially low ANC as this enzyme is used to identify neutrophils in automated counters |
| Congenital: Chediak–Higashi, Kostmann synd, glycogen storage dz, cyclic neutropenia (autosomal dominant, occurs q14–35 d) (NEJM 2009;360:3; Semin Hematol 2002;39:89) |
| Benign chronic neutropenia/Chronic idiopathic neutropenia: Seen in 4.5% of pts w/ African ancestry → no further w/u needed (Ann Int Med 2007;146:486) |
| Causes of Lymphocytopenia |
| Infectious: Viral (HIV, measles, HepB/C), bacterial (TB, histoplasma, brucella), malaria |
| Medications: ATG, rituximab, steroids, chemotherapy (fludarabine, cladribine) |
| Autoimmune: Lupus, rheumatoid arthritis, Sjögren |
| Malignancy: Lymphoma, cancers that metastasize to bone |
| Other: EtOH, zinc & vitamin deficiency, physiologic stress (i.e., post-op, sepsis) |
History: Often asx/incidental; may present w/ fevers, chills, diarrhea, abdominal pain, joint pain, opportunistic/recurrent infection, FTT, food allergies; fatigue, pallor, easy bruising/bleeding, petechiae (if RBC or PLT affected); complete medication & supplement hx; cyclic sx (i.e., q3 wks may suggest cyclical neutropenia)
Exam: Lymph nodes, spleen, dental exam to r/o abscesses & gingivitis Workup: CBC w/ diff, peripheral smear, viral serologies (HIV, HepB & C, EBV), B12, folate, MMA, homocysteine, copper/ceruloplasmin level, ESR/CRP, ANA, complement, flow cytometry, retic; Lyme, RMSF, & ehrlichia serologies, PPD, RF, & anti-CCP Ab based on clinical
suspicion; may need hematology referral for bone marrow biopsy if above w/u unrevealing, neutropenia is persistent, & ANC <1000; role of antineutrophil Ab for autoimmune dz unclear; neutrophil function assays include bacterial killing, nitroblue tetrazolium (to r/o chronic granulomatous disease), chemotaxis; if congenital cause suspected, consider referral to geneticist for specialized testing
Neutropenia: Infectious risk ↑ w/ ↓ ANC, especially for ANC <500 (Ann Int Med 1966;64:328); ANC 1000–1500: Mild; ANC 500–1000: Mod. ANC
<500: Sev; recurrent infections usually only seen when ANC <200
Asx: D/c offending meds, monitor CBC w/ diff q2–12 wks, counsel pt about importance of reporting signs of infection; consider neutropenic diet if ANC <500
Febrile: Admit for IV abx; most often GI/GU source (GNRs, Staph aureus) or candida G-CSF (filgrastim): In consultation w/ hematology, consider for pts w/ recurrent infections, congenital neutropenia, fever/infection w/ medication associated neutropenia, or HIV-or AIDS-associated neutropenia (AIDS 1998;12:65; Blood 1993;81:2496); acute s/e include bone pain, myalgias, flu-like symptoms; chronic G-CSF use assoc w/ osteoporosis & ? ↑ malignancy; pegfilgrastim is given as a single injection, in contrast to filgrastim which is dosed daily for up to 14 d
Lymphocytopenia: D/c offending med & treat supportively; lymphocyte count will almost always return to nl unless malignancy involved (Aust N Z J Med 1997;27:170)
LEUKOCYTOSIS (AFP 2014;89:731; 2015;92:1004)
History: H/o of recent infection, fevers, chills, night sweats, wt loss; complete medication & supplement hx; allergic reactions & exposures; travel hx; h/o asthma, bronchiectasis, inflammatory bowel disease, anxiety, or exercise; smoking hx
Exam: Lymph nodes, spleen, skin (rash/petechiae)
Workup: CBC w/ diff, peripheral smear, viral serologies (HIV, EBV, CMV), flow cytometry (for CLL & other leukemias), peripheral blood for FISH for BCR-ABL (Philadelphia chromosome – CML), ESR, CRP, SPEP, TSH; stool culture, ova, parasites depending on clinical
scenario; the presence of blasts or numerous atypical lymphocytes on the peripheral smear is concerning for malignancy; hematology referral for bone marrow bx if above workup unrevealing or suggestive of malignancy
Management: Identification & emergency referral of pts w/ acute leukemia is key; acute leukemia is suggested by suppression of other cell lines (RBC, PLT), coagulopathy (bleeding, petechiae), fevers, & circulating blast; tx o/w directed at underlying cause (i.e., withdrawal of offending medication), referral to heme/onc for chronic leukemias, smoking cessation, management of infection or autoimmune disease
| Causes of Neutrophilia (AFP 2000;62:2053) |
| Infection: Any acute infectious process, esp. C. diff, pneumococcus, Staph |
| Smoking: Most common cause of ↑ ANC, likely due to chronic inflammation; WBC in population studies of smokers 27% higher than nonsmokers (Am J Clin Pathol 1997;107:64); leukocytosis may persist for up to 5–10 y after cessation (Arch Med Res 2004;35:246) |
| Medications: Steroids, lithium (Semin Hematol 1983;20:129) |
| Malignancy: Leukemia, MDS, multiple myeloma, large cell lung CA (Cancer 1987;60:903) Chronic myelogenous leukemia: Proliferation of mature/immature granulocytes (mainly neutrophils, but also basophils & eosinophils) due to BCR-ABL translocation (t9;22) found in 90–95% of pts (Hematology ASH Educ Program 2003:132; NEJM 2007;357:258) |
| Other: Pregnancy, physiologic stress (vigorous exercise, surgery, sepsis, panic attacks), IBD, bronchiectasis, thyroid storm, asplenia, polycythemia vera (in assoc w/ ↑ HCT), post seizure, heatstroke, sickle cell anemia, platelet clumping, or cryoglobulinemia (both may result in spurious ↑ ANC) (J Clin Pathol 1987;40:120), hereditary neutrophilia, chronic idiopathic neutrophilia |
| Causes of Lymphocytosis |
| Infectious: Viral (HIV, EBV, CMV, HTLV-1, HepB & C, enterovirus), bacterial (pertussis, brucella, TB, toxoplasmosis, babesia, typhus) |
| Medications: Serum sickness & other drug hypersensitivity reactions |
| Malignancy: Thymoma, lymphoma (mantle cell, follicular, lymphoplasmacytic, splenic marginal zone), prolymphocytic leukemia, hairy cell leukemia Chronic lymphocytic leukemia: Sustained absolute lymphocyte count ≥5000 with clonality on flow cytometry (Blood 2008;111:5446) Monoclonal B-cell lymphocytosis: Clonal lymphocyte count ≤5000 w/o cytopenias, LAN, organomegaly, or sx; patients w/ MBL & CLL phenotype cells have a
∼1%/y risk of developing CLL requiring treatment (NEJM 2008;359:575) |
| Other: Hyperthyroidism, postsplenectomy, posttransplant lymphoproliferative d/o, cigarette smoking, rheumatoid arthritis, Addison disease, splenomegaly |
| Causes of Monocytosis |
| Infectious: Brucellosis, VZV, TB, malaria, bacterial endocarditis, syphilis, trypanosomiasis,
typhoid fever. |
| Malignancy: Leukemia, Hodgkin lymphoma, myelodysplastic syndrome Chronic myelomonocytic leukemia: Absolute peripheral monocytosis >1000 that persists ≥3 m w/ myelodysplastic/myeloproliferative features in bone marrow; important to r/o CML & PDGF rearrangements (Am J Hematol 2012;87:611) |
| Other: Steroids, pregnancy, asplenia, sarcoidosis, inflammatory bowel disease, lupus |
| Causes of Eosinophilia |
| Leukemia (usually CML), lymphoma, polycythemia vera, myelofibrosis, adrenal insufficiency, solid tumors, allergic rxns, RA, lupus, Addison disease; asthma, Churg–Strauss; drug hypersensitivity; infections (HIV, scarlet fever, leprosy, GU, fungi) |
| Causes of Basophilia |
| Leukemia (usually CML), myelofibrosis, polycythemia vera, essential thrombocytosis, myelodysplastic syndromes, allergic rxns, ulcerative colitis, RA, hypothyroidism, estrogen supplementation, ovulation, infection (viral, TB, helminth, varicella, chronic sinusitis) |
Background (AFP 1998;58:1313; 2002;66:2103; Hematol Oncol Clin N Am 2012;26:395)
Definitions: >600 LN exist; malignancy found in 1.1% of pts w/ unexplained LAN in primary care; risk ↑ w/ age (J Fam Pract 1988;27:373); risk of malignancy or granulomatous dz 0% if LN <1 cm, 8% 1–2.25 cm, 38% >2.25 cm (Semin Oncology 1993;20:570)
Lymphadenopathy (LAN): >2 cm inguinal, >5 mm epitrochlear, any palpable supraclavicular/iliac/popliteal LN, & >1 cm for all others; inguinal & cervical LN often palpable in healthy pts; Generalized LAN: ≥2 LN regions Lymphangitis: Inflammation of lymphatics, typically presenting w/ red streaks from a wound towards the nearest LN; typically caused by Strep pyogenes.
Lymphadenitis: Inflammation of a LN which may be enlarged, red, or tender Splenomegaly: Greatest dimension >11–13 cm; size of spleen proportional to height; up to 3% of healthy college students have splenomegaly (JAMA 1993;270:2218)
Asplenia/hyposplenism: The spleen phagocytoses bacteria & senescent RBC, & produces IgM Ab against encapsulated bacteria (S
pneumoniae, N meningitidis, & H influenza type b); Assoc w/ ↑ prevalence of infection (3.2%) & mortality (1.4%), usually due to fulminant Streptococcal sepsis in a 7 y observational study (J Infect 2001;43:182)
Hyposplenism: Caused by sickle cell, IBD, celiac dz, Whipple dz, hepatitis, EtOH, cirrhosis, BMT, leukemia, myeloproliferative dz, autoimmune dz, HIV, high-dose steroids, thrombosis of splenic vasculature, TPN, amyloidosis; dx by ↓ spleen size, Howell–Jolly bodies (erythrocytes w/ nuclear remnants) on smear (Lancet 2011;378:86)
Evaluation (AFP 1998;58:1313; 2002;66:2103)
History: Duration, fatigue, infections, easy bruising, pruritis, new/changing skin lesion or rash, joint pain, weakness, exposures (travel, sick contacts, pets, rabbits [Tularemia], cats [cat scratch dz]), EtOH, allergies, IVDU, sexual behavior, meds, ingestion of raw or undercooked food/milk (Toxoplasma or Brucellosis), dental procedures; personal or FHx of infections, malignancy, autoimmune dz, CTD; painful LAN after EtOH (Hodgkin)
Diagnostic clues: Rate of growth (benign LAN suggested by <2 wks or >1 y w/o change); pain (infectious or inflammatory), B-type symptoms (fever >38°C, night sweats, >10% wt loss in previous 6 mos) → lymphoma Splenomegaly sx: Early satiety, left abdominal fullness/pain, L shoulder pain
Exam: Description of LN: Size, consistency (firm, rubbery, shotty, matted/confluent, tender, warm); Valsalva maneuver w/ supraclavicular palpation ↑ detection of supraclavicular LAN; skin exam to r/o melanoma; eval of dentition
Diagnostic clues: Rubbery LN → lymphoma; firm, “rock hard” LN → metastatic CA; LAN can wax & wane w/ lymphoma/CLL; ∴ important to follow even after resolution Waldeyer ring: Pharyngeal lymphatics formed by palatine, pharyngeal, & lingual tonsils Examination of the spleen: Wide interobserver variability; nl-sized spleen typically difficult to palpate; splenomegaly may be detected by percussion of Traube space (formed by the 6th rib, midaxillary line, & left costal margin w/ the pt supine); tympanic/resonant percussion is nl due to the lung or gastric
bubble while splenomegaly is suspected by dull sounds; percussion Se/Sp ↑ when pt is nonobese & has not recently eaten
(JAMA 1993;270:2218)
Workup: Directed by clinical hx: CBC w/ diff, peripheral smear, Chem- 12, HIV, CMV (PCR & IgM), EBV serologies, HepB, LDH, CRP, ESR,
RF, ANA, RPR, PPD, toxoplasma IgM, throat Cx, Lyme; CXR or CT if malignancy suspected; ultrasound/MRI may distinguish LN from other anatomic structures
Biopsy: Consider in pts w/ unexplained LAN, if LN is large, rapidly growing, persistent, or otherwise suspicious; biopsy the most suspicious LN (i.e., largest, most abnormal) for highest yield; bx of inguinal or axillary LN have highest likelihood of being nondiagnostic due to reactive hyperplasia; excisional bx preferred due to difficulty of diagnosing lymphoma from an FNA which does not capture enough tissue to eval LN architecture; if LN is not accessible for excisional bx then core preferred; bx of spleen generally avoided due to risk of hemorrhage Flow cytometry: Consider if LAN and lymphocytosis w/o signs of infection
Treatment (AFP 1998;58:1313; 2002;66:2103)
Primary treatment cause-related: Close f/u to ensure resolution
Empiric treatment: Steroids not recommended due to effect of glucocorticoid on LN which may complicate pathologic interpretation if bx needed; abx recommended only infection suspected
LAN of unknown etiology: Low suspicion for malignancy:
Observation ×4–8 wks
High suspicion for malignancy or persistent enlargement: (i.e., older age, firm or fixed LN, constitutional symptoms, duration >4–6 wks, supraclavicular) → bx
| Differential Diagnosis of Lymphadenopathy & Splenomegaly | |
| Splenomegaly
(NEJM 2008;359:2707) |
Benign: Portal vein thrombosis/hypertension, CHF, cirrhosis, hemolysis, chronic anemia, malaria, infection, autoimmune, CTD, sarcoid, amyloid, Gaucher/Niemann–Pick dz, thalassemia; Malignant: Leukemia, lymphoma, myeloproliferative d/o, metastases |
| Generalized LAN | Benign: Infection (viral [EBV, CMV, HIV, HHV8 (Castleman’s), |
| HepB, strep], fungal, bacterial, protozoal, tick borne,
toxoplasma), autoimmune (RA, lupus, sarcoid), drug hypersensitivity (allopurinol, atenolol, captopril, carbamazepine, cephalosporins, hydralazine, indomethacin, PCN, phenytoin, primidone, pyrimethamine, quinidine, sulfonamides, sulindac, silicone); Malignant: Leukemia, lymphoma |
|
| Head & neck | Benign: URI, skin/scalp/ear/eye sinus/dental/soft tissue infxn, EBV, CMV, HIV, toxoplasma, rubella, B. henselae, mycobacterial, CTD; Malignant: Head & neck CA, melanoma, lymphoma, leukemia |
| Supraclavicular | Most worrisome for malignancy: Left LN drains abdomen, R drains mediastinum/lungs; Benign: Fungal, mycobacterial, CTD; Malignant: Left (Virchow’s Node): abdominal/thoracic/testicular/pelvic malignancy, breast cancer, lymphoma, leukemia; Right: esophageal, lung, breast, thyroid, or laryngeal cancers, lymphoma, leukemia |
| Epitrochlear | Benign: Infxn of hand/forearm, tularemia, sarcoid, 2° syphilis (sailor’s handshake), CTD; Malignant: Melanoma, lymphoma, leukemia |
| Axillary (drains L neck, UE, lateral breast, chest wall) | Benign: Skin & soft tissue infxn of arm, chest wall or breast, B. henselae, tularemia, CTD; Malignant: Breast or lung cancers, melanoma, lymphoma, leukemia |
| Inguinal (drains genitals, perineum, lower anal canal, lower abd wall) | Drains LE, genitals, buttock, abdominal wall below umbilicus; Benign: STD, skin & soft tissue infection of the lower extremities; Malignant: Squamous cell carcinoma of the penis, vagina or vulva, melanoma, lymphoma, leukemia |
| Thoracic (hilar & mediastinal) | Benign: PNA, mycobacterial, sarcoid, CTD; Malignant: Lung, esophageal, breast CA, melanoma, lymphoma, leukemia |
| Abdominal (mesenteric & RP) | Paraumbilical LN drains abdomen (Sister Mary Joseph node) → may be sign of abdominal/pelvic CA. Benign: Mycobacterial, sarcoid, CTD. Malignant: GI & GU cancers, melanoma, lymphoma, leukemia |
(AFP 1998;58:1313; 2002;66:2103; Hematol Oncol Clin N Am 2012;26:395)
CARE OF THE ASPLENIC/HYPOSPLENIC PATIENT (Lancet 2011;378:86;
NEJM 2014;371:349)
Functional asplenia/hyposplenia: ↓ splenic function seen in sickle cell, chronic GVHD, untreated HIV, celiac dz
Pt education: Pts should seek medical attention immediately w/ any
fevers or rigors because of ↑↑ mortality in postsplenectomy sepsis related to impaired bacterial clearance from blood, & ↓ humoral immunity
Prophylactic antibiotics: Pts should be given Rx for amoxicillin– clavulanate 875 mg PO BID, levofloxacin 750 mg PO QD, or moxifloxacin 400 mg PO QD, & instructed to use if they develop fevers/rigors in addition to promptly seeking medical attention; role for prophylactic dental abx unclear. Role for daily abx unclear & not supported by RCT; some groups recommend amoxicillin 250-500 mg PO QD, especially if pt has survived pneumococcal sepsis, have HIV, or are immunosuppressed posttransplant.
Vaccines: Pneumococcal (both PPSV-23 & PCV13, given 8 wks apart) preferably 2 wks before or at least 2 wks after splenectomy; PPSV-23 again after 5 y (MMWR Morb Mortal Wkly Rep 2012;61:816); Meningococcal (Menactra or Menveo if <55 y; Menomune (MPSV4) if
>55 y) q5y; Menactra should not be administered w/ pneumococcal vaccine (Ann Intern Med 2012;156:211; MMWR Morb Mortal Wkly Rep 2011;60:72); Influenza annually, especially to prevent 2° bacterial infections. There is no contraindication to live attenuated vaccines (i.e., shingles); Tetanus q10y. One time doses of diphtheria, H influenza type b
Background (AFP 2013;87:183; BMJ 2011;342:c7251; Clin Pathol 2011;64:287)
Genetics: Autosomal recessive syndrome of ↑ iron absorption → iron overload + organ damage; penetrance (symptomatic hemochromatosis) varies, ranging from 1–28% in homozygous ♂ & ∼1% in homozygous
♀ likely due to the protective effect of iron loss w/ menstruation (Lancet
2002;359:211; NEJM 2008;358:221)
HFE C282Y mutation: Missense mutation found in 70–90% of pts w/ hemochromatosis Other: HFE C282Y/H63D compound heterozygotes (3–5%), H63D homozygotes (1%)
Epidemiology: Caucasians: 10% heterozygotes, 0.5% homozygotes (JAMA 2001;285:2216; NEJM 1988;318:1355); most common genetic dz in Caucasians; presents at age 40–50 y, w/ later onset in ♀ due to iron
loss w/ menstruation; age of symptomatic onset related to gradual accumulation of iron to toxic levels over decades (WJM 1995;162:370); ♀ who have early menopause (i.e., due to hysterectomy or prolonged OCP use) may present earlier
Pathophysiology: Normally, ∼1–2 mg iron absorbed from diet balances losses in GI tract, skin, menses, & sweat; iron stores regulated by absorption as no excretion mechanism exists; ↓ hepcidin expression due to HFE mutations → ↑ iron absorption
| Consequences of Iron Overload (Rare in Heterozygotes) |
| Liver: 20–220-fold ↑ in hepatocellular carcinoma (Gastroenterology 2003;125:1733); cirrhosis (especially if pts consume >30–60 g EtOH/d), hepatomegaly, abnormal LFTs |
| Endocrine: DM2 due to iron accumulation in pancreas; hypogonadism (impotence in ♂, amenorrhea in ♀, ↓ muscle & bone mass) due to pituitary iron overload; hypothyroidism |
| Rheumatology: Excess iron in joints → inflammation & calcium crystal formation; arthropathy, especially in 2nd & 3rd MCP joints & wrists; osteoporosis |
| Cardiovascular: Cardiomyopathy/CHF due to iron accumulation; Arrhythmias (SSS, afib) |
| Dermatology: Hyperpigmentation “bronze diabetes” due to melanin/iron deposition |
DDx: Iron overload anemias due to chronic transfusion, hemolytic anemias, liver dz (HepC, NASH, EtOH), dialysis, a1-antitrypsin deficiency, aceruloplasminemia, porphyria, African iron overload (due to consumption of iron-rich beer)
Evaluation (Gastroenterology 2010;139:393; Hepatology 2011;54:328; NEJM 2012;366:348)
History: Weakness, impotence, joint pain, fatigue; most pts asx
Exam: Skin exam, palpation of liver, spleen
Workup: CBC, LFTs, ECG, AFP, A1c, stool guaiac if anemic (GIB due to varices), EGD if cirrhotic to screen for varices. Hep serologies if risk factors present; ECHO if cardiac sx
Iron studies: Transferrin saturation ([serum iron], μmol/L/TIBC, g/L)
≥50% in ♀ or ≥60% in ♂ &/or ferritin >200 ng/mL in ♀ & >300 ng/mL in ♂ prompt suspicion for hemochromatosis (Lancet 1997;349:73); American Association for the Study of Liver disease advocates cutoff transferrin saturation >45% in ♀ & ♂; transferrin saturation <45% w/ normal ferritin is 97% specific to r/o hemochromatosis (AFP 2013;87:183) Other causes of ↑ ferritin:
EtOH, HIV, inflammation, malignancy, metabolic syndrome, hepatitis, autoimmune dz, renal insufficiency Gene testing: Indicated in pts whom hemochromatosis is suspected when transferrin saturation >45% or ferritin is abnormally ↑ w/o explanation; HFE C282Y & H63D most common; if these are nl & hemochromatosis still suspected, ✓ liver MRI or bx; high liver iron suggests rare hemochromatosis mutations → refer to geneticist for specialized testing; Nl liver iron suggests inflammation or other iron loading anemias (i.e., thalassemia, sideroblastic anemia, hemolytic anemia, aplastic anemia); HFE heterozygotes w/ ↑↑ ferritin should be tested for mutations found in type II–IV hemochromatosis & consider liver bx if these are negative (NEJM 2004;350:23) Liver bx: Consider if pt is >40 y & has ↑ LFTs or ferritin
>1,000 ng/mL
Liver MRI: Useful to evaluate for hemochromatosis or other iron overload dz in pts who test negative for HFE mutations but have clinical/laboratory signs of iron overload dz (Best Pract Res Clin Gastroenterol 2009;23:171); may help quantify hepatic Fe concentration
Screening:
Normal population: USPSTF and American Academy of Family Physicians recommend against screening asx individuals; ACP concluded there was insufficient evidence to make a recommendation (Ann Intern Med 2005;143:517; 2006;145:204) First-degree relatives of hemochromatosis pts: ✓ fasting transferrin saturation, ferritin level, & HFE mutation (if proband has an HFE mutation); ∼50% of ♂ relatives & 10% of 1° ♀ relatives who are also homozygotes for hemochromatosis have dz-related conditions (NEJM 2000;343:1529); probands who are symptomatic are likely to have relatives who become symptomatic which is why screening is recommended DM2: Screening not recommended since incidence of hemochromatosis not enriched in pt populations w/ DM2 (J Lab Clin Med 2000;135:170) Patients with liver dz: American Association for the Study of Liver Dz recommends all pts w/ liver disease be evaluated for hemochromatosis (Hepatology 2011;54:328)
Prognosis: Nl life expectancy in pts who do not develop cirrhosis or DM2 (Gastroenterology 1996;110:1107); men homozygous for C282Y mutation & w/ ferritin >1000 mg/L more likely to have sx or liver dz (NEJM
2008;358:221); tx may reverse cirrhosis, cardiac dysfunction, hypogonadism, & varices
Treatment (Ann Intern Med 1998;129:932; Blood 2010;116:317; Hepatology 2011;54:328)
Observation: Appropriate for asx patients w/ ferritin <1000 μg/L; F/u includes annual H&P, iron studies; these patients should be encouraged to donate blood; screen for hepatocellular CA w/ U/S ± AFP q6 mos (Hepatology 2011;53:1020)
Indications to treat: Sx &/or end-organ damage. Consider in asx pts w/ ferritin >1000 μg/L. Consider in pts at risk for liver dz (EtOH, obesity, hepatitis), regardless of ferritin
Phlebotomy: 500 mL of blood contains 200–250 mg iron & removal will ↓ ferritin by 30 ng/mL (AFP 2013;87:183); Hgb & HCT should remain
>80% of baseline level during phlebotomy; ✓ ferritin q3mos
Schedule: Remove 1-unit q1–2 wks until ferritin <50–150 μg/L, transferrin saturation <30–50%; it may take 1–3 y of weekly phlebotomy to achieve this. Time to achieve nl iron levels may be estimated: (pt ferritin – 150)/30 = # of phlebotomy sessions needed; lifelong maintenance phlebotomy q2–6 mos to target ferritin 50–300 μg/L (optimal level unclear) (Best Pract Res Clin Gastroenterol 2009;23:171) Blood donation: Centers that accept blood from hemochromatosis pts may be found at hemochromatosis.org; this may be an alternative to phlebotomy in physician’s office for some if ferritin & transferrin saturation closely monitored by supervising MD
Impact of phlebotomy: In asx pts phlebotomy may prevent complications of iron overload; phlebotomy improves fatigue, arthralgias, skin hyperpigmentation, normalize LFTs, & ↓ hepatomegaly/RUQ pain; phlebotomy not effective at restoring pituitary/thyroid function, lowering the risk of liver CA or infection; phlebotomy may improve cardiomyopathy, cirrhosis (rarely) & DM
(Ann Intern Med 1998;129:932)
Diet: Avoid iron & vitamin C supplements (contributes to oxidant damage, iron mobilization) (Ann Intern Med 1999;131:475), uncooked seafood (Vibrio vulnificus infxn), & EtOH (due to risk of cirrhosis) (Gastroenterology 2002;122:281); otherwise no restrictions
Heterozygotes: Most never come to medical attention. Observe w/
annual ferritin levels w/ tx implemented if signs of iron overload develop
(NEJM 2004;350:23)
Patient information: hemochromatosis.org, irondisorders.org, americanhs.org
Background (Blood 2008;112:2214; J Nutr 1999;129:779; Neurology 1995;45:1435; NEJM
2013;368:149)
Epidemiology: Prevalence of B12 deficiency = 5–400 per 10,000 people; more common in the elderly & in pts of African/European ancestry; folate deficiency mainly found in pts >65 y (5–10% prevalence) (Age Ageing 2004;33:34) & in alcoholics
| B12 Deficiency | Folate Deficiency |
| 2 μg/d RDA, 2–5 mg body stores | 400 μg/d RDA (600 μg/d in pregnant ♀, 500 μg/d in lactating ♀); 5–10 mg in body stores |
| Deficiency takes years to develop | Deficiency takes 4–5 mos (smaller body stores) |
| Absorbed in terminal ileum | Absorbed in jejunum |
| ↑ homocysteine & ↑ methylmalonic acid | Only homocysteine elevated |
| B12 found exclusively in animal products | Found in animal products & leafy vegetables |
| Develops mainly due to malabsorption | Develops mainly due to malnutrition/EtOH |
| Megaloblastic anemia | Megaloblastic anemia |
| Neurologic changes may be present | Neurologic changes absent |
Pathophysiology of B12 deficiency: B12 (cobalamin) is a cofactor for conversion of homocysteine to methionine; deficiency ↑ homocysteine (cytotoxic), ↓ methionine (neurotoxic), ↓ tetrahydrofolate (↓ DNA synthesis → delayed RBC maturation → megaloblastic anemia);
cyanocobalamin is a prodrug of cobalamin; B12 absorption requires: (1)
Adequate intake; (2) Gastric acid & pepsin to release B12 from protein & allow it to bind R factor; (3) Pancreatic proteases release B12 from R factors; (4) Intrinsic factor (IF) to bind B12. (5) Functional B12-IF receptors to facilitate ileal uptake
“Pernicious anemia:” Loss of IF due to IF Ab & autoimmune atrophic gastritis & destruction of parietal cells (which secrete IF) by Ab (NEJM 2014;370:773); present in up to 2% of pts >60 y (NEJM 1997;337:1441); most common cause of severe B12 deficiency Risk
factors: Vegetarian diet during pregnancy, strict vegans, tropical sprue, gastrectomy, chronic gastritis, HIV, chronic antibiotic use → bacterial overgrowth, PPI/antacid/H2 blocker use, metformin, EtOH abuse, bariatric surgery, Sjogren
Pathophysiology of folate deficiency: Inadequate intake or EtOH (↓ absorption); folate (= vitamin B9) is the naturally occurring form; folic acid is the therapeutic vitamin
Risk factors: Conditions that ↑ folate demand (i.e., pregnancy, hemolytic anemia, severe dermatitis) or meds that interfere w/ metabolism (trimethoprim, pyrimethamine, methotrexate, phenytoin); eating d/o, depression → malnutrition; ↓ absorption in celiac dz, IBD, short bowel syndrome, gastric bypass Neural tube defects (NTD): Folic acid supplementation ↓ incidence of NTDs
Evaluation (NEJM 2013;368:149; 2015;373:1649)
History: Sx of anemia (Chap X); symmetric paresthesias, numbness, gait instability, memory loss, personality or MS Δ (found only in B12 deficiency); sx of malabsorption (wt loss, diarrhea); h/o blood clots, incl cerebral venous sinus due to ↑ homocysteine; diet, screen for eating
d/o & depression which can lead to poor PO intake; medications; GI hx
(gastritis, gastrectomy, Crohn, intestinal surgery, pancreatitis, IBD); EtOH; h/o autoimmune dz (DM1, thyroid, vitiligo)
Exam: Wt; prematurely graying hair; glossitis; gait, peripheral sensation (incl vibratory/position sense; check Romberg), motor strength; MMSE, depression screen; pallor, vitiligo, hyperpigmentation; vaginal atrophy
| Common Tests Used to Assess B12 & Folate Deficiency (J Clin Pathol 2003;56:924) |
| B12 levels: <200 pg/mL = likely deficiency (Se/Sp = 65–95%/50–60%), >350 pg/mL = nl; falsely
↓ in pregnancy, OCP use, multiple myeloma, folate deficiency, excessive vitamin C intake; |
| falsely ↑ in liver dz, myeloproliferative d/o; cannot r/o deficiency on basis of a nl B12 level alone if clinical suspicion high; measure before treating folate deficiency |
| Folate levels: >4 ng/mL = nl; serum folate represents short-term folate balance, may be influenced by eating, & is a good initial screening test; RBC folate representative of tissue stores & is useful for pts w/ borderline serum folate/suspected folate + B12 deficiency |
| Methylmalonic acid (MMA) & homocysteine: Both ↑ in B12 deficiency (Se 94%, Sp 99%) (Am J Med 1994;96:239); MMA nl & ↑ homocysteine suggestive of folate deficiency (Se 86%, Sp 99%); if both MMA & homocysteine are nl then B12 & folate deficiency unlikely; useful for intermediate B12 (200–350 pg/mL) or folate values, or pt has a condition that falsely ↑ or ↓ B12 levels, but clinical picture consistent w/ deficiency; measure before B12 repletion; homocysteine ↑ w/ nl MMA suggestive of folate deficiency, renal dz, or homocystinuria; MMA falsely ↑ in renal failure |
| Anti IF Ab: Se 60–70% for pernicious anemia, Sp >95%; antiparietal cell Ab ↑ Se but ↓ Sp, limiting use; has supplanted Schilling test in dx of pernicious anemia |
Workup: Serum B12 & folate (& RBC folate if serum folate borderline), CBC w/ diff, MCV, peripheral smear (hypersegmented neutrophils), retic, anemia w/u if anemic (Chap X); consider H. pylori testing
Treatment (AFP 2011;83:1425; Blood 2008;112:2214; Cochrane 2005;20:CD004655)
B12 repletion: Asx: Cobalamin 1 mg PO QD until serum level normalizes; symptomatic: 1 mg IM QD x 7 d then weekly × 4 wks; prompt recognition & tx needed to prevent permanent neurologic damage; neurologic recovery may take 1.5–3 mos if sx due to B12 deficiency
Maintenance: 1 mg PO QD or 1 mg IM qmonth (if neuro sx → 2×/mo
× 6 mos then monthly); indefinite IM tx may be needed for pts permanently unable to absorb B12 (i.e., as in pernicious anemia, gastrectomy, bariatric surgery) Monitoring: CBC 1–2 mos after tx
starts (anemia normalizes in ∼6–8 wks), then q6–12 mos; follow K
in severely B12 deficient pts as ↑↑ BM erythropoiesis may lead to ↓ K
Pernicious anemia: IM B12 due to poor GI absorption to correct initial deficiency; maintenance IM B12 or high dose oral (i.e., 1–2 mg/d) may be used; ✓ TFTs since thyroid dz often present; chronic atrophic
gastritis due to pernicious anemia assoc w/ ↑ risk of gastric CA,
carcinoid; age-appropriate CA screening; American Society for GI Endoscopy recommends 1× EGD to confirm dx & r/o CA/carcinoid,
consensus lacking
Folate deficiency: Oral folate 1 mg PO QD until HCT/Hgb normalizes on CBC; test for B12 deficiency prior to folate supplementation Bacterial overgrowth: Poor movement of stool → ↑↑ bacteria; may be 2° to IBS, diverticulosis, dysmotility (i.e., narcotics); treat bacterial
overgrowth w/ abx (rifaximin, norfloxacin) & restore motility (i.e., d/c
offending medication, or Rx metoclopramide)
Tropical sprue: Found in warm climate developing countries; toxins from bacterial overgrowth/gastroenteritis → small bowel damage → vitamin malabsorption; ✓ stool Cx; Rx appropriate abx/anthelminthic + folic acid + B12 (if deficient) (Dig Dis 2007;25:237)
Prevention: B12 supplementation in vegetarians, pregnant & breast feeding ♀, pts who have had bariatric or other major intestinal surgery; nitrous oxide irreversibly oxidizes the cobalt in cobalamin, & may precipitate altered mental status in pts deficient at baseline (Neurology
1995;45:1435); initiate folic acid supplementation (i.e., prenatal vitamins w/
0.4–0.8 mg QD) 1 mo prior to conception in ♀ planning to become pregnant; continue through 1st trimester (Am J Clin Nutr 2006;83:993); folic acid supplementation neither ↑ nor ↓ risk of CA