1 HEMATOLOGY Suggestions for Lecturer -1-hour lecture-Use GNRS slides alone or to supplement own teaching materials. -Refer to GNRS for further content and for strength of evidence (SOE) levels. -Refer to Geriatrics At Your Fingertips for updated information on patient evaluation and management. -Supplement lecture with handouts. -The GNRS Teaching Slides reflect care that can be provided to older adults in all settings. The words patient, resident, and older adult have been used interchangeably, as have the words provider, clinician, and primary care provider. Given the continually ongoing changes in health care today, some of the guidelines around reimbursement may have changed since publication. Topic

2 OBJECTIVES Know and understand: How hematopoiesis changes with ageThe classification and work up of different types of anemia Rational use of exogenous erythropoietin Indications for vitamin B12 and folate replacement How to identify and treat thrombocytopenia, thrombopathy, clotting factor deficiencies, and chronic myeloproliferative disorders Topic

3 Effect of Aging on Hematopoiesis Different Types of Anemia TOPICS COVERED Effect of Aging on Hematopoiesis Different Types of Anemia Vitamin B12, Folate, and Homocysteine Platelets and Coagulation Chronic Myeloproliferative Neoplasms Topic

4 HEMATOPOIETIC STEM CELLS AND AGING (1 of 2)The hematopoietic system derives from a small pool of hematopoietic stem cells (HSCs) that can either self-renew or differentiate to form mature RBCs, WBCs, or platelets This process requires a strict balance between self renewal, differentiation, maturation, and cell loss Accumulated DNA damage has been proposed as the principal and unifying mechanism underlying age-dependent decline of HSCs Hematopoiesis is tightly regulated by a complex series of interactions between HSCs, their stromal microenvironment, and diffusible regulatory molecules, the hematopoietic growth factors (HGFs) that effect cellular proliferation. This accumulated DNA damage appears to be mediated by Batf (basic leucine zipper transcription factor, ATF-like). Batf induces differentiation in cells of lymphoid and myeloid lineage and restricts the self-renewal of HSCs with deficient telomeres. HSCs lacking Batf have evidence of persistent DNA damage, a finding consistent with that reported to occur in HSCs of old mice and older adults.

5 HEMATOPOIETIC STEM CELLS AND AGING (2 of 2)Major question: Do pluripotent HSCs have finite replicative capacity? Studies in mice have shown that with aging, HSCs demonstrate: Reduced ability to regenerate the hematopoietic system Increased propensity for myeloid differentiation Decreased ability to generate mature lymphocytes Not influenced by the aging marrow microenvironment Thought to be an inherent attribute of the aging HSC Postulated that the myeloid dominance of adult human leukemia maybe be caused by age-related deficient lymphopoiesis

6 EFFECTS OF AGING ON HEMATOPOIESIS (1 of 2)Reduced reserve capacity Occurs across all HSC lineages Diminished adaptive immune response Given comparable stress, hematologic abnormalities are likely to occur earlier, be more severe than in younger people Slower return to normal Hb following phlebotomy Reduced ability to mount granulocyte response to infection Hb = hemoglobin Age-related deficient hematopoiesis is characterized by decreased competence in the innate immune system (decreased natural-killer activity, decreased phagocytic ability of neutrophils and macrophages, and a proinflammatory state) and the adaptive immune system (decreased numbers of memory B and T cells), the expansion of myeloid elements, and the occurrence of a mild to moderate normocytic anemia. Topic

7 EFFECTS OF AGING ON HEMATOPOIESIS (2 of 2)With aging: No significant change in basal blood cell counts Prevalence of anemia tends to increase modestly, especially in men Aging reduces hematopoietic reserve, but is only of clinical significance in the presence of comorbid conditions Aging does not appear to affect the circulating concentrations of erythropoietin and most other hematopoietic growth factors (HGFs) In response to stress, there is a blunted hematopoietic response that is attributed to an impaired ability to release HGFs This is more evident in men ≥75 years old, which in cross-sectional studies have lower hemoglobin values than their younger counterparts (≤65 years old). The mechanism for the difference is unclear but is thought to reflect the presence of comorbid illness or reduced erythropoietin drive, or both, as a result of declines in androgen. Topic

8 INCIDENCE AND PREVALENCE OF ANEMIAMost common age-related hematologic abnormality In those >65, incidence is higher in men than in women Affects 12%–16% of women and 18%–22% of men after age 80 According to World Health Organization criteria, anemia is diagnosed if the hemoglobin concentration is <13 g/dL in men and <12 g/dL in women. Studies have shown a high prevalence of anemia in hospitalized older people, patients attending geriatric clinics, or in nursing homes Results from the third National Health and Nutrition Examination Survey (NHANES III) in the United States indicated that the prevalence of anemia was 11% in community-dwelling men and 10.2% in women >65 yr old. Most anemia among NHANES III participants was mild; only 2.8% of women and 1.6% of men had Hb < 11 g/dL. NHANES III also found that of all anemia cases among older adults in the United States, 35% resulted from nutrient deficiencies (iron, vitamin B12, and/or folate); 45% was attributable to chronic disease(s); and 20% was unexplained despite an exhaustive evaluation. Topic

9 IMPLICATIONS OF ANEMIA IN AGING (1 of 2)Studies have shown that morbidity and mortality outcomes are worse with Hb concentrations both <12 g/dL and >15 g/dL Postulated that even mild anemia in older adults leads to: Decreases in cardiac output and local tissue hypoxia Aggravation of already existent comorbidities Functional decline Women >65 years old with Hb concentrations <11 g/dL have a higher risk of all-cause mortality than those whose Hb concentrations were ≥12 g/dL This increased risk of mortality is independent of the presence of other comorbidities Hb= Hemoglobin

10 IMPLICATIONS OF ANEMIA IN AGING (2 of 2)Anemia in older adults is associated with: Impaired performance-based mobility function such as walking speed or ability to rise from a chair Impaired cognitive performance Occurrence of depressive symptoms Decrease in quality of life. Increases in muscle weakness Severity of frailty Impaired balance Risks of falls Increased mortality risk

11 PRESENTATION OF ANEMIAWhen Hb < 10 g/dL is associated with anemia of chronic disease or inflammation, consider possibility of multiple causes, eg: Blood loss Malnutrition Folate deficiency Hemolysis Bone marrow exam may be required, because lab results are often equivocal The presence of multiple pathologies in older people often makes the evaluation of anemia difficult. In hospitalized patients, multiple disorders can contribute to the anemia. A classic example is a patient with active rheumatoid disease who has lost blood from aspirin ingestion. Similarly, protein-energy malnutrition or blood loss will markedly aggravate the anemia associated with neoplasia. Iron deficiency and vitamin B12 deficiency may coexist, presenting confusing red blood cell indices. Topic

12 CLASSIFICATION OF ANEMIA: Hypoproliferative AnemiaIron-deficient erythropoiesis Iron deficiency Chronic disease Erythropoietin lack Renal Endocrine Stem-cell dysfunction Aplastic anemia See Table 65.1 in GNRS5. SOURCE: Chatta GS, Lipschitz DA. Aging and hematopoiesis. In: Hazzard WR, Blass JP, Ettinger WH Jr., et al., eds. Principles of Geriatric Medicine and Gerontology. 5th ed. New York: McGraw-Hill Health Professions Division; 2003:763–770. Topic

13 CLASSIFICATION OF ANEMIA: Ineffective ErythropoiesisMacrocytic anemia Vitamin B12 deficiency Folate deficiency Myelodysplastic syndrome (refractory anemia) Microcytic anemia Thalassemia Sideroblastic Normocytic anemia Myelodysplastic syndrome See Table 65.1 in GNRS5. SOURCE: Chatta GS, Lipschitz DA. Aging and hematopoiesis. In: Hazzard WR, Blass JP, Ettinger WH Jr., et al., eds. Principles of Geriatric Medicine and Gerontology. 5th ed. New York: McGraw-Hill Health Professions Division; 2003:763–770. Topic

14 CLASSIFICATION OF ANEMIA: Hemolytic AnemiaImmunologic Idiopathic Secondary Intrinsic Metabolic Abnormal hemoglobin Extrinsic Mechanical See Table 65.1 in GNRS5. SOURCE: Chatta GS, Lipschitz DA. Aging and hematopoiesis. In: Hazzard WR, Blass JP, Ettinger WH Jr., et al., eds. Principles of Geriatric Medicine and Gerontology. 5th ed. New York: McGraw-Hill Health Professions Division; 2003:763–770. Topic

15 WORK-UP OF ANEMIA (1 of 2) Practically speaking, Hb = 12 g/dL is lower limit of normal for older men and women Clinical judgment is important in deciding how aggressively to evaluate borderline low Hb; however, must exclude iron deficiency Principles of evaluating anemia do not vary based on patient age Initial Evaluation: Thorough H & P to include medication, alcohol, and dietary history CBC with absolute reticulocyte count Fecal blood testing H & P = history and physical examination; CBC = complete blood count. Even at Hb = 12 g/dL, the decision about how aggressively to evaluate a patient with borderline low hematocrit must rest on clinical judgment. The complex nature of the problems that present in older people, together with the high risk of simultaneous multiple pathologies, makes this decision much more critical. Results of the H & P may include: Results may reveal pale conjunctiva, chronic indigestion, and dark stools or urine. A specific inquiry should be made about medications that increase risk of bleeding such as anticoagulants and NSAIDs. Topic

16 WORK-UP OF ANEMIA (2 of 2) Microcytosis (MCV < 84) indicates impairment of Hb synthesis Macrocytosis (MCV > 100) may indicate reticulocytosis or abnormality in nuclear maturation Red cell production is estimated by interpreting the absolute reticulocyte count (ARC) Hemolytic anemia: ARC ≥ 100,000/ µL Failure of production: ARC < 75,000/ µL MCV = mean corpuscular volume In the absence of anemia, the normal absolute reticulocyte count is between 25,000 and 75,000/μL. Absolute reticulocyte counts between 75,000 and 100,000/μL should be interpreted in the context of the clinical presentation. Decreased red cell production is caused by the hypoproliferative anemias or by ineffective erythropoiesis. An elevated lactate dehydrogenase (LDH) level and indirect hyperbilirubinemia result from the increased destruction of red cell precursors in the marrow and may be used to distinguish ineffective erythropoiesis from hypoproliferative anemia. Topic

17 EVALUATION OF HYPOPROLIFERATIVE ANEMIA DUE TO POSSIBLE VITAMIN B12 OR FOLATE DEFICIENCYCheck vitamin B12 and serum RBC and folate levels Vitamin B12 low (<150 pg/mL) Vitamin B12 (150–300 pg/mL) and folate (3–5 ng/mL) normal Folate low (<3 ng/mL) Check MMA and homocysteine levels MMA and homocysteine normal MMA elevated Homocysteine elevated, MMA normal Vitamin B12 deficiency See Figure 65.2 in the GNRS5 SOURCE: Adapted from Reuben DB, Herr K, Pacala JT, et al. Geriatrics At Your Fingertips, 14th ed. New York: American Geriatrics Society; 2012;126. Used with permission. Obtain iron studies and ferritin level; If results are normal, cause of anemia is unknown Folate deficiency Treat with folic acid, 1 mg/day Tx: parenteral or oral vitamin B12 Consider bone marrow biopsy Recheck hemoglobin and reticulocyte count after 1–2 wk of therapy

18 EVALUATION OF HYPOPROLIFERATIVE ANEMIA DUE TO POSSIBLE IRON DEFICIENCY ANEMIAObtain ferritin (SF), serum iron, % saturation (TSAT) SF<30ng/mL and/or TSAT <20% SF ng/mL and/or TSAT <20% SF> 100 ng/mL and/or TSAT >20% eGFR eGFR <60 eGFR >60 Possible Iron Deficiency Iron Deficiency Evaluate source of blood loss (eg, GI, GU) Chronic kidney disease Evaluate B12 and folate; if normal See Figure 65.1 in the GNRS5 Source: Adapted from Reuben, DB, Herr, K, Pacala JT, et al. Geriatrics At Your Fingertips, 17th ed. New York: American Geriatrics Society; Used with Permission Response Consider ESA No Response Iron Therapy ACI UAE MDS

19 HYPOPROLIFERATIVE ANEMIAS: Iron-Deficiency AnemiaDiagnosed by: Decreased serum iron Reduced transferrin saturation (serum iron/TIBC) Normal or Increased serum ferritin In younger people, the most common cause is absolute iron deficiency (blood loss, malabsorption, or nutritional deficiency)  low serum ferritin, high TIBC In older adults, the most common causes are: Blood-loss anemia, anemia of chronic disease, anemia associated with inflammation, and anemia associated with protein-energy malnutrition TIBC = total iron binding capacity Iron is the only nutrient that limits the rate of erythropoiesis. Thus, inadequate iron supply for erythropoiesis results in a hypoproliferative anemia. This iron restriction is diagnosed by the presence of a decreased serum iron, a decreased transferrin saturation (serum iron concentration divided by the serum total iron binding capacity or serum transferrin concentration, expressed as a percentage), and a normal or increased serum ferritin concentration. Topic

20 HYPOPROLIFERATIVE ANEMIAS: Iron-Deficiency AnemiaNutritional iron deficiency is rare in older adults Unexplained iron deficiency in older adults is almost exclusively due to GI blood loss Common causes: Medication-related gastritis, angiodysplasia, benign tumors Consider these only after excluding neoplasm Blood-loss anemia  low iron, low serum ferritin, high TIBC In the presence of both iron deficiency and anemia of chronic inflammation, the serum ferritin may be within the normal range. Rarely, iron deficiency can result from malabsorption or urinary losses of iron, which occur in the face of intravascular hemolysis. Topic

21 HYPOPROLIFERATIVE ANEMIAS: Iron-Deficiency Anemia: TreatmentParenteral or oral iron preparations Oral is preferred as first-line Oral treatment: Ferrous sulfate or Ferrous gluconate Ferrous gluconate will provide less elemental iron per dose No difference in efficacy or adverse-event profile Increased absorption with Vitamin C May need treatment for ≥ 6 months to replace iron stores Oral iron absorption requires that the upper portion of the small bowel be intact and appropriately acidified by gastric secretions. In the presence of achlorhydria from gastric resection or atrophic gastritis, or medications that suppress gastric acid secretion, medicinal iron absorption may be impaired. Often, supplementation with orange juice or oral vitamin C preparations will correct their malabsorption defect. Common dose-related adverse events of oral iron preparations include mild nausea and constipation. For this reason, the frequency and dosage of administration may require adjustment to ensure compliance. Tablets containing a lower elemental dose of iron (15–20 mg), such as ferric gluconate, may be better tolerated than higher dose preparations. Iron elixir and liquid iron drops may be better absorbed; however, the adverse-event profile is similar to that for tablet preparations. Treatment may need to continue for ≥6 months to adequately replace iron stores. Topic

22 HYPOPROLIFERATIVE ANEMIAS: Iron-Deficiency Anemia: TreatmentParenteral can be IV or IM IV is preferred as IM can be painful and requires significant muscle mass for the target injection site Choice of agent is based on the patient’s allergy history and the length of infusion course desired Newer agents have shorter administration courses but are expensive IV= Intravenously IM= Intramuscularly Intravenous administration is indicated in patients receiving an erythrocyte-stimulating agent during dialysis, or if the use of oral iron preparations is untenable. Multiple intravenous iron products are available, with similar efficacy and a reasonable safety profile. The choice of agent is based on the patient’s allergy history and the length of infusion course desired. Newer agents have shorter courses of administration but are costly and also may be complicated by iron overload, hypertension, and hypophosphatemia, compared with iron sucrose, sodium ferric gluconate, or low-molecular-weight iron dextran preparations. Topic

23 HYPOPROLIFERATIVE ANEMIA: Anemia Of Chronic DiseaseLaboratory features: Mild anemia Low serum iron Low transferrin saturation Normal to increased iron stores (ferritin > 150 ng/mL) Occasionally the initial manifestation of occult disease Distinguish from iron-deficiency anemia in order to avoid unnecessary GI tests, oral iron therapy The pathophysiology of the anemia of chronic disease is complex and is due to an inability of macrophages to release iron from the breakdown of senescent red cells. As a consequence, the serum iron falls and, as with blood-loss anemia, there is inadequate iron supply for erythropoiesis. The term anemia of chronic disease is often used to explain an anemia associated with some other major disease process. Examples include cancer, collagen vascular disorders, rheumatoid arthritis, and inflammatory bowel disease. Laboratory parameters often can be equivocal, and it may be difficult to distinguish between iron deficiency and defective iron utilization. In this setting, measuring an erythrocyte sedimentation rate or C-reactive protein level may be helpful, because these will often be increased in the presence of an occult inflammatory condition. Topic

24 HYPOPROLIFERATIVE ANEMIA: Anemia Of Chronic Disease: TreatmentClinical judgement is critical in deciding how aggressive the evaluation of anemia needs to be Treatment is directed towards the underlying disease Some evidence that patients with profound fatigue may benefit from transient iron infusions Topic

25 Decreased erythropoietin (EPO) production:HYPOPROLIFERATIVE ANEMIA: Anemia from Decreased Erythropoietin Production Decreased erythropoietin (EPO) production: Anemia of ESRD Some anemias of cancer and chronic diseases Characterized by an inability to use iron stores and an inadequate EPO response (inappropriately low EPO levels) ESRD: End-Stage Renal Disease Topic

26 USE OF EXOGENOUS ERYTHROPOIETIN (1 of 2)May be indicated for patients with Hb < 10 mg/dL (SOE= B) Alternative to packed red cell transfusions Must exclude hemolysis, iron deficiency, and bleeding, especially in symptomatic older adults Use with caution due to increased risk of cardiovascular events and mortality with Hb > 11 mg/dL Serum ferritin concentrations should not exceed 500 ng/mL, because serum ferritin concentration greater than this has been associated with an increased risk of bacterial infection. A temporary cessation of therapy followed by a 25% dosage reduction in erythropoietin therapy is indicated if the hemoglobin concentration approaches 12 g/dL or if the rate of rise is >1 g/dL every 2 weeks. If the hemoglobin concentration remains <10 g/dL and does not increase by 1 g/dL after 4 weeks, or if the hemoglobin concentration falls to <10 g/dL, a 25% increase in dosage is in order. If the target range of hemoglobin >10 g/dL is not achieved after appropriate dosage adjustments over 12 weeks, the patient should be reevaluated for infection, iron restriction, or the presence of an anemia not responsive to epoetin alpha. If after reassessment and iron replacement, the anemia remains refractory to treatment, epoetin alfa therapy should be discontinued. Although it is difficult to prospectively identify nonresponders, it has been reported that patients with endogenous erythropoietin levels >500 mU/mL are unlikely to respond. Topic

27 USE OF EXOGENOUS ERYTHROPOIETIN (2 of 2)Iron stores should be monitored monthly Replace iron if ferritin falls to < 100 ng/mL or transferrin saturation falls to < 20% If Hb does not become > 10 mg/dL after 12 weeks, patients should be reassessed If patients remain refractory to treatment EPO should be discontinued Serum ferritin concentrations should not exceed 500 ng/mL, because serum ferritin concentration greater than this has been associated with an increased risk of bacterial infection. A temporary cessation of therapy followed by a 25% dosage reduction in erythropoietin therapy is indicated if the hemoglobin concentration approaches 12 g/dL or if the rate of rise is >1 g/dL every 2 weeks. If the hemoglobin concentration remains <10 g/dL and does not increase by 1 g/dL after 4 weeks, or if the hemoglobin concentration falls to <10 g/dL, a 25% increase in dosage is in order. If the target range of hemoglobin >10 g/dL is not achieved after appropriate dosage adjustments over 12 weeks, the patient should be reevaluated for infection, iron restriction, or the presence of an anemia not responsive to epoetin alpha. If after reassessment and iron replacement, the anemia remains refractory to treatment, epoetin alfa therapy should be discontinued. Although it is difficult to prospectively identify nonresponders, it has been reported that patients with endogenous erythropoietin levels >500 mU/mL are unlikely to respond. Topic

28 HYPOPROLIFERATIVE ANEMIA: Due to Marrow FailurePancytopenia without iron-deficient erythropoiesis suggests marrow failure due to interference with proliferation of hematopoietic cells Common causes: Medications, immune damage to stem cells, intrinsic marrow lesions, marrow replacement by malignant cells or fibrous tissue Bone marrow aspiration and biopsy are indicated Pure red cell aplasia = isolated suppression of erythropoiesis Causes: Medications, lymphocyte abnormalities, parvovirus B19 Features: Isolated anemia, elevated serum iron, no erythroid precursors on bone marrow exam Marrow replacement by malignant cells or fibrous tissue is usually associated with a myelophthisic blood picture (nucleated red cells, giant platelets, and metamyelocytes on smear) as a reflection of the disruption of marrow stromal architecture. Patients with parvovirus infection typically have reduced red cell precursors, which, if present, may have peculiar intranuclear inclusion bodies. Parvovirus-related pure red aplasia often responds to intravenous immunoglobulin infusions and sometimes antivirus therapy. Topic

29 INFFECTIVE ERYTHROPOIESIS: Macrocytic AnemiasPernicious anemia: Increases with age, most common in adults > 60 years old Common in women and patients with autoimmune thyroid disease In most cases, caused by atrophic gastritis leading to vitamin B12 malabsorption Megaloblastic anemia: Signs include: Macrocytosis, hypersegmented neutrophils in the peripheral smear, decreased reticulocyte index, increased LDH, indirect hyperbilirubinemia The prevalence of pernicious anemia increases with advancing age. The action of antibodies against gastric parietal cells and intrinsic factor (the substance responsible for absorption of vitamin B12) leads to atrophic gastritis and decreased secretion of intrinsic factor, resulting in malabsorption of vitamin B12. Pernicious anemia occurs most commonly in people over the age of 60 and is more common in women. Chronic pancreatitis and diseases of the distal ileum (blind loop syndrome) may also cause vitamin B12 deficiency. Topic

30 VITAMIN B12, FOLATE, AND HOMOCYSTEINE (1 of 4)Older people are more likely than younger people to have low levels of vitamin B12 and folate Low levels of B12 and folate are not necessarily accompanied by macrocytosis or evidence of megaloblastic anemia Of apparently healthy people ≥70: 10% have B12 deficiency 5%–10% have low folate Topic

31 VITAMIN B12, FOLATE, AND HOMOCYSTEINE (2 of 4)Causes of vitamin B12 deficiency: Atrophic gastritis causing malabsorption Surgery in the GI tract (resection of the terminal portion of the small intestine or gastrectomy) Patients taking metformin Chronic use of proton-pump inhibitors Causes of folate deficiency: Alcohol abuse Drug Interactions (metformin, valproic acid) with folate absorption Inadequate dietary intake (vegan diets without supplementation) Even in patients with atrophic gastritis, oral vitamin B12 is generally adequate; 1%–2% of orally administered vitamin B12 will be absorbed by mass action alone and does not require the presence of intrinsic factor. Folate deficiency of sufficient severity to cause anemia in older adults is rare. Alcohol and various drugs (eg, metformin, valproic acid) interfere with folate absorption and metabolism. Vulnerability to deficiency is significantly greater when folate requirements are increased as a result of inflammation, neoplastic disease, or hemolytic anemia. Topic

32 VITAMIN B12, FOLATE, AND HOMOCYSTEINE (3 of 4)In older adult patients with low-normal B12 (<350 pg/mL), check methylmalonic acid (MMA) level to exclude metabolically active B12 deficiency Severe B12 deficiency (<100 pg/mL), and possibly mildly low levels, can result in cognitive impairment and significant neurologic deficits No evidence of a link between low B12 and dementia Nevertheless, aggressive replacement of B12 and folate is warranted in patients with dementia Oral vitamin B12 is equally as effective as parenteral replacement Keep in mind that kidney failure can artificially raise the serum MMA level. Even in patients with atrophic gastritis, oral vitamin B12 is generally adequate; 1%–2% of orally administered vitamin B12 will be absorbed by mass action alone and does not require the presence of intrinsic factor. Thus, patients with vitamin B12 concentrations in the low-to-normal range should receive a daily oral dose of 1 mg (1,000 mcg). Oral vitamin B12 is equally effective as parenteral replacement, and it also provides a significant cost-advantage. In patients with severe vitamin B12 deficiencies (ie, concentrations <100 pg/mL) or with neurologic symptoms, parenteral replacement of 1,000 mcg/d for 1 week initially via intramuscular (or deep subcutaneous) route, then 1,000 mcg/week for 1 month, and then reduced to 1,000 mcg/month for maintenance, should be used. Levels of serum vitamin B12 should be checked at 4 weeks to assess repletion. Folic acid can be replaced in dosages ranging from 1 to 5 mg/d for 3–4 months (1 mg/day is usually sufficient). Topic

33 VITAMIN B12, FOLATE, AND HOMOCYSTEINE (4 of 4)Low B12 or folate is accompanied by increased homocysteine Trials of lowering homocysteine through vitamin therapy did not reduce end points of stroke and myocardial infarction and may increase cancer risk Increased homocysteine concentrations are common in patients with renal impairment, should be interpreted with caution Low concentrations of vitamin B12 or folate are accompanied by increased concentrations of homocysteine. Epidemiologic studies initially found that B12 and folate deficiencies with high levels of homocysteine are associated with cardiovascular disease; however, subsequent trials of homocysteine lowering through vitamin therapy did not reduce end points such as stroke and myocardial infarction, and may increase cancer risk. Topic

34 VITAMIN B12 REPLACEMENT Particularly if MMA level is elevated, consider for patients with: Low-normal B12 levels and macrocytosis (with or without anemia) Neurologic changes 1 mg/day oral B12 is generally sufficient for patients with low-normal B12 Parenteral replacement for B12 < 100 pg/mL or in those with neurologic symptoms Even in patients with atrophic gastritis, oral vitamin B12 is generally adequate; 10% will be absorbed by mass action alone and not require the presence of intrinsic factor. Topic

35 INFFECTIVE ERYTHROPOIESIS: Microcytic AnemiasThalassemia Occasionally detected initially in older people Mild anemia, disproportionately low MCV, and absence of iron deficiency suggest thalassemia trait, a condition of little or no consequence Do not treat with iron supplements as these can be detrimental Acquired sideroblastic anemia Primarily a disease of older adults Heterogeneous group of disorders marked by iron deposits in mitochondria of normoblasts All patients should receive a trial of pyridoxine, 200 mg every 8 hours, for 3 months, but few respond Treat non-responders symptomatically Acquired sideroblastic anemia is a consequence of impaired heme synthesis. It usually reflects an intrinsic marrow lesion (idiopathic) but may be secondary to inflammation, neoplasia, or drug ingestion. The common finding is the presence of a dimorphic red cell population, in part markedly hypochromic and in part well filled with hemoglobin. The diagnosis is made by the demonstration of ringed sideroblasts in the bone marrow as well as the presence of maturation abnormalities of myeloid and erythroid precursors. Older adults with sideroblastic anemia may show some response to pyridoxine (200 mg q8h). This dosage should be given for 3 months until it becomes apparent that hemoglobin concentration will not increase. For patients who are unresponsive to pyridoxine, the anemia should be treated symptomatically. Topic

36 INFFECTIVE ERYTHROPOIESIS: Myelodysplastic SyndromesGroup of stem cell disorders characterized by disordered hematopoiesis Occur primarily in the older adult age group Cytogenetic abnormalities are relatively common in MDS 5q– syndrome: more common in women Treatment is primary supportive Risk stratification (low-, intermediate-, high-risk) based on an International Prognostic Scoring System (IPSS) Refractory anemia with or without ringed sideroblasts is associated with 25% to 30% of the MDS syndromes. Refractory anemia commonly presents as a macrocytic anemia with marrow erythroid hyperplasia and relatively normal myeloid and megakaryocytic lineages. A cytogenetic abnormality of particular interest in older adult patients is deletion of the long arm of chromosome 5 (5q−). The median age at presentation is 66 years. The syndrome is characterized by macrocytic anemia, modest leukopenia, normal or increased platelet counts, marrow erythroid hypoplasia or hyperplasia, and female preponderance. Prognosis in MDS correlates with the IPSS: median survival for low, intermediate, and high risk disease being ≥10 years, 2–5 years, and <12 months respectively. Topic

37 EFFECTS OF AGING ON PLATELETS AND COAGULATIONPlatelet counts do not change with age Concentrations of many coagulation enzymes increase with age, including factor VII, factor VIII, and fibrinogen Studies of centenarians suggest that aging  increased hypercoagulability In centenarians, highly significant increases in the concentrations of factor VII, factor VIII, and fibrinogen are noted, as are levels of factors IX and X and thrombin-antithrombin complexes. Fibrin formation is also increased, as evidenced by higher concentrations of fibrinopeptide A. In addition, elevated levels of d-dimers suggest increased hyperfibrinolysis. These facts suggest that aging may be accompanied by increased hypercoagulability. Hyperhomocysteinemia, secondary to low vitamin B12 levels, is also more common in the older age group and may be an additional factor associated with hypercoagulability. However, the very high level of clotting factors and evidence of hypercoagulability in remarkably healthy centenarians have also led to the suggestion that elevated coagulation factors may not be markers of increased risks of thrombosis. Topic

38 BLEEDING DIATHESIS Common in older people Examples:Unexplained bruises Repeated nosebleeds GI blood loss Excessive blood loss during surgery or following tooth extraction Patients should have screening platelet count and coagulation study; platelet aggregation test may also be worthwhile Topic

39 THROMBOCYTOPENIA Platelet count < 150,000/mL is considered significant, but bleeding usually occurs at much lower levels Treatment depends on the cause: Decreased platelet production—irrespective of platelet count, consider platelet transfusion if blood loss is significant Increased peripheral destruction—usually drug-induced or secondary to autoimmune disease, so treat primary disorder; order trial of steroids if no cause is found Isolated thrombocytopenia—exclude MDS; also consider DIC and TTP Thrombocytopenia is a common cause of bleeding problems in older people. Generally, bleeding occurs when the platelet count drops to 20,000/μL or less. Common causes include decreased production of platelets in the bone marrow, sequestration in enlarged spleens, and increased peripheral destruction. Decreased production of platelets occurs in the leukemias, marrow aplasia, or, most commonly in older people, in association with drugs that suppress platelet production. Topic

40 PLATELET FUNCTION DISORDERS (THROMBOPATHIES)Uncommon but can cause significant bleeding in older people on aspirin therapy, sometimes requiring platelet transfusion von Willebrand’s disease Hereditary—can present initially in older people Acquired—disease of older people, commonly associated with monoclonal gammopathies, lymphomas, or myeloma Desmopressin acetate may be used when treatment necessary; if adverse effects are intolerable, try recombinant factor VIII concentrate that has high dose of vWF vWF = von Willebrand’s factor Aspirin irreversibly acetylates cyclooxygenase, affecting arachidonic acid metabolism. The net effect is significant loss of platelet function. In the rare circumstance, spontaneous bleeding may occur or may be precipitated by injury or surgery. von Willebrand’s disease is caused by a reduction in vWF concentration, which is accompanied by a reduction in factor VIII concentration. vWF is essential for normal platelet function, so bleeding occurs because of a platelet function defect. Monoclonal factor VIII does not contain vWF, and viral contamination may occur with cryoprecipitates (which used to be the treatment of choice for von Willebrand’s disease). Desmopressin acetate, a synthetic analogue of arginine vasopressin, stimulates endothelial cells to release stored vWF. Treatment is often successful, but adverse effects are common. Topic

41 CLOTTING FACTOR DEFICIENCIESMost common: acquired inhibitor to factor VIII Onset is often sudden Titers to anti-factor VIII antibodies can be very high Presents with bleeding into joints and muscle Besides factor replacement, prednisone or cyclophosphamide may be needed Deficiency of vitamin K–dependent clotting factors Tends to occur in older people with major illnesses Consider inappropriate warfarin use, even if not prescribed Readily treated with vitamin K (orally or IV) Clotting factor deficiencies in older adults are usually acquired and caused by the presence of circulating clotting factor inhibitors. Deficiency of the vitamin K–dependent clotting factors is caused by disorders of the hepatobiliary tree, antibiotics that neutralize bowel bacteria (a major source of the vitamin), malabsorption, and severe malnutrition. The subcutaneous administration of vitamin K is discouraged because of a slower time to correction of the prolonged INR and variable absorption. In patients receiving warfarin with severe bleeding and who are unable to receive fresh frozen plasma or in those in need of urgent reversal, a 4- factor prothrombin complex concentrate (Kcentra®) or 3-factor prothrombin complex concentrate plus recombinant activated factor VIIa (Profilnine® + rHFVIIa) may be administered. Patients with previous episodes of immune-mediated heparin-induced thrombocytopenia should not receive Kcentra, because it contains trace amounts of heparin. Topic

42 EXCESSIVE BLEEDING AND LIVER DISEASEConsider liver disease in all patients who present with excessive bleeding Prothrombin time is prolonged even in mild liver disease Liver disease reduces all clotting factors except factor VIII, results in lack of clearance of fibrin degradation products, and can affect platelet function Liver disease is associated with DIC Treatment of a bleeding diathesis in liver disease is fresh frozen plasma or a nonactivated prothrombin complex concentrate The prothrombin time is prolonged even in mild to moderate liver disease because of the short plasma half-life of factor VII. The partial thromboplastin time remains normal until liver disease becomes severe, because the half-lives of the coagulation factors effecting the partial thromboplastin time are more prolonged Topic

43 CHRONIC MYELOPROLIFERATIVE DISORDERSThe Philadelphia chromosome–negative chronic myeloproliferative disorders occur primarily in older adults: Polycythemia vera (PV) Essential thrombocytopenia (ET) Idiopathic myelofibrosis (IMF) ET and PV have a long natural history with a low incidence of leukemia transformation PV, ET, and IMF are characterized by the involvement of a multipotent hematopoietic progenitor cell, marrow hypercellularity, overproduction of one or more marrow lineages, thrombotic and hemorrhagic diatheses, exuberant extramedullary hematopoiesis, and a slow rate of spontaneous transformation to acute leukemia. The main cause of morbidity and mortality in PV and ET is thrombosis, which occurs more commonly in older patients or in those with previous vascular complications. Severe bleeding is rare and is limited to patients with a very high platelet count or to those taking antiplatelet drugs. Cytotoxic therapy is effective in preventing thrombosis but increases the risk of leukemic transformation. Since there is no curative therapy for PV and ET, the goals of therapy are to minimize thrombotic risk and prevent progression to marrow fibrosis or acute leukemia. Given the results of the European Collaboration on Low-dose Aspirin in Polycythemia Vera trial, low-dose aspirin is recommended for all patients with PV. Consensus-based practice guidelines for ET include observation in asymptomatic low-risk patients with platelet counts <1,500 × 109/L, and hydroxyurea plus aspirin in high-risk patients with platelet counts ≥1,500 × 109/L. Topic

44 MANAGEMENT OF POLYCYTHEMIA VERAPhlebotomy in all patients to keep hematocrit < 0.45 Myelosuppressive agents like hydroxyurea in patients at high risk of thrombosis (> 60 years old) and in those with excessive phlebotomy requirements Hydroxyurea and an antiplatelet agent for symptomatic thrombocytosis 32P, busulfan, pegylated interferon, and anagrelide remain as viable options in these patients; however, they are usually reserved for patients with disease that is difficult to control. Patients receiving anagrelide have been reported to have an increased risk of developing myelofibrosis and arterial thrombosis. Pegylated interferon is effective but may not be well tolerated. Additionally, given the results of the European Collaboration on Low-dose Aspirin in Polycythemia Vera trial, low-dose aspirin is recommended for all patients with PV. In this trial, 531 patients with PV were randomized to receive either no aspirin or low-dose aspirin. In those treated with aspirin, cardiovascular mortality was reduced by 59%, with a nonsignificant risk of increased bleeding. Topic

45 MANAGEMENT OF ESSENTIAL THROMBOCYTOPENIAObservation for asymptomatic low-risk patients with platelet counts < 1500 × 109/L Hydroxyurea plus aspirin for high-risk patients with platelet counts > 1500 × 109/L Anagrelide is very effective at reducing high platelet counts, but compared with hydroxyurea, it is less effective in reducing thrombotic events An RCT comparing hydroxyurea + ASA to anagrelide + ASA demonstrated that hydroxyurea was more effective and associated with less adverse events, better overall survival, less serious hemorrhagic events, and fewer fibrotic transformations RCT= Randomized Controlled Trial ASA = aspirin The incidence of thrombotic and hemorrhagic complications in ET was recently analyzed in 1850 patients from 21 retrospective cohort studies. Rates of thrombosis and hemorrhage ranged from 7% to 17% and 8% to 14%, respectively. Age over 60 years, a prior thrombotic event, and a long duration of thrombocytosis were the major risk factors for thrombotic events. Topic

46 SUMMARY (1 of 2) The reserve capacity of hematopoiesis diminishes with advancing age Anemia is the most common age-related hematologic abnormality; it should be evaluated in the same way as in younger adults In older adults, the most common causes of iron-deficient erythropoiesis are anemia of chronic disease and anemia associated with inflammation Clinical judgment is important in deciding how aggressively to evaluate anemia Vitamin B12 deficiency and low folate are common in apparently healthy people ≥70, and can be clinically important Topic

47 SUMMARY (2 of 2) Patients with a bleeding diathesis should have a screening platelet count and coagulation study; a platelet aggregation test may also be worthwhile A platelet count < 150,000/mL is significant Clotting factor deficiencies in older adults are usually acquired and are caused by circulating clotting factor inhibitors Acquired sideroblastic anemia, myelodysplastic syndromes, and Philadelphia chromosome-negative myeloproliferative disorders occur primarily in older people Topic

48 CASE 1 (1 of 3) An 80-year-old woman and her daughter come to discuss laboratory findings related to a dementia evaluation. History: recently diagnosed dementia, osteoarthritis, hypertension, hypothyroidism, gout Medications: acetaminophen, lisinopril, levothyroxine, allopurinol Laboratory results: macrocytic anemia, normal folate level, decreased vitamin B12 level (220 pg/mL) Topic

49 CASE 1 (2 of 3) Which one of the following best describes the relationship between her low B12 level and cognitive disorder? B12 deficiency is the likely cause of her dementia. B12 deficiency is an incidental finding. B12 deficiency increases her risk of Alzheimer disease B12 deficiency contributes to vascular brain pathology. Topic

50 CASE 1 (3 of 3) Which one of the following best describes the relationship between her low B12 level and cognitive disorder? B12 deficiency is the likely cause of her dementia. B12 deficiency is an incidental finding. B12 deficiency increases her risk of Alzheimer disease B12 deficiency contributes to vascular brain pathology. ANSWER: B Vitamin B12 deficiency can cause a wide spectrum of clinical symptoms: neuropathies, cognitive impairments, delirium, and dementia. Dementia caused by vitamin B12 deficiency, while it is a clinical reality, is rare. Even in the context of vitamin B12 deficiency, the most likely cause of this patient’s dementia is Alzheimer disease (or mixed dementia). Even though the low B12 level is incidental, supplementation of vitamin B12 should be started in patients with dementia and vitamin B12 deficiency, given its potential for benefits, its low cost, and its risk profile. Cobalamin administered either by oral or parenteral route is effective for correcting moderate vitamin B12 deficiency, as seen in this patient. Mild to moderate deficiency (B12 levels between 100–350 pg/mL and a normal methylmalonic acid level) can be replaced using the oral route. In epidemiologic studies, there is an association between low B12, folate, and increased homocysteine levels and incident dementia (SOE=C). Clinical studies of B12 treatment even when it normalizes homocysteine levels have not shown clinical benefit on cognitive decline or dementia (SOE=A). One longitudinal trial has shown cognitive benefit from folate treatment in healthy older adults with increased homocysteine and normal B12 levels. There is also no current evidence that B12 deficiency is associated with vascular brain changes. Topic

51 CASE 2 (1 of 3) A 65-year-old woman recently received a diagnosis of polycythemia vera. For several years she has had unexplained itchiness, tingling, and stinging of her skin after contact with water. History: hypertension, type 2 diabetes mellitus, osteoarthritis Topic

52 CASE 2 (2 of 3) Which one of the following most likely explains her symptoms? Erythromelalgia Aquagenic pruritus Diabetic neuropathy Cold-induced urticaria Topic

53 CASE 2 (3 of 3) Which one of the following most likely explains her symptoms? Erythromelalgia Aquagenic pruritus Diabetic neuropathy Cold-induced urticaria ANSWER: B This patient’s symptoms are characteristic of aquagenic pruritus. It is often the predominant complaint in patients with polycythemia vera, and may precede diagnosis by several years. Aquagenic pruritus is characterized by intense itching (72%), stinging (31%), tingling (21%), or burning (18%) sensation at the skin level after contact with water. There are no visible changes at the skin level. The prevalence of pruritus in patients with polycythemia vera could be as high as 68% (SOE=B). The exact mechanism of aquagenic pruritus is unknown; however, it seems to involve mast cell degranulation. The most affected sites are the chest, back, medial side of the arms, and ventral side of the legs. Pruritus starts <10 minutes after contact with water. In most cases, warm water causes worse symptoms than cold water. Aquagenic pruritus significantly affects the quality of life of patients with polycythemia vera. Erythromelalgia is characterized by burning pain in the hands or feet, as well as erythema, pallor, or cyanosis of the affected area. It is seen in polycythemia vera (in 28% of cases) and essential thrombocythemia. Patients who have aquagenic pruritus seem to report erythromelalgia more frequently. Erythromelalgia responds to aspirin. Depending on the affected nerves, symptoms of diabetic neuropathy can include tingling, numbness, burning (especially in the evening), and pain. Although diabetic neuropathy may be symptomatically similar to aquagenic pruritus, it usually does not have any association with contact with water. Although cold-induced urticaria may induce the development of hives in response to cold stimuli, including a drastic drop in temperature, cold air, and cold water, the hives are usually seen among people 18–25 years old. Topic

54 GNRS5 Teaching Slides Editor: Barbara Resnick, PhD, CRNP, FAAN, FAANP, AGSF GNRS5 Teaching Slides modified from GRS9 Teaching Slides based on chapter by Gurkamal S. Chatta, MD and Roy E. Smith, MD and questions by Lorand Kristoff, MD, MSc Managing Editor: Andrea N. Sherman, MS Copyright © 2016 American Geriatrics Society Topic