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Introduction to Hematology and Anemia Classification
- 1. INTRODUCTION TO HEMATOLOGY Erlinda E. Samson-Cruz, MD, FPCP, FPSHBT
- 32. Sites of BMA
- 34. How to examine a bone marrow aspirate
- 44. HEMATOPOIESIS PLURIPOTENT STEM CELL MYELOID MULTIPOTENT STEM CELL LYMPHOID MULTIPOTENT STEM CELL LYMPHOCYTES BFU-EYTHROID MEG PROGENITOR CFU-MEG GRAN/MONO PROGENITOR CFU-GM EO PROGENITOR CFU-Eo E PROGENITOR CFU-E RBC PLATELET MONOCYTE NEUTROPHIL BASOPHIL EOSINOPHIL
- 45. ERYTHROPOIESIS
- 49. Physiologic regulation of red cell production
- 54. Cytokines effect
- 64. APLASTIC ANEMIA
Editor's Notes
- There are three types of granulocyte named according to their staining characteristics in blood films. They are neutrophils, eosinophils and basophils. Mononuclear cells are divided into lymphocytes and monocytes.
- Eosinophils have granules which take up the acidic dye, eosin, hence their name. Eosinophil granules stain orange and usually pack the cytoplasm The eosinophil is produced in the bone marrow. It is released into the blood stream where it spends, on average, about 6 hours before migrating to tissues. Eosinophil functions include chemotaxis, phagocytosis and killing of bacteria and parasites. Eosinophils have harmful as well as beneficial effects, being implicated in allergic disease.
- Basophils are produced in the bone marrow. They are released into the blood and then migrate into tissues. They have a role in allergic and inflammatory responses.
- B lymphocytes differentiate into antibody-secreting plasma cells. The role of T lymphocytes and natural killer cells is in cell-mediated immunity.
- Large lymphocytes sometimes have a visible nucleolus, a small round or oval structure within the nucleus which stains more lightly than the rest of the nucleus. The nucleolus is the site of synthesis and processing of ribosomal nucleic acid (RNA). Large lymphocytes may be either B, T or NK cells. They are somewhat more frequent in children than in adults.
- Large granular lymphocytes include cytotoxic T lymphocytes and natural killer cells. Cytotoxic T cells are responsible for HLA-dependent cell-mediated immunity. Natural killer cells are responsible for HLA-independent cell mediated immunity
- Monocytes are produced in the bone marrow. They spend several days in the circulation before migrating to the tissues where they differentiate into macrophages. Macrophages are also known as histiocytes. Monocytes and macrophages are phagocytic and can kill ingested bacteria and fungi. distinguished from large granular lymphocytes by their larger size, more opaque greyish cytoplasm and finer although often more numerous granules cytoplasmic outline is irregular and may be indented by surrounding red cells
- neutrophils in the circulating blood are mainly mature segmented neutrophils smaller numbers of cells of neutrophil lineage with non-segmented nuclei. They are referred to as. They are less mature than segmented neutrophils. An increased number of band cells is referred to as a 'left shift'.
- Platelets are produced in the bone marrow by demarcation of small areas of megakaryocyte cytoplasm which are then released into bone marrow sinusoids and thus into the circulating blood. Some budding of platelets may also occur from megakaryocytes lodged in pulmonary capillaries. Pulmonary megakaryocytes are derived from the bone marrow. composed of a central granulomere containing azurophilic granules and a peripheral hyalomere that is agranular
- measurements of iron supply including serum iron, total iron-binding capacity (TIBC; an indirect measure of the transferrin level), and serum ferritin description of both the red and white cells, a white cell differential count, and the platelet count. may be important to assist in the diagnosis.
- complete blood count (CBC) physiologic factors affect the normal CBC values including age, gender, pregnancy, smoking, and altitude High-normal hemoglobin values may be seen in men and women who live at altitude or smoke heavily. Hemoglobin elevations due to smoking reflect normal compensation due to the displacement of O2 by CO in hemoglobin binding. reticulocyte count
- a complement to the red cell indices The degree of anisocytosis usually correlates with increases in the RDW or the range of cell sizes. Poikilocytosis suggests a defect in the maturation of red cell precursors in the bone marrow or fragmentation of circulating red cells The blood smear may also reveal polychromasia — red cells that are slightly larger than normal and grayish blue in color on the Wright-Giemsa stain. These cells are reticulocytes that have been prematurely released from the bone marrow, and their color represents residual amounts of ribosomal RNA. These cells appear in circulation in response to EPO1 stimulation or to architectural damage of the bone marrow (fibrosis, infiltration of the marrow by malignant cells, etc.) that results in their disordered release from the marrow. The appearance of nucleated red cells, Howell-Jolly bodies, target cells, sickle cells, and others may provide clues to specific disorders
- Anisocytosis is a common, non-specific abnormality which can be associated with almost any type of anaemia. It is therefore not particularly useful in making a specific diagnosis. Anisochromasia indicates a changing situation, i.e. that haemoglobin synthesis has been reduced during production of some of the circulating red cells. It is usually caused by iron deficiency or 'anaemia of chronic disease'. When there is anisocytosis automated full blood counters show an increase in the RDW (red cell distribution width), a measurement of the amount of variation in red cell size. Some instruments can also measure the variation in the degree of haemoglobinization of individual red cells. In the presence of anisochromasia such instruments show an increase in the HDW (haemoglobin distribution width). Some cells are normally haemoglobinized while others show only a thin rim of haemoglobinized cytoplasm
- suggests a defect in the maturation of red cell precursors in the bone marrow or fragmentation of circulating red cells
- The reticulocyte count is often expressed as a percentage of red cells but is better expressed as an absolute count. The normal range is approximately 0.5-2% or 40-140 X 109/l. identified on a reticulocyte preparation rather than on a blood film stained in the normal way
- With anemia, the percentage of reticulocytes may be increased while the absolute number is unchanged Abs retic = retic % x rbc count Nv after correction is same as normal retic va;es 0.5-1.5%
- Correction of the reticulocyte count. In order to use the reticulocyte count as an indicator of effective red cell production, the reticulocyte number must be corrected based on the level of anemia and the circulating life span of the reticulocytes. Erythroid cells take ~4.5 days to mature. At normal hematocrit levels, they are released to the circulation with ~1 day left as reticulocytes. However, with different levels of anemia, erythroid cells are released from the marrow prematurely. Most patients come to clinical attention with hematocrits in the mid-20s and thus a correction factor of 2 is commonly used because the observed reticulocytes will live for 2 days in the circulation before losing their RNA. NORMAL bm activity RPI IS 1 Hemolysis 3 to 7 x higher Bone marrow damage index is 2 or less Measures erythropooietic act when stress retic are present, rationale of obtaining this value is that life span of circulating stress retic in 2 days instead of 1 TO compensate for the increased maturation time and consequent retention of residuals
- +polychromatophilic macrocytes correction is necessary because these prematurely released cells survive as reticulocytes in circulation for >1 day, providing a falsely high estimate of daily red cell production divided by 2 to account for the prolonged reticulocyte maturation time -polychromatophilic cells second correction is not required doubly corrected reticulocyte count is the reticulocyte production If the reticulocyte production index is <2 in the face of established anemia, a defect in erythroid marrow proliferation or maturation must be present.
- Iron studies reflect the availability of iron for hemoglobin synthesis Percent transferrin saturation derived by dividing the serum iron level (× 100) by the TIBC transferrin saturation ranges from 25 to 50% diurnal variation in the serum iron leads to a variation in the percent transferrin saturation Serum ferritin to evaluate total-body iron stores Adult males have serum ferritin levels that average about 100 ug/L, corresponding to iron stores of about 1 g Adult females have lower serum ferritin levels averaging 30 ug/L, reflecting lower iron stores serum ferritin level of 10 to 15 ug/L represents depletion of body iron stores ferritin is also an acute-phase reactant and, in the presence of acute or chronic inflammation, may rise severalfold above baseline levels As a rule, a serum ferritin >200 ug/L means there is at least some iron in tissue stores.
- Bone marrow aspiration and biopsy. After a small area of skin is numbed, a Jamshidi needle (a long, hollow needle) is inserted into the patient’s hip bone. Samples of blood, bone, and bone marrow are removed for examination under a microscope.
- The storage iron is in the form of ferritin or hemosiderin. On carefully prepared bone marrow smears, small ferritin granules can normally be seen in 20 to 40% of developing erythroblasts. Such cells are called sideroblasts
- Even films without fragments are worth examining as useful information may be gained. However, assessment of cellularity and megakaryocyte numbers is unreliable and dilution with peripheral blood may lead to lymphocytes and neutrophils being over-represented in the differential count. make sure that particles or fragments are present Bone marrow aspirates which lack particles may be diluted with peripheral blood and may therefore be unrepresentative
- Continuing with a low power examination, the number of megakaryocytes should be assessed. Most megakaryocytes [arrows] are large cells which can be identified with low power. Their numbers are very variable in normal bone marrow films, being partly related to the number of fragments present. This image shows increased megakaryocyte numbers.
- A mature megakaryocyte sheds almost all its cytoplasm as platelets which are released into the circulating blood.
- When there is iron deficiency the bone marrow iron stain shows no blue staining. Initial assessment should be with a medium power objective but absent iron should be confirmed by examination with a X 100 oil objective. If an adequate number of fragments are present, e.g. five to six fragments, this should be reported as 'absent storage iron'. Once all normal and abnormal bone marrow cells have been assessed on a routine stain an iron stain should be examined, using a medium power objective (X 40 or X 50). Storage iron, which stains blue, should be assessed in bone marrow fragments. This image shows normal bone marrow iron.
- Commitment of the stem cell to the specific cell lineages appears not to be regulated by known exogenous growth factors or cytokines Following lineage commitment (or differentiation), hematopoietic progenitor and precursor cells come increasingly under the regulatory influence of growth factors and hormones
- Pronormoblast 20-25um Baso 16 to 18um Poly 12 to 15 Ortho 10 to 15
- stimulus for EPO production is the availability of O2 for tissue metabolic needs produced and released by peritubular capillary lining cells within the kidney (highly specialized epithelial-like cells) Impaired O2 delivery to the kidney can result from a decreased red cell mass (anemia) impaired O2 loading of the hemoglobin molecule (hypoxemia) impaired blood flow to the kidney (renal artery stenosis) normal level 10 to 25 U/L hemoglobin concentration falls below 100 to 120 g/L (10 to 12 g/dL), plasma EPO levels increase in proportion to the severity of the anemia
- Hypoproliferative anemias are the most common anemias and anemia associated with acute and chronic inflammation is the most common of these. The anemia of acute and chronic inflammation, like iron deficiency, is related in part to abnormal iron metabolism. The anemias associated with renal disease, inflammation, cancer, and hypometabolic states are characterized by an abnormal erythropoietin response to anemia.
- most important in the differential diagnosis of iron deficiency, many of the features brought about by inadequate iron delivery to the marrow, despite the presence of normal or increased iron stores serum ferritin values are often the most distinguishing feature between true iron deficiency anemia and the iron-deficient erythropoiesis associated with inflammation. Typically, serum ferritin values increase threefold over basal levels in the face of inflammation. All of these changes are due to the effects of inflammatory cytokines and hepcidin, the storage iron regulator, acting at several levels of erythropoiesis
- level of the anemia correlates with the severity of the renal failure PTH Suppress erythropoiesis by renal calcification (decreased EPO formation) marrow sclerosis ( decreased proliferation of erythroid precursors)
- ; tissues dependent on active mitosis are particularly susceptible Nuclear accidents can involve not only power plant workers but also employees of hospitals, laboratories, and industry (food sterilization, metal radiography, etc.), as well as innocents exposed to stolen, misplaced, or misused sources. While the radiation dose can be approximated from the rate and degree of decline in blood counts, dosimetry by reconstruction of the exposure can help to estimate the patient's prognosis and also to protect medical personnel from contact with radioactive tissue and excreta.
- association between marrow failure and other chemicals is much less well substantiated
- Aplasia is a major consequence and the cause of death in transfusion-associated graft-versus-host disease, which can occur after infusion of unirradiated blood products to an immunodeficient recipient plastic anemia is strongly associated with the rare collagen vascular syndrome called eosinophilic fasciitis, which is characterized by painful induration of subcutaneous tissues (Chap. 303). Pancytopenia with marrow hypoplasia can also occur in systemic lupus erythematosus
- Patients with an initial clinical diagnosis of PNH, especially younger individuals, may later develop frank marrow aplasia and pancytopenia patients with an initial diagnosis of aplastic anemia may suffer from hemolytic PNH years after recovery of blood counts
- . The common X-linked variety is due to mutations in the DKC1 (dyskerin) gene; the more unusual autosomal dominant type has been linked to hTERC, the RNA component of the telomerase complex. These two gene products cooperate in maintaining telomere length.
- cells bearing the CD34 antigen, a marker of early hematopoietic cells, are greatly diminished
- days to weeks of easy bruising, oozing from the gums, nose bleeds, heavy menstrual flow, and sometimes petechiae will have been noticed. With thrombocytopenia, massive hemorrhage is unusual, but small amounts of bleeding in the central nervous system can result in catastrophic intracranial or retinal hemorrhage. , including lassitude, weakness, shortness of breath, and a pounding sensation in the ears. Infection is an unusual first symptom in aplastic anemia (unlike in agranulocytosis, where pharyngitis, anorectal infection, or frank sepsis occur early).
- . Patient with Fanconi's anaemia showing short stature, hypoplastic thumbs and a typical 'Fanconi's facies' - small eyes, small chin and small mouth A central venous line has been inserted in preparation for bone marrow transplantation. autosomally recessive inherited conditions characterized by susceptibility to chromosome breakage and progressive bone marrow failure
- severe aplasia, may show only red cells, residual lymphocytes, and stromal cells Residual hematopoietic cells should have normal morphology, except for mildly megaloblastic erythropoiesis; megakaryocytes are invariably greatly reduced and usually absent
- showing a large poorly formed erythroblastic island with increased numbers of early erythroblasts
- Human leukocyte antigen (HLA) typing should be ordered as soon as the diagnosis of aplastic anemia is established in a child or younger adult. In transplant candidates, transfusion of blood from family members should be avoided so as to prevent sensitization to histocompatibility antigens; while transfusions in general should be minimized, limited numbers of blood products probably do not seriously affect outcome.