Hematology I (SCIE2020) PDF

Hematology I (SCIE2020) Harmening – Chapter 8 (5th Ed) Harmening – Chapter 13 (6th Ed) Aplastic Anemias including Pure Red Cell Aplasia, Congenital Dyserythropoietic Anemia, and Paroxysmal...

Hematology I (SCIE2020) Harmening – Chapter 8 (5th Ed) Harmening – Chapter 13 (6th Ed) Aplastic Anemias including Pure Red Cell Aplasia, Congenital Dyserythropoietic Anemia, and Paroxysmal Nocturnal Hemoglobinuria OBJECTIVES 4.1 Describe clinical signs of anemia 4.2 State the laboratory criteria for the diagnosis of anemia 4.3 State the significance of red blood cell indices as related to the diagnosis of anemia 4.9 Define anisocytosis and poikilocytosis and list clinical conditions in which they may be reported 4.10 Define the terms normochromic, hypochromic, microcytic, and macrocytic as they relate to red cell indices 4.11 Correlate red cell indices with red cell morphology and the diagnosis of anemia 4.20 Identify and describe the morphological alterations of size, shape, colour, and abnormal distribution patterns in erythrocytes 4.21 List any inclusions that may be found in erythrocytes 4.22 Compare the categories of anemia based on morphology 4.23 Describe the clinical presentation and laboratory findings of the following conditions: 4.23.2 Megaloblastic anemia * Partial list Begin today Non-Hemolytic : “Under- production” Aplastic Anemia Hemolysis Pancytopenia Note: A patient having Destructio Aplastic Anemia is Chronic kidney n disease more likely to have Myelofibrosis PNH (Paroxysmal Leukemia Nocturnal TB Hemoglobinuria) … Chemotherapy And for a patient with PNH PNH (Paroxysmal Nocturnal Hemoglobinuria), it may transform to Aplastic Anemia … Ma to A em y pla ia tra s An ns tic fo rm 4 Inherited (Genetic) Acquired Consider MCV and Retic count Today Aplastic Anemia MDS (Myelodysplastic Syndrome) Myelofibrosis Leukemia Amyloidosis Sarcoidosis Chemotherapy PNH (Paroxysmal Nocturnal 5 Hemoglobinuria)  PNH Aplastic Anemia Aplastic Anemia  Normocytic Anemias Aplastic Anemia Flow  Failure of the bone marrow leading to cellular cytometry: depletion and fatty replacement in bone marrow for ALL CELL LINES (!) Decreased CD34  Results in lower numbers of progenitor stem cells (Progenitor cells) in bone marrow, which are needed to produce WBCs, RBCs, and PLTs  Decreased progenitor cells in bone marrow ultimately leads to pancytopenia  Decrease in WBCs, RBCs, and PLTs 8 Aplastic Anemia  Causes:  (1) Primary (1o)  Inherited / Genetic Congenital disorder known as “Fanconi’s Anemia”  (2) Acquired / Secondary (2o)  Results from other conditions / diseases Exposure to: o Ionizing radiation (ex. gamma rays, X-rays) o Chemical agents (ex. insecticides, weed killers) o Drugs (ex. chloramphenicol, phenylbutazone) o Infections or virus (ex. Hepatitis, EBV, CMV, HIV) PNH (Paroxysmal Nocturnal Hemoglobinuria) can also develop into Aplastic Anemia Thosewith Aplastic Anemia are also more at-risk of developing PNH (Paroxysmal Nocturnal Hemoglobinuria) in a terrible cycle Aplastic Anemia  There’s autoimmune destruction of hematopoietic stem cells (HSC) in the bone marrow  Mechanism is not fully understood  Immune system – the stem cells start expressing non-self antigens and the lymphocytes become confused and get activated and target/attack stem cells in the bone marrow for destruction. Treatment - new medication “reboots” marrow - may involve high doses of cyclophosphamide (HiCy) that eradicates the immune system, causing it to “reboot” and once rebooted, the lymphocytes no longer attack the hematopoietic stem cells  Radiation  Drugs – Chemotherapy drugs such as chloramphenicol and others  Infectious agents, EBV and HIV  Fanconi’s NOTE: Don’t Anemia– Thewith confuse this most common Pure inherited Red Cell disorder Aplasia associated – which with is specific for Aplastic Anemia erythroid stem cells ONLY  Example of bone marrow in Aplastic Anemia Aplastic Anemia Diagnosis of Aplastic Anemia  CBC  Pancytopenia  Increased EPO  Because there’s decreased stem cells, EPO can stimulate cell production  Bone marrow biopsy / aspiration  Results in “dry tap”; “empty marrow”; and fat infiltrates on specimen Treatment for Aplastic Anemia  Bone marrow transplant  Immunosuppressive therapy Example of normal bone marrow  Example of bone marrow in Aplastic Anemia Aplastic Anemia  The loss of functional bone marrow may occur following a variety of bone marrow events that include drugs, chemicals, irradiation, infections, and immune dysfunction.  These lead to the loss of bone marrow precursor cells and/or damage of the bone marrow microenvironment required to sustain bone marrow cell growth and differentiation.  Thus, the hematopoietic progenitor cells that give rise to the various peripheral blood elements lose their ability to self renew and produce cells.  This leads to a loss of bone marrow cellular mass and bone marrow failure. Example of normal bone marrow Leads to pancytopenia 13 Pathogenesis  The basic defect in aplastic anemia is a failure of blood cell production by the bone marrow, involving erythrocytes, leukocytes, and platelets.  With normal healthy bone marrow: blood cell production within the bone marrow is dependent on the growth, differentiation, and self-renewal of a common, pluripotential stem cell (CFU-S).  And, for normal healthy bone marrow to proliferate and differentiate into mature blood elements, the CFU-S responds to cytokines and other growth factors produced in the bone marrow microenvironment.  With aplastic anemia, bone marrow failure may develop as a consequence of decreased hematopoietic stem cells resulting from decreased self-renewal or cellular destruction.  Alternatively, a disruption of the bone microenvironment, leading to decreased signal for cellular proliferation and differentiation, could lead to bone marrow aplasia (see fig 8-1). Source: Harmening Figure 8-1 Schematic representation of possible defects in hematopoiesis that may give rise to aplastic anemia. It is postulated that decreased numbers of bone marrow stem cells and/or changes in the bone marrow microenvironment that alter cytokine levels, or both, may cause aplasia to develop. Most evidence points to decreased stem cells caused by the lack of self-replication (1) or direct destruction of stem cells (2), rather than changes in the bone marrow microenvironment (3), as pathogenetic mechanisms for development of aplastic anemia, p.157   Most studies to date show decreases in bone marrow stem cells rather than a defective microenvironment to be the underlying defect in development in most cases of aplastic anemia. Aplastic  Because the bone marrow is unable to respond to the developing peripheral blood cytopenias by Anemia increased hematopoiesis, it has been classified as a refractory or a regenerative process.  No clear-cut cause for the loss of blood cell production is applicable to all causes of aplastic anemia. In some cases, a clear-cut mechanism for the development of bone marrow failure cannot be identified (see Harmening table 8-1, p. 157).  Etiology Clinically, it is useful to divide aplastic anemia into:  Acquired (more common) or  Congenital (hereditary) - Fanconi’s anemia (See table 8-2 next slide and Harmening p.158). Aplastic Anemia  The acquired cases of aplastic anemia are considered to be secondary, resulting from documentable exposure to chemicals, drugs, irradiation, or infection. (Several slides on these later in this Powerpoint)  Hereditary cases of aplastic anemia are rare, with the most common group designated as Fanconi's anemia. Source: Harmening Table 8-2, p. 158 Fanconi’s Anemia  Fanconi’s Anemia Named for famous Swiss pediatrician, Dr. Guido Fanconi Fanconi’s Anemia (FA) is a rare autosomal recessive disorder affecting physical characteristics as well as bone marrow development; a rare inherited pancytopenia Researchers have shown that defects (mutations) in one of at least 15 different genes can cause FA. Fanconi’s anemia is a congenital disorder of the FA is diagnosed equally in boys + girls and can be found in all hematopoietic stem cell ethnic groups that results in aplasia of all cell lines (WBCS, RBCS, & PLTS) The main mechanism behind FA is defective repair of DNA; There are numerous chromosomal abnormalities in FA Hemoglobin F values are increased in FA Bone marrow may show a macrocytic process with thrombocytopenia and leukopenia, developing before red cell depletion 19 Physical characteristics for patients with FA: Short statue, skin  Fanconi's anemia is characterized at a molecular and cytogenetic level by increased chromosomal breakage and defective DNA repair (!) Fanconi’s Anemia - Missing thumb/part of thumb; Fanconi’s Anemia – “Café au lait” spots on skin abnormal thumb 20 Aplastic Anemia Abnormal alignment of the eyes 21 22  Congenital Aplastic Anemia Fanconi's Anemia  Congenital aplastic anemia is characterized by hematologic abnormalities that have been present since birth.  Fanconi's anemia is a rare disorder, that shows variable clinical features.  Developmental abnormalities, include one or more of the following: skeletal defects (usually aplasia or hypoplasia of the thumb), cutaneous hyperpigmentation, renal abnormalities, microcephaly, mental retardation, and poor growth.  Patients develop pancytopenia that progresses with age and is usually symptomatic within 5-to-10 years after birth.  Anemia (normochromic and normocytic; may be macrocytic) and thrombocytopenia usually precedes development of leukopenia.  There may be increased expression of antigen on red cells, increased fetal hemoglobin (HbF) levels, and elevated erythropoietin levels (EPO).  The bone marrow may be originally normocellular or hypercellular, but over time hypoplasia develops.  These patients also have an increased susceptibility to development of cancer.  Fanconi's Anemia  Fanconi's anemia is characterized by a number of genetic abnormalities involving at least fifteen different genes that interact physically or functionally in cell cycle control and DNA repair.  This may be seen functionally by special studies that show a high level of chromosomal breakage, DNA cross-linking, and defective DNA repair in Fanconi Anemia patient cells treated with cross-linking agents or genotoxic stresses.  It is therefore not surprising that these patients may also have an increased incidence of Acute Myelogenous Leukemia (AML) and other malignancies, leading to characterization as a genetic-cancer syndrome.  Nine different Fanconi's anemia-associated genes have been cloned, which are all linked to DNA damage response. This also aids reseacrhers in developing a potential treatment / cure.  Untreated, patients with Fanconi's anemia usually die from infections or hemorrhage secondary to blood cytopenias or development of malignancy.  Laboratory Findings:  Peripheral Blood: Pancytopenia: RBCs, WBCs, platelets, reticulocytes are Aplastic N/N RBCs all decreased Anemia Decreased platelets Decreased granulocytes (Summary)  Bone Marrow: Often dry tap; fatty replacement Marked (4+) hypocellular marrow Pancytopenia: Decreased myelocytic, erythrocytic and megakaryocytic elements 25  Clinical Conditions:  Life span shortened; prognosis poor if untreated  Tendency toward the development Aplastic of leukemia and other cancers Anemia Treatment:  Treatment is supportive as complications from aplasia develop (Summary)  Bone marrow (stem cell) transplant is the treatment of choice and the only curative therapy to “cure” the disease 26 Pure Red Cell Aplasia Normocytic Anemias Pure Red Cell Aplasia Problem with erythroid stem cells, ONLY Erythroid cells (RBCs) in the bone marrow are destroyed No other cell lines are affected, so normal WBCs and normal PLTs Characterized by severe, chronic, normocytic anemia Decreased Hgb, Hct, & reticulocytes No evidence of hemolysis or hemorrhage Bone marrow: Normal cellularity with a notable absence of erythroid precursor cells EPO increased by kidneys to try and compensate, to stimulate erythroid production 28 Pure Red Cell Aplasia Causes of Pure Red Cell Aplasia:  May be acquired (very common) or congenital (rare)  (1) Acquired (Secondary - 2o)  Hemolytic anemia crisis, caused by certain drugs (ex. chloramphenicol, phenytoin), viral infections (paravovrius B19), malnutrition for vitamins and/or iron, thymoma (tumor of thymus) or lymphoid neoplasms, or certain drugs  (2) Inherited / Congenital (Primary - 1o)  Diamond & Blackfan Anemia 29 Pure Red Cell Aplasia  Is an uncommon disorder in which the erythroid cells in the bone marrow are selectively destroyed. This gives rise to an anemia without other associated “-cytopenias” in WBCs or PLTs.  May be an acquired or congenital process (see Table 8-8).  Pure red cell aplasia is characterized by severe, chronic, normocytic to slightly macrocytic anemia. Reticulocytes are decreased and may be absent.  There is no evidence of hemolysis or hemorrhage.  White blood cells and platelets are normal.  A bone marrow biopsy usually demonstrates normal cellularity with a notable absence of erythroid precursor cells.  Erythropoietin (EPO) levels are often markedly increased as the body attempts to compensate for the profound anemia, although cases arising secondary to development of anti-erythropoietin antibodies may have low or absent erythropoietin levels.  Acquired (2o) causes of ‘Pure Red Cell Aplasia’ are the most common.  These may be short-lived acute illnesses or have a more prolonged chronic course.  Viral illnesses have been associated with development of a transient cessation of red cell production and disappearance of erythroblasts from the bone marrow.  In most patients this would be relatively asymptomatic; however, in patients with long-standing hemolytic disease and rapid cell turnover (e.g., sickle cell disease, hereditary spherocytosis), this loss of red cell production causes a precipitous decrease in hematocrit urce: Harmening Figure 8-8 - Pg. 164 or an aplastic crisis. ythroid precursors containing parvovirus B19  In some cases, aplastic crisis has al inclusions. (Wright–Giemsa stain, ×500 agnification), been associated with parvovirus B19 infection.  Parvovirus B19 selectively infects red blood cell Source: https://www.youtube.com/watch?app=desktop&v=Z2rsax6yKBQ 32 Harmening Table 8-8, p. 164 Diamond-Blackfan anemia Diamond-Blackfan Anemia  Discovered in 1938 by Dr. Diamond and Dr. Blackfan  The congenital conditions shows both dominant and recessive Diamond- inheritance patterns Blackfan Anemia is a congenital  Congenital hypoplastic disorder is usually diagnosed in early infancy disorder that depresses only  Several physical abnormalities have been observed, including short red blood cell stature, low birth weight, head and facial abnormalities production  The bone marrow is usually lacking in red cell precursors (ONLY) with a slightly decreased number of leukocytes  Hemoglobin F is increased; The average patient hemoglobin is 70 g/L  Treatment includes steroids and transfusional support with careful attention to the possibility of hemosiderosis 34 Diamond-Blackfan Anemia  It is characterized by a chronic, moderate to severe anemia that usually manifests early in infancy and is associated with normal numbers of white cells and platelets.  The reticulocyte count is decreased.  Bone marrow examination shows a normocellular bone marrow with erythroid hypoplasia. Usually normal or increased numbers of proerythroblasts are present in the marrow with marked decreases in the more mature stages of differentiation in the erythroid cells.  Minor congenital abnormalities of the head and upper limbs may be present, similar to Fanconi's anemia.  Diamond-Blackfan Anemia  The mode of inheritance is uncertain; Both recessive and dominant inheritance patterns have been described. There is a wide variation in the age at onset, severity, and natural course of the disease.  Most patients respond to steroids and are able to maintain adequate hemoglobin levels   Some patients may become transfusion dependent and develop possible iron overload from long-term transfusion therapy.  Bone marrow transplantation is curative.  There is a marked increase in the incidence of Acute Myelogenous Leukemia (AML) late in the course of the disease.  Although the pathogenetic mechanism underlying Diamond-Blackfan anemia is not clear, most studies point to a molecular defect in signal transduction in the erythroid bone marrow progenitors that leads to decreased responsiveness to erythropoietin or other cytokines.  RECAP TIME! Let’s review what we’ve learned so far and then look at what comes next ….  Normocytic Anemias 1. Aplastic Anemia ☑ Decreased bone marrow progenitor stem cells, leading to cellular depletion and fatty replacement ☑ Decreased production of RBCs, WBCs, and PLTs leads to pancytopenia in PB and BM Causes: ☑ Acquired (secondary) to radiation, drugs, infections, etc. ☑ Inherited / Congenital: PNH Fanconi’s anemia ☑ Peripheral blood RBCs may be Norm/Norm or Micro/Hypo 2. Pure Red Cell Aplasia ☑ Problem with erythroid stem cells in the bone marrow are destroyed ☑ No evidence of hemolysis or hemorrhage ☑ Normal WBC’s and PLTs ☑ Bone marrow: normal cellularity with a notable absence of erythroid precursor cells ☑ EPO increased 38  Normocytic Anemias 3. Congenital Dyserythropoietic Anemia (CDA) ☑ Rare group of familial disorders; 7 types (Harmening p. 165) ☑ Anemia and ineffective erythropoiesis are associated with bizarre binuclear and multinuclear erythroblasts ☑ Present clinically with anemia, erythroid hyperplasia with variable degrees of dyserythropoiesis, and indirect hyperbilirubinemia or mild jaundice 4. Acute Post-Hemorrhagic Anemia ☑ Not immediate, as both plasma & RBCs are decreased ☑ Fluid enters intravascular space to restore blood volume ☑ After 24-48 hours anemia is evident due to dilution effect ☑ Then, reticulocytes increase 5. Anemia of Chronic Disorders ☑ Secondary anemia (2o) ☑ Peripheral smear RBCs may be Norm/Norm or Micro/Hypo 39 RECAP: Acquired (2o) Aplastic Anemia Idiopathic or Primary Causes  Aplastic anemia is most often thought to be idiopathic in nature, because no clear-cut primary cause of the bone marrow failure can be identified despite decades of research. Secondary Causes  A wide variety of chemical, physical, and infectious agents have been associated with the development of aplastic anemia (see Harmening table 8-3 next slide).  Usually these agents are divided into:  Those that regularly produce bone marrow aplasia upon sufficient exposure (e.g., benzene, irradiation, and chemotherapeutic agents) and  Those for which development of aplasia is considered a rare or idiosyncratic event (e.g., chloramphenicol, phenylbutazone) (see Harmening table 8-4). Source: Harmening Table 8-3, p. 158  Acquired (2o) Aplastic CHEMICAL AGENTS Anemia  Some of the chemical agents linked with bone marrow failure or aplastic anemia include: benzene, arsenic, insecticides, and weed killers.  Benzene has been known to cause varying degrees of bone marrow failure. Benzene has a variety of industrial applications. These include use as a solvent for rubber, fats, and alkaloids, and the manufacture of drugs, dyes, and explosives. Because most benzene compounds are volatile, they are easily absorbed by inhalation.  Benzene may induce a wide spectrum of bone marrow suppression, ranging from mild anemia or thrombocytopenia to fatal pancytopenia.  It is thought that benzene acts to inhibit synthesis of DNA and RNA, inhibiting cellular proliferation and differentiation of bone marrow cells.  Benzene has also been associated with accumulation of chromosomal abnormalities and development of acute leukemia in some patients.  Acquired (2o) Aplastic Anemia DRUGS  A wide variety of drugs have been associated with development of aplastic anemia  The antibiotic chloramphenicol and the anti-inflammatory drug phenylbutazone are probably the best documented examples of drugs causing aplastic anemia.  The mechanism of drug-induced bone marrow failure suppression is usually unknown, and it is impossible to identify which patients will react adversely to a drug. Luckily, such reactions to drugs are relatively rare.   Chloramphenicol has been shown to cause two types of bone marrow effects.  The most common reaction is a reversible bone marrow suppression is associated with vacuolization of bone marrow precursor cells and increased serum iron levels, reflecting ineffective erythropoiesis.  The second reaction seen is development of an Source: Harmening Figure 8-2 Vacuolization of bone marrow hematopoietic precursor irreversible aplastic cells indicating toxicity in a patient being anemia that occurs weeks to treated with chloramphenicol. (Wright– Giemsa stain, ×1000 magnification), p 159 months after drug exposure.  Acquired (2o) Aplastic IONIZING RADIATION Anemia  It is well known that ionizing radiation has an acute destructive effect on the rapidly dividing cells of the bone marrow, which is predictable based on the radiation dosage.  High doses of radiation, lead to complete loss of hematopoietic cells that is irreversible. Lesser doses lead to reversible anemia, leukopenia, and thrombocytopenia with full recovery of counts in 4-6 weeks.  Ionizing radiation affects bone marrow and other rapidly proliferating cells by disrupting chemical bonds.  NOTE: This is why hair loss and nausea are common with chemotherapy and radiation – Hair and cells lining the stomach are “rapidly proliferating” cells, so they are often causalities when targeting malignant cell growths.  The disruption of chemical bones leads to the formation of free radicals and other biologically active compounds. These interact with DNA to cause breaks or cross- linking of the DNA strands.  This results in cellular death or – unfortunately -- acquisition of genetic abnormalities.  Acquired (2o) Aplastic Anemia INFECTIONS  Many infections have suppressive effects on the bone marrow.  Acute, self-limited infections may suppress bone marrow activity for 10-to-14 days with minor effects on the peripheral blood counts.  Chronic infections may have more severe effects on hematopoiesis.  Several viral infections, including hepatitis, Epstein–Barr virus (EBV), and cytomegalovirus (CMV), have been associated with the development of Aplastic Anemia.  Clinical Manifestations of Aplastic Anemia  Aplastic anemia often presents as an insidious process, owing to the gradual decrease in bone marrow production of erythrocytes, leukocytes, and platelets. Aplastic  It may occur in all age groups. Anemia  Most patients present with symptoms of progressive fatigue, dyspnea (difficulty breathing), and palpitations.  However, bleeding or infection may also be seen. Physical examination may reveal pallor secondary to the anemia, or evidence of thrombocytopenia (including petechiae, purpura, ecchymoses, and mucosal bleeding).  Clinical Manifestations of Aplastic Anemia  Signs of infection, resulting from the decrease in leukocytes, are usually late manifestations of the disease. Aplastic  Other physical findings are minimal. Mild Anemia lymphadenopathy may be seen, but splenomegaly is unusual.  A detailed history of drug ingestion, toxic exposure, or infection is essential, as well as a family history of similar hematologic problems.  Laboratory Evaluation of Aplastic Anemia  The laboratory studies to evaluate a Aplastic patient with aplastic anemia are aimed at defining the degree of bone marrow Anemia dysfunction.  Laboratory evaluation usually involves a complete blood count (CBC) and reticulocyte count, peripheral smear, and bone marrow examination.  Laboratory Evaluation of Aplastic Anemia  The CBC shows pancytopenia of varying degrees, often with anemia being the most notable.  The hemoglobin concentration may be low, Aplastic and the anemia is usually normochromic and normocytic, although the cells may Anemia occasionally be macrocytic with moderate anisocytosis and poikilocytosis.  The corrected reticulocyte count is characteristically low (less than 2%), reflecting the lack of bone marrow regenerative activity (i.e. bone marrow is not responsive). Source: Harmening Table 8-5, p. 161 Source: Harmening Table 8-6, p. 161 Note pancytopenia Note: