BMS310 Pathophysiology: Module 7 - Hematology

BMS310 Pathophysiology - Module 7: Hematology Study Guide

Lecture Unit 3: Hematology 1

7.1 Components of Whole Blood
  1. Whole Blood Composition: The blood sample consists of three primary components:
    • Plasma: Comprising about 55% of whole blood; plasma is the liquid non-cellular portion that contains water, proteins, nutrients, and hormones.
    • Red Blood Cells (RBCs): Constituting about 45% of whole blood; this measurement is referred to as the hematocrit.
    • White Blood Cells and Platelets: Together, WBCs and platelets form less than 1% of whole blood and are visible in the thin "buffy coat" layer.
7.2 Hematopoietic Stem Cells
  1. Location: Hematopoietic stem cells are found in the bone marrow, specifically concentrated in the flat bones such as the sternum, ribs, pelvis, and vertebrae.
  2. Blood Cell Classification:
    • Myeloid Cells: This lineage includes red blood cells, platelets, neutrophils, eosinophils, basophils, and monocytes/macrophages.
    • Lymphoid Cells: This lineage includes T-lymphocytes, B-lymphocytes, and natural killer (NK) cells.
7.3 Red Blood Cells (Erythrocytes)
  1. Shape: RBCs are characterized by a biconcave disc shape, which increases their surface area for gas exchange and flexibility to traverse capillaries.
  2. Life Span: The average life span of an RBC in circulation is approximately 120 days.
  3. Average Count:
    • Males: About 5.4 million cells/µL
    • Females: About 4.8 million cells/µL
  4. Diameter: The typical diameter of a red blood cell is 7–8 micrometers (µm).
7.4 Hematocrit
  1. Definition: Hematocrit represents the percentage of whole blood that is composed of red blood cells.
  2. Normal Values:
    • Males: Approximately 47%
    • Females: Approximately 42%
7.5 Hemoglobin Values
  1. Range for Hemoglobin:
    • Males: Normal hemoglobin levels range from 13–18 g/dL (approximately 16 g/dL is common).
    • Females: Normal hemoglobin levels range from 12–16 g/dL (approximately 14 g/dL is common).
7.6 Mean Corpuscular Volume (MCV)
  1. Average value: The average MCV is approximately 87 femtoliters (fL).
  2. Characterization:
    • Macrocyte: RBCs characterized as large (MCV > 95 fL).
    • Microcyte: RBCs characterized as small (MCV < 80 fL).
7.7 Mean Corpuscular Hemoglobin (MCH)
  1. Average value: The average MCH is about 29 picograms (pg).
  2. Characterization:
    • Normochromic: Cells with normal hemoglobin content (MCH ≥ 25 pg).
    • Hypochromic: Cells with low hemoglobin content, appearing pale (MCH < 25 pg).
7.8 Mean Corpuscular Hemoglobin Concentration (MCHC)
  1. Definition: MCHC measures the concentration of hemoglobin inside each red blood cell.
  2. Average value: The average MCHC is approximately 34 g/dL.
7.9 Erythropoiesis Process
  1. Definition: Erythropoiesis is the process of producing new red blood cells in the bone marrow, which includes stages from stem cell to proerythroblast, reticulocyte, and finally mature RBC.
  2. Nutritional Requirements:
    • Vitamin B12 and Folic Acid: Essential for DNA synthesis for proper RBC division.
    • Erythropoietin (EPO): This hormone stimulates the bone marrow to increase red blood cell production when needed.
7.10 Erythropoietin Regulation
  1. Organ: The kidneys produce the hormone erythropoietin (EPO).
  2. Regulation: EPO formation is stimulated by hypoxia or low oxygen levels detected by the kidneys.
  3. Effect of EPO: EPO enhances the production of red blood cells in the bone marrow.
  4. Clinical Use: EPO is commonly administered to patients with chronic kidney disease or chemotherapy-induced anemia to promote RBC production.
7.11 Definition and Causes of Anemia
  1. Definition: Anemia refers to a reduction in the total number of RBCs, hemoglobin content, or hemoglobin quality; this results in a decreased capacity for oxygen transport.
  2. Common Causes:
    • Reduced production of RBCs due to nutrient deficiencies or bone marrow failure.
    • Increased destruction of RBCs (hemolysis).
    • Blood loss (hemorrhage).
  3. Symptoms of Anemia: Symptoms include fatigue, weakness, shortness of breath (dyspnea), and pallor.

Lecture Unit 3: Hematology 2 - Red Blood Cells

7.12 Iron Deficiency Anemia
  1. Pathophysiology: Iron deficiency leads to microcytic and hypochromic RBCs, which contain less hemoglobin and subsequently carry less oxygen.
  2. Treatment: Recommended treatments involve iron supplementation and identifying/correcting the underlying cause, such as dietary factors or bleeding.
7.13 Folic Acid and Vitamin B12 Anemia
  1. Pathophysiology: Deficiencies in folate or vitamin B12 impair DNA synthesis, causing macrocytic RBCs. Vitamin B12 deficiency may lead to pernicious anemia due to a lack of intrinsic factor.
  2. Treatment:
    • Folate deficiency: Oral folic acid supplementation.
    • Vitamin B12 deficiency: Injections of B12 are necessary due to the requirement of intrinsic factor for absorption.
7.14 Aplastic Anemia
  1. Pathophysiology: Aplastic anemia results from bone marrow failure, resulting in decreased production of RBCs, WBCs, and platelets.
  2. Treatment: Options include bone marrow transplant or immunosuppressive therapy.
7.15 Anemia Related to Renal Failure
  1. Pathophysiology: In renal failure, kidneys do not produce sufficient erythropoietin, leading to normocytic, normochromic anemia due to decreased RBC production.
  2. Treatment: Treatment strategies involve administering synthetic EPO.
7.16 Hemorrhagic Anemia
  1. Acute Hemorrhagic Anemia: Caused by sudden blood loss (e.g., trauma); leads to a rapid drop in RBC count and reduced oxygen delivery. The body compensates with increased heart rate and vasoconstriction to sustain perfusion.
  2. Chronic Hemorrhagic Anemia: Occurs due to small, persistent blood loss over time (e.g., GI bleeding, heavy menstruation); can lead to iron deficiency as iron stores become depleted, causing microcytic and hypochromic RBCs.
7.17 Hereditary Spherocytosis
  1. Pathophysiology: This condition leads to a genetic defect resulting in spherical RBCs instead of biconcave discs. These cells are more fragile and are destroyed by the spleen, leading to hemolytic anemia.
  2. Treatment: A common therapeutic approach is splenectomy to prevent premature destruction of RBCs.
7.18 Thalassemia
  1. Pathophysiology: Thalassemias are genetic disorders characterized by defective synthesis of alpha or beta globin chains in hemoglobin, leading to unbalanced alpha/beta chains:
    • Alpha-Thalassemia: Decrease or absence of alpha-chain production resulting in excess beta chains; leads to microcytic hypochromic anemia.
    • Beta-Thalassemia: Decrease or absence of beta-chain production resulting in excess alpha chains that damage RBC membranes, resulting in hemolysis.
7.19 Sickle Cell Anemia
  1. Pathophysiology: Sickle cell anemia arises from a substitution of valine for glutamic acid in the beta-globin chain of hemoglobin, resulting in polymerization under low oxygen conditions, leading to rigid, sickled RBCs that block capillaries, causing ischemia and pain crises.
  2. Treatment: Includes oxygenation, hydration, pain management, and hydroxyurea, which stimulates fetal hemoglobin production.
7.20 Macrocytic Normochromic Anemia
  1. Lab Changes:
    • Hematocrit (HCT): Decreased
    • Hemoglobin (Hgb): Decreased
    • Mean Corpuscular Volume (MCV): Increased (macrocytic)
    • Mean Corpuscular Hemoglobin Concentration (MCHC): Normal.
  2. Causes: Primarily due to impaired DNA synthesis from vitamin B12 or folate deficiency.
7.21 Microcytic Hypochromic Anemia
  1. Lab Changes:
    • HCT: Decreased
    • Hgb: Decreased
    • MCV: Decreased (microcytic)
    • MCHC: Decreased (hypochromic).
  2. Causes: Often results from iron deficiency anemia or thalassemias.
7.22 Normocytic Normochromic Anemia
  1. Lab Changes:
    • HCT: Decreased
    • Hgb: Decreased
    • MCV: Normal
    • MCHC: Normal.
  2. Causes: Common causes include aplastic anemia and renal failure-related anemia.
7.23 Polycythemia
  1. Definition: Polycythemia refers to an abnormal increase in red blood cell mass.
  2. Types:
    • Primary Polycythemia (Polycythemia Vera): A myeloproliferative disorder where RBCs are overproduced independent of physiology, leading to increased blood viscosity and thrombosis risks.
    • Secondary Polycythemia: A compensatory increase due to hypoxia or excess erythropoietin, often seen with chronic lung disease, high altitude adaptations, or smoking exposure.
  3. Symptoms: Typical manifestations of polycythemia include a ruddy complexion, headache, dizziness, hypertension, and a tendency for thrombosis.
  4. Treatment: Management strategies focus on reducing RBC mass and include periodic phlebotomy and in specific cases, radioactive phosphorus therapy to decrease RBC production.

Lecture Unit 3: Hematology 3 - Platelets

7.24 Platelet Evolution and Function
  1. Platelet Formation: Platelets are formed from cytoplasmic fragments of bone marrow megakaryocytes. They circulate in an inactive state and activate at sites of vascular injury to form hemostatic plugs.
  2. Normal Values: A typical platelet count ranges from 150,000 to 350,000 per microliter of blood.
7.25 Thrombocytosis
  1. Definition: Thrombocytosis (thrombocythemia) is characterized by a platelet count exceeding 400,000/µL.
  2. Types:
    • Transient Thrombocytosis: This occurs due to conditions such as stress, infection, trauma, exercise, or ovulation.
    • Chronic Thrombocytosis: This reflects increased marrow production, often due to a myeloproliferative disorder.
  3. Associated Risks: The major clinical risk of thrombocytosis is pathologic thrombosis or abnormal clotting.
7.26 Thrombocytopenia Diagnosis
  1. Definition: Thrombocytopenia is diagnosed when the platelet count falls below 100,000/µL. The risks of bleeding markedly increase when counts fall below:
    • 50,000/µL: Increased bleeding risk.
    • 30,000/µL: Petechial or purpuric bleeding presents.
    • 20,000/µL: Spontaneous bleeding risk.
7.27 Thrombocytopenic Conditions
  1. Bone Marrow Pathology: Conditions like aplastic anemia, leukemia, and chemotherapy can lead to diminished platelet production due to bone marrow failure.
  2. Decreased Platelet Survival: This occurs through peripheral destruction activities, such as immune-mediated thrombocytopenic purpura (ITP), viral infections, or drug-induced destruction.
7.28 Symptoms and Distinctions of Thrombocytopenia
  1. Symptoms in ITP: Presenting symptoms include mucocutaneous bleeding, petechiae, purpura, easy bruising, and bleeding from the skin and mucous membranes.
  2. Definitions:
    • Petechiae: Pinpoint, non-blanching hemorrhages on the skin.
    • Purpura: Larger confluent hematomas or bleeding areas under the skin.
7.29 Treatment of ITP
  1. Primary Treatments: Options for managing immune-mediated thrombocytopenic purpura (ITP) include corticosteroids (first-line), intravenous immunoglobulin (IVIG) for rapid platelet increase, and splenectomy for patients with refractory ITP (after improving counts).

Lecture Unit 3: Hematology 4 - White Blood Cells

7.30 White Blood Cell Terminology
  1. Definitions:
    • Leukocytosis: Refers to an elevated WBC count, typically greater than 10,000/µL, frequently associated with inflammatory conditions.
    • Leukopenia: Denotes a decreased WBC count, often signifying neutropenia, which dramatically increases infection risk when counts drop below 1,000/µL and poses severe risk below 500/µL.
    • Leukemia: Characterized by malignant neoplasms arising from hematopoietic stem cells, leading to a diffuse replacement of bone marrow with neoplastic leukocyte proliferation and spillover into the bloodstream.
7.31 Manifestations of Leukemia
  1. Infections: Result from marrow crowding and chemotherapy-induced neutropenia, leading to increased vulnerability to recurrent or severe infections.
  2. Bleeding Manifestations: Arise due to marrow replacement effects suppressing megakaryocyte production, resulting in thrombocytopenia and resulting mucosal bleeding and purpura.
  3. Anemia Symptoms: Occur as neoplastic cells outcompete erythroid precursors, leading to anemia that presents as fatigue and pallor.
7.32 Acute Lymphocytic Leukemia (ALL)
  1. Cell Characteristics: The predominant cells include lymphoblasts in the marrow and blood; these immature lymphoid cells proliferate rapidly.
  2. Progression: If untreated, ALL demonstrates abrupt onset and rapidly progressive disease.
  3. Therapeutic Approaches: Treatment often starts with induction chemotherapy (which may involve agents like vincristine, L-asparaginase, and prednisone) followed by a maintenance phase (using methotrexate and 6-mercaptopurine). Children often have high cure rates.
7.33 CAR T-cell Therapy
  1. Definition: CAR T-cell therapy stands for Chimeric Antigen Receptor T-cell therapy.
  2. Strategy: Involves modifying a patients' T-cells to express a CAR that recognizes specific leukemic surface antigens (primarily CD19). These engineered T-cells are expanded ex vivo and reinfused into the patient to locate and eliminate malignant cells.
7.34 Procedure for CAR Creation
  1. Process: T-cells are harvested; a gene coding for the CAR, composed of antigen-binding scFv, hinge, transmembrane, and intracellular signaling domains, is introduced into the cells using a viral vector; the modified T-cells are then expanded and reinfused following lymphodepleting chemotherapy.
7.35 Acute Myelocytic Leukemia (AML)
  1. Cell Characteristics: AML presents with myeloblasts in the blood or marrow; an important diagnostic feature is the presence of Auer rods, which are linear granules aggregated within these cells.
  2. Progression: The disease has a rapid, aggressive course if left untreated.
  3. Therapeutic Approaches: Treatment typically involves cytotoxic chemotherapy (e.g., cytarabine with anthracycline), with bone marrow or stem cell transplantation being considered for eligible patients; CAR T-cell therapy remains investigational.
7.36 Chronic Lymphocytic Leukemia (CLL)
  1. Cell Characteristics: CLL is characterized by accumulation of mature yet functionally incompetent B-lymphocytes in blood and marrow, commonly associated with hypogammaglobulinemia.
  2. Symptoms: Patients may experience painless lymphadenopathy, fatigue, infection susceptibility, hepatosplenomegaly, and weight loss; CLL often has an indolent course.
  3. Therapeutic Approaches: Asymptomatic patients may be monitored (watchful waiting); treatment options include chemo-immunotherapy (e.g., using anti-CD20 monoclonal antibodies), targeted therapies, and CAR T-cell therapy in cases with refractory disease.
7.37 Chronic Myelocytic Leukemia (CML)
  1. Genetic Mutations: CML is associated with the Philadelphia chromosome, primarily the translocation t(9;22), resulting in the BCR-ABL fusion tyrosine kinase.
  2. Symptoms: Symptoms include anemia, fatigue, night sweats, weight loss, splenomegaly, and remarkably elevated WBC counts.
7.38 Treatment Approaches for CML
  1. Historical Therapy: Traditional treatment included chemotherapy and may involve bone marrow transplantation.
  2. Modern Therapy: Current first-line therapy includes imatinib (Gleevec) and other BCR-ABL tyrosine kinase inhibitors that specifically target the mutation.
  3. Mechanism of Action: Imatinib selectively inhibits BCR-ABL tyrosine kinase, effectively halting the aberrant proliferative signals that promote CML progression.
7.39 Common Symptoms of Lymphoma
  1. Symptoms: Common symptoms include painless lymphadenopathy, fever, night sweats, weight loss (collectively known as “B symptoms”), and in some instances, pruritus.
  2. Definition of Lymphadenopathy: Lymphadenopathy is defined as enlarged lymph nodes.
7.40 Stages of Lymphoma
  1. Stage Definitions:
    • Stage I: Involvement of one lymph node region or a single extralymphatic site.
    • Stage II: Involvement of two or more node regions on the same side of the diaphragm.
    • Stage III: Involvement of lymph node regions on both sides of the diaphragm.
    • Stage IV: Disseminated disease with extranodal involvement such as bone marrow.
  2. Chemotherapy Responsiveness: Generally, Stages I and II exhibit the best response rates to chemotherapy and thus offer improved prognoses.
7.41 Hodgkin’s Lymphoma
  1. Disease Characteristics: Hodgkin’s lymphoma is noted for contiguous spread of disease alongside a characteristic inflammatory context.
  2. Reed-Sternberg Cell Significance: The presence of Reed-Sternberg cells, which are large malignant binucleated cells, serves as a diagnostic hallmark and contributes to the inflammatory environment in Hodgkin’s lymphoma.
7.42 Non-Hodgkin’s Lymphoma (NHL)
  1. Characteristics: NHL encompasses a wide variety of B- or T-cell neoplasms, often associated with non-contiguous spread and frequent extranodal involvement.
  2. Differentiation from Hodgkin’s Disease: Unlike Hodgkin’s lymphoma, NHL lacks Reed-Sternberg cells, tends to exhibit more heterogeneity, and is more prone to extranodal site involvement.
7.43 Patterns of Malignant Spread in Lymph Nodes
  1. Nodular vs. Diffuse Patterns:
    • Nodular (Follicular): Characterized by clusters of malignant cells in the lymph nodes.
    • Diffuse: Exhibits a uniform spread throughout the lymph node with no follicular structure.
  2. Prognosis: The nodular (follicular) pattern generally indicates a more favorable prognosis.
7.44 Treatment Approaches for Lymphoma
  1. Traditional Therapy: Routes for treatment predominantly involve radiation and combination chemotherapy.
  2. Modern Innovations: Recently, treatments incorporate monoclonal antibodies (such as anti-CD20), targeted risk factor therapies, immunotherapy, and selected CAR T-cell therapies.
7.45 Multiple Myeloma Malignant Cell Type
  1. Malignant Cell Type: The defining malignant cell is the plasma cell.
  2. Distinction from Plasmacytoma: Plasmacytoma indicates a singular localized plasma cell tumor, whilst multiple myeloma is characterized by multiple skeletal sites exhibiting diffuse marrow infiltration.
7.46 Blood and Urine Analysis in Multiple Myeloma
  1. Blood Findings: Blood analysis often reveals an M-protein spike (usually IgG or IgA) and anemia; elevated creatinine and common hypercalcemia are present.
  2. Urine Findings: Urinalysis commonly demonstrates Bence-Jones proteins, which represent free light chains resulting from excessive immunoglobulin production.
7.47 Hypercalcemia in Multiple Myeloma
  1. Mechanism: Hypercalcemia arises due to tumor-induced activation of osteoclasts leading to increased bone resorption.
  2. Skeletal Changes: Skeletal alterations manifest as “punched out” lytic lesions, increased risk of pathologic fractures, and generalized osteopenia.
7.48 Bence-Jones Protein Pathophysiology
  1. Pathophysiology: Myeloma cells excessively produce free immunoglobulin light chains (Bence-Jones proteins) that are processed by the kidneys, leading to nephrotoxic effects including tubular cast nephropathy and renal failure. In some cases, light chains can deposit as amyloid, resulting in restrictive cardiomyopathy and further renal impairment.
7.49 Multiple Myeloma Treatment Approaches
  1. Intensive Chemotherapy: A primary approach includes intensive chemotherapy followed by autologous stem cell rescue through bone marrow transplantation.
  2. Other Approaches: Additional strategies may involve proteasome inhibitors, immunomodulatory drugs, glucocorticoids, and CAR T-cell therapies targeting plasma cell-specific antigens.