Hematology

Pathophysiology of Hematology

Hematology Medical Terms

• Prefix and Suffix Terms
    - Hem (o) / Hemat (o): Blood
    - Erythr (o): Red
    - Leuk (o): White
    - An-: Without
    - Immun-: Immunity
    - Lymph-: Clear water or fluid
    - Thromb-: Clot
    - Necr-: Death
    - -ology: Study or science of
    - -rrhage: Excessive flow
    - -oma: Tumor or specified by the base
    - -poiesis: Production or making
    - -penia: Deficiency
    - -cytes: Cells
    - -emia: Condition of blood
    - -globin: Protein
    - -osis: Abnormal conditions
    - -philia: Abnormal attraction, or love of

Basic Laboratory Values in Hematology

• White Blood Cell Count (WBC): 4,000 to 10,000 cells/mcL
    - Function: Fight infection

• Red Blood Cell Count (RBC):
    - Males: 4.5 to 5.5 million cells/mcL
    - Females: 4.0 to 5.5 million cells/mcL
    - Function: Carry oxygen

• Hematocrit (HCT):
    - Males: 45-52%
    - Females: 37-48%
    - Definition: Proportion of red blood cells to the fluid component (plasma)

• Hemoglobin (HB) Concentration:
    - Males: 13-18 gm/dL
    - Females: 12-16 gm/dL
    - Definition: Oxygen-carrying protein in red blood cells

• Platelet Count (PLT): 90,000 to 450,000 mcL
    - Function: Blood clotting

• Prothrombin Time (PT): 10.0-13.0 seconds
    - Measure of bleeding and clotting

• Partial Thromboplastin Time (PTT): 60-70 seconds
    - Response to anticoagulant therapies

• International Normalized Ratio (INR): 1.1 or below
    - Measure of bleeding and clotting

Hematopoiesis

• Definition: Process of blood cell production in adult bone marrow and fetal liver/spleen

• Requirement: Humans need approximately 100 billion new blood cells per day.

• Purpose: Continuous throughout life to replace old, diseased, or lost blood cells.

• Two Stages:
    - Mitosis (Proliferation)
    - Maturation (Differentiation)

Overview of Disorders of White Blood Cells (WBCs)

• Function: WBCs (leukocytes) protect against infection and are produced in bone marrow.

Types of Immunity

• Innate Immunity:
    - 1st line of defense (e.g., Neutrophils, macrophages)
    - Inflammatory response

• Adaptive Immunity:
    - Specific and acquired immunity involving B and T lymphocytes
    - Includes memory cells

Epidemiology of Hematologic Disorders

Leukemia

• Description: Proliferation of cancerous WBCs

• Statistics: 90% of cases diagnosed in adults; is the 3rd most common cancer type in children.

Lymphomas

• Description: Solid tumors of lymphoid cells with abnormal proliferation of B and T cells.

• Statistics: Affects approximately 3% of the US population per year.

Basic Concepts of WBC Function

• Three Major Categories:
    1. Monocytes:
        - Maturation into macrophages.
        - Synthesize and secrete cytokines.
        - Mature into dendritic cells (APCs).
    2. Lymphocytes:
        - Comprise T and B cells.
    3. Granulocytes:
        - Includes basophils, eosinophils, and neutrophils; neutrophils are the most common granulocyte.

Agranulocytes (WBCs)

• Monocytes: 200-800 cells/mcL, 2%-10% of circulating WBCs.
    - Mature into macrophages in tissues; participate in phagocytosis and cytokine synthesis.
    - Dendritic Cells: Antigen-presenting cells (APCs).

• Lymphocytes: 1,000-4,000 cells/mcL, 20%-40% of circulating WBCs; involved in long-term immunity.
    - B Cells: Produce antibodies (Immunoglobulins IgA, D, E, G).

Macrophage and Phagocytosis

• Process:
    1. A macrophage moves out of the capillary.
    2. Engulfs and captures an antigen.
    3. Digest the antigen using lysosomal enzymes.

Granulocytes (WBCs)

• Eosinophils: <500 cells/mcL; 1%-7% of circulating WBCs; elevate during parasitic infections and allergies.

• Basophils: 0-300 cells/mcL; less than 2% of circulating WBCs; elevated during infection and inflammation; granules contain histamine which signals neutrophil migration.

• Neutrophils: 1,500-7,000 cells/mcL; 40%-80% of circulating WBCs; act as first responders; carry out phagocytosis; release enzymes to destroy microorganisms; classified as polymorphonuclear (PMNs).

Alterations in WBC Number

• Leukocytosis: Abnormally high WBC count (over 11,000 cells/mcL).

• Leukemoid Reaction: Extremely high WBC count (over 50,000 cells/mcL); physiological response to stress or infection.

• Leukopenia: Abnormally low WBC count (less than 4,000 cells/mcL); commonly affects neutrophils.

• Neutrophilia: Elevated neutrophils during leukocytosis (greater than 7,000/mcL).

• Neutropenia: Neutrophil count less than 1,500/mcL; compromises immune response; can result from medications or chemotherapy.

Hematologic Neoplasms

• Leukemia: Neoplastic proliferation of blood cells.

• Lymphoma: Proliferation of B or T lymphocytes in lymphoid tissue.

• Risk Factors: DNA-damaging agents such as intense radiation, benzene exposure; some viruses (e.g. EBV, HIV) predispose; chronic infections (e.g., H. pylori) linked to lymphoma.

Ph Chromosome

• Definition: Translocation between chromosomes 9 and 22, resulting in BCR-ABL oncogene.

• Function: Activates tyrosine kinase leading to leukemia; some treatments aim to inhibit tyrosine kinase.

Symptoms of Hematologic Neoplasms

• Symptoms common to both leukemias and lymphomas include:
    - Anemia
    - Leukopenia (due to dysfunctional WBCs)
    - Thrombocytopenia (causing bleeding and bruising)
    - Bone pain (from proliferating cancerous blood cells)
    - Enlarged lymph nodes
    - Splenomegaly

Types of Leukemia

Acute Lymphocytic Leukemia (ALL)

• Characteristics: Aggressive, more common in children; faster response to treatment leads to better prognosis.

• Key Features: Immature T or B cells (lymphoblasts); several chromosomal/genetic alterations (including Ph chromosome).

• Signs/Symptoms: Non-specific; can include anemia, increased bleeding, lymph node enlargements, splenomegaly, risk of increased infections, and bone pain.

Chronic Lymphocytic Leukemia (CLL)

• Characteristics: Most common type of leukemia in the US, especially in individuals over 70; more common in males.

• Etiology: DNA-disrupting agents; occupational history is relevant.

• Key Biomolecule: Zeta-chain-associated protein tyrosine kinase 70 (ZAP-70); positive indicates worse prognosis, negative indicates better prognosis.

• Diagnosis: Lymphocytosis (WBC > 20,000/mcL) and bone marrow biopsy showing "smudge cells" (abnormal lymphocytes).

Acute Myelogenous Leukemia (AML)

• Characteristics: Proliferation of undifferentiated myeloid blast cells; can invade tissues (skin, lungs, spleen, liver).

• Increased risk with prior chemotherapy/radiation treatments; commonly activated oncogenes (e.g., FLT3, c-KIT).

• Diagnosis: CBC shows abnormal results; genetic translocation common between chromosome 8 and 12.

Chronic Myelogenous Leukemia (CML)

• Symptoms: Typical symptoms of leukemia (e.g., anemia, increased risk of infection, bleeding).

• Diagnosis: CBC showing WBC count greater than 100,000 cells/mcL and presence of Philadelphia chromosome.

• Clinical course: Three phases - Chronic phase (neutrophils begin to lose differentiation), Accelerated phase (neutrophils become increasingly undifferentiated), Blast crisis phase (myeloid blast cells do not differentiate).

Overview of Lymphomas

Hodgkin’s Lymphoma (HL)

• Demographics: Most common in ages 15-20 years and over 50 years.

• Characteristics: Accounts for ~20% of lymphomas; presence of Reed-Sternberg cells (characteristic "owl eyes").

Non-Hodgkin’s Lymphoma (NHL)

• Accounts for over 80% of lymphoma cases; more common in older adults; affects B, T, or NK cells with over 30 subtypes.

• Risk factors: Chromosomal translocations (like chromosomes 14 and 18), some pathogens (e.g. HIV, H. pylori) may increase risk.

• Diagnosis: Lymph node biopsy.

Basic Concepts of Red Blood Cells (RBCs)

General Characteristics

• Definition of RBC: Erythrocytes containing hemoglobin (Hgb), a key protein in oxygen transport.

• Major Pathologies: Two main conditions affecting RBC function: polycythemia (overproduction of blood cells) and anemia (insufficient oxygen delivery due to inadequate healthy RBCs).

Prevalence of Anemia

• Data: In the US, 6.6% of men and 12.4% of women are diagnosed with anemia.

• Risk factors may vary based on racial and ethnic background:
    - Sickle cell anemia (SCA) is more common in lower socioeconomic countries.

Erythrocyte Synthesis

Erythropoiesis

• Definition: Process by which RBCs are synthesized from pluripotent stem cells in the bone marrow.

• Mature RBCs: Lack a nucleus; average lifespan approximately ~120 days.

• Reticulocytes: Immature RBCs, elevated levels in circulation indicate increased synthesis of RBCs.

Erythropoietin (EPO)

• Response to hypoxia: Kidneys release EPO, stimulating bone marrow to produce more RBCs to compensate for decreased oxygen levels.

Breakdown of RBCs

• Hemoglobin Composition: Consists of heme and globin components. Metabolized to biliverdin and subsequently to bilirubin.

• Hyperbilirubinemia: Condition where there is an excess of bilirubin in the blood, which can cause jaundice.

Anemia: Possible Etiologies

• Causes include:
    - Nutritional deficiencies (Iron, Vitamin B12, Folic Acid)
    - Blood loss (chronic and acute)
    - Hemoglobinopathies
    - Medications
    - Hemolysis (destruction of RBCs)

Symptoms of Anemia

• Can be asymptomatic or present with:
    - GI tract blood loss
    - Heavy menstrual periods (menorrhagia)
    - Tachycardia
    - Jaundice
    - Splenomegaly
    - Nutritional anemias often include glossitis, cheilitis, koilonychia, or pica.

Anemia Caused by Decrease in RBC Mass

• Average Adult Blood Volume: Approximately 5 liters.

• Loss of 500 mL of blood: Usually manageable without serious effects.

• Loss of 1,000 mL or more:
    - Potential for severe complications like hypovolemic shock and cerebral hypoperfusion.

Anemia of Acute Blood Loss

• Common causes: Trauma, hemorrhage, clotting disorders.

• Diagnosis: NCNC (normocytic normochromic) with reticulocytosis; FOBT (fecal occult blood test) to detect gastrointestinal bleeding.

• Symptoms based on blood volume loss:
    - Less than 15%: Orthostatic hypotension and anxiety.
    - 15%-30%: Increased sympathetic nervous system activity, elevated heart rate, restlessness, altered consciousness.
    - 30%-40%: Heart rate exceeds 120 bpm, hypotension, reduced urine output.
    - Greater than 40%: Severe hypotension, decreased consciousness, heart rate greater than 140 bpm, no urine output.

Anemia from Chronic Blood Loss

Causes

• Commonly due to gastrointestinal bleeding (e.g. melena or dark stool), menorrhagia, hemolysis, or NSAIDs could lead to GI bleeding.

Symptoms

• Symptoms can be subtle due to the gradual nature of blood loss.

Diagnosis

• Iron depletion is common; may lead to microcytic and hypochromic anemia. Typical lab findings:
    - Low Iron, low ferritin, increased Total Iron Binding Capacity (TIBC).
    - Low Hemoglobin (Hgb) and Hematocrit (Hct).

Hemolytic Anemias

• Definition: Destruction of erythrocytes outpaces their replacement.

• Causes: Include hemoglobinopathies, autoimmune disorders, transfusion reactions, hemolytic disease of the newborn (HDN), lead poisoning, and differing antibody reactions (Warm and Cold agglutinin syndrome).

• Symptoms: Present as typical anemia signs along with jaundice, dark urine, and enlarged spleen.

Specific Conditions: Sickle Cell Anemia (SCA)

• Type: Autosomal hemoglobinopathy affecting HbS formation.

• Key Points: Complications increase after the age of 10; impacts include fragile, misshapen RBCs; can lead to renal disease, chronic tissue hypoxia, organ damage, and hand-foot syndrome.

Blood Transfusion Reactions

• Known as hemolytic transfusion reactions: when recipient blood-type antibodies attack transfused cells.

• Procedure: Strict double-checking of donor-recipient blood types, immediate stoppage of transfusion in case of a suspected reaction.

• Common reactions: Nonhemolytic febrile reactions and mild allergies; potential severe cases: hypotension, bleeding, and renal failure.

RBC Maturation Defects

• Contributing Factors: Various factors can affect RBC maturation which leads to anemia symptoms, such as:
    - Iron deficiency,
    - Vitamin B12 deficiency,
    - Folic Acid deficiency.

Iron Deficiency Anemia

• Description: Most common cause of anemia globally.

• Population at Risk: Women of childbearing age, infants, elderly, vegetarians, and those with gastro-intestinal bleeding.
    - Primary causes include menorrhagia, GI bleed, inadequate iron intake.

• Signs & Symptoms: Include typical anemia signs along with hair loss, nail changes (koilonychias), and pica (craving non-nutritive substances).

• Diagnosis: Through CBC, peripheral blood smear, serum iron, and ferritin assessment; FOBT to rule out GI bleeding.

Vitamin B12 Deficiency (Pernicious Anemia)

• Causes: Lack of intrinsic factor (IF) needed for B12 absorption; dietary deficiency; chronic diseases (e.g., gastric atrophy, Helicobacter pylori infection, chronic alcoholism, gastric bypass surgery).

Folic Acid Deficiency

• At-risk Groups: Pregnant and lactating women, the elderly, those with celiac disease.

• Result: Causes megaloblastic anemia (requires both folate and vitamin B12 for RBC DNA synthesis); symptoms may be asymptomatic.

• Important: Ensure to test folate and vitamin B12 levels in cases of megaloblastic anemia.

Lack of Bone Marrow Production of RBCs

• Potential Causes: Lack of erythropoietin (EPO), aplastic anemia, infections, chemicals, and immune diseases can lead to decreased RBC production.

• Symptoms: Anemia, leukopenia, and thrombocytopenia may develop gradually.

• Diagnosis: Begins with CBC, often necessitating blood transfusions.

Hemostasis Overview

Definition

• Hemostasis: Normal reaction to injury resulting in bleeding control.

Two Main Processes

1. Primary Hemostasis: Involves platelet aggregation.

2. Secondary Hemostasis: Involves fibrin formation that produces a clot (thrombus).

Types of Hemostatic Disorders

• Excessive bleeding

• Excessive clotting

Normal Platelet Levels

• Normal range: 150,000 to 450,000 cells/uL.

• Thrombocytopenia: Less than 100,000 per microL.

• Thrombocytosis: More than 750,000 per microL.

• Causes of altered platelet levels include medications, illnesses, and genetic disorders.

Three Major Steps in Hemostasis

1. Vasoconstriction

2. Platelet Plug Formation

3. Blood Coagulation
      - Thrombosis occurs in response to injury or sluggish blood flow.
      - Clot formation is balanced by fibrinolysis (clot dissolution).

Platelets

• Source: Derived from megakaryocytes; stimulated by thrombopoietin from the liver.

• Lifespan: 7-10 days; many platelets sequestered in the spleen.

• Activation Process: Endothelial injury exposes collagen and releases von Willebrand factor (vWF) which attracts platelets.

• Glycoprotein IIb/IIIa receptors play key roles in platelet aggregation.
    - Antiplatelet agents may block this receptor.

• Thromboxane A2 release promotes aggregation.

Coagulation Factors

• Coagulation is a cascade reaction requiring calcium and vitamin K.

• Two Pathways:
    - Intrinsic Pathway: Triggered by vessel damage.
    - Extrinsic Pathway: Triggered by damage outside the vessel.

• Both pathways converge to activate factor X, converting prothrombin to thrombin, leading to fibrin formation.

Clot Dissolution (Fibrinolysis)

• Tissue plasminogen activator (tPA): Converts plasminogen to plasmin, resulting in clot breakdown.

• Recombinant tissue plasminogen activator (rtPA) (e.g., alteplase) can therapeutically break down clots.

Increased Platelet Number and Activity

• Causes of increased platelet counts: splenectomy, myeloproliferative disorders.

• Paradoxical bleeding may occur when platelets are dysfunctional.

• Increased platelet activity can arise from endothelial injury, sluggish blood flow, smoking, hyperlipidemia, or diabetes.

• Primary thrombocytosis: Primary bone marrow issue.

• Secondary thrombocytosis: Associated with cancer, inflammation, or infection.

Increased Coagulation Activity

• Risk Factors:
    - Blood stasis due to immobility or conditions like atrial fibrillation.
    - Deep vein thrombosis (DVT) can cause pulmonary embolism.

• Coagulation factors may be increased by estrogen (risk for women over 35 with oral contraceptives), cancerous tumors that secrete prothrombotic factors.

Antiphospholipid Syndrome

• Characterization: Multiple clots with unknown etiology; autoimmune diseases raise risk.

• Risk Increased for strokes, myocardial infarctions, renal failure, and miscarriages.

• Catastrophic Antiphospholipid Syndrome: Results in multiple organ failures due to clot complications.

Decreased Platelet Number and Activity

• Decreased production: Bone marrow suppression (e.g., aplastic anemia, leukemia, radiation exposure).

• Excessive pooling of platelets: Pooling in the spleen.

• Decreased survival: Due to antiplatelet antibodies or mechanical injury.

Impaired Platelet Activity

• Drug Effects: Antiplatelet therapy (e.g., aspirin, which irreversibly acetylates platelet cyclo-oxygenase, leading to decreased adherence).

• Renal failure can also lead to toxin buildup and platelet lysis.

Defective Coagulation and Impaired Synthesis

• Deficiencies in clotting factors include hemophilia, Von Willebrand disease (vWD).

• Impaired synthesis occurs in liver diseases or low vitamin K levels.

Assessment of Bleeding and Clotting Disorders

• Symptoms may include: Nosebleeds, bruising for bleeding; DVT, pulmonary embolism for clotting.

• Medication review is critical to assess for effects.
    - Increased clotting factors often occur in cancers or atherosclerosis; decreased clotting can occur in leukemia or recent infections.
    - Lifestyle choices (e.g., smoking, alcohol abuse) can also affect hemostatic health.

Hemostasis Disorders and Diagnosis

• Tests: CBC, peripheral blood smear, PT, INR, aPTT.

• Anticoagulants prolong clotting time, hence PT, INR, and aPTT should be higher than normal in those receiving anticoagulant therapy.

• Normal INR is 1; acceptable anticoagulation usually sets the INR between 2 and 3.

• Common anticoagulants include unfractionated heparin, fondaparinux (factor Xa inhibitors), warfarin, and thrombolytic agents.

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