Hematopathology Summary

• Definition: An increase in red blood cells per unit volume, usually with an increase in hemoglobin.
• Relative Polycythemia: Caused by decreased plasma volume (e.g., dehydration), not a true increase in RBC mass.
• Absolute Polycythemia: A true increase in total red cell mass.
  • Primary (Polycythemia Vera): A myeloproliferative neoplasm where all cell lines are increased. It is characterized by low Erythropoietin (EPO).
  • Secondary: Caused by an appropriate (e.g., high altitude) or inappropriate (e.g., tumors) increase in EPO.

Aplastic Anemia

• Definition: Bone marrow failure leading to pancytopenia (anemia, leukopenia, thrombocytopenia) and a hypocellular bone marrow (empty, fatty marrow).
• Causes: Mostly idiopathic (65%), but can be caused by toxins, drugs, radiation, or viral infections.

Megaloblastic Anemia

• Pathogenesis: Caused by Vitamin B12 or Folate deficiency, which impairs DNA synthesis and replication.
• Morphology: Macrocytic RBCs (macro-ovalocytes, high MCV), hypersegmented neutrophils, and large, abnormal hematopoietic precursors (megaloblasts) in the marrow.
• Pernicious Anemia: A specific type caused by autoimmune gastritis that destroys parietal cells, leading to a loss of Intrinsic Factor and inability to absorb Vitamin B12. It is uniquely associated with neurologic symptoms (posterolateral spinal tracts).

Iron Deficiency Anemia

• Pathogenesis: Negative iron balance from low intake, malabsorption, increased demand (pregnancy), or chronic blood loss.
• Morphology: Microcytic, hypochromic anemia (low MCV, low MCHC).
• Clinical: Fatigue, pallor, alopecia, koilonychia (spoon nails), and atrophic glossitis.

Hereditary Spherocytosis

• Pathogenesis: Autosomal dominant genetic defect in RBC membrane skeleton proteins (e.g., ankyrin, spectrin).
• Morphology: RBCs become spherocytes (small, round, no central pallor). These cells are less deformable and are trapped and destroyed in the spleen.
• Lab Finding: Increased osmotic fragility. Splenectomy is often helpful.

G6PD Deficiency

• Pathogenesis: X-linked enzyme deficiency makes RBCs susceptible to oxidative damage from triggers (e.g., fava beans, drugs like primaquine).
• Morphology: Oxidized hemoglobin precipitates as Heinz bodies, which are removed by splenic macrophages, creating "bite cells". This leads to intravascular hemolysis.

Sickle Cell Disease

• Pathogenesis: Point mutation in β-globin gene. Deoxygenated HbS polymerizes, causing RBCs to sickle.
• Consequences: Chronic hemolysis, vaso-occlusive crises (severe pain), and autosplenectomy due to repeated splenic infarctions.

Thalassemias

• Pathogenesis: Deficient synthesis of globin chains (α or β). Leads to ineffective erythropoiesis and hemolysis due to precipitation of excess unpaired chains.
• β-Thalassemia: Excess α-chains precipitate. Severe anemia leads to massive marrow expansion ("crew cut" skull) and systemic iron overload from transfusions.
• α-Thalassemia: Due to gene deletions. 3 deletions = HbH disease (unstable β4 tetramers). 4 deletions = Hydrops Fetalis (lethal, γ4 tetramers).

• Neutrophilia: Increase in neutrophils, typically due to bacterial infections, sterile inflammation (burns), or abscesses.
• Eosinophilia: Increase in eosinophils, associated with parasitic infections, asthma, and allergic drug reactions.
• Lymphocytosis: Increase in lymphocytes, common in viral infections (IMN), chronic inflammation (TB), and whooping cough.
• Neutropenia/Agranulocytosis: Severe reduction in neutrophils. Caused by drugs, aplastic anemia, or hypersplenism. High risk of severe infections.

General Concepts

• Definition: Malignant proliferation of WBC precursors in the bone marrow, leading to suppression of normal hematopoiesis and presence of abnormal cells in the blood.
• Causes: Viruses (HTLV-1, EBV), chemicals (benzene), radiation, and chromosomal abnormalities.

Chronic Leukemias

• Chronic Myeloid Leukemia (CML): Affects middle-aged adults. Markedly high TLC with a full spectrum of maturing myeloid cells. Leads to massive splenomegaly.
• Chronic Lymphocytic Leukemia (CLL): Affects older adults. High TLC of small, mature-looking lymphocytes. "Smudge cells" are characteristic. Associated with generalized lymphadenopathy and hypogammaglobulinemia (risk of infection).

Acute Leukemia

• General: More common in children. Rapid, aggressive course with symptoms related to marrow failure.
• Clinical Picture: Abrupt onset of high fever, fatigue (anemia), bleeding (thrombocytopenia), infections (neutropenia), and bone pain.
• Blood Findings: Anemia and thrombocytopenia are prominent. WBC count is variable but dominated by immature blast cells with a "leukemic gap" (few intermediate forms).

• Follicular Hyperplasia: Proliferation of B-cell germinal centers. Seen in rheumatoid arthritis, toxoplasmosis.
• Paracortical Hyperplasia: Expansion of T-cell zones. Seen in viral infections like Infectious Mononucleosis (IMN).
• Sinus Histiocytosis: Increased macrophages in sinuses. Seen in lymph nodes draining a cancer.

• General: Malignancies of mature (peripheral) or immature (precursor) lymphocytes.
• Microscopy: Nodal architecture is replaced by a homogenous "effacing" population of neoplastic cells.
• Classification: Low-grade (indolent) vs. high-grade (aggressive).

Key NHL Subtypes

• Follicular Lymphoma: Low-grade, germinal center B-cell origin, nodular pattern. Associated with t(14;18) translocation involving the BCL2 gene.
• Diffuse Large B-cell Lymphoma (DLBCL): Most common NHL. High-grade/aggressive, but potentially curable with aggressive chemotherapy.
• Burkitt's Lymphoma: Very high-grade, associated with EBV and t(8;14) involving the MYC gene. Shows a "starry sky" pattern.
• MALT Lymphoma: Low-grade, marginal zone origin, often in the stomach due to chronic H. pylori infection. Can regress with antibiotic treatment.

General Concepts

• Hallmark Cell: The neoplastic Reed-Sternberg (RS) cell, which is rare and found in a background of abundant reactive inflammatory cells (lymphocytes, eosinophils, etc.).
• Spread: Tends to arise in a single node and spread in an orderly, contiguous fashion to adjacent nodes.

Classification & Key Features

• Classical HL: RS cells are CD15+ and CD30+. Subtypes include:
  • Nodular Sclerosis: Most common type, often in young adults. Features lacunar RS cells and collagen bands.
  • Mixed Cellularity: Associated with EBV. Many classic RS cells in a mixed inflammatory background.
• Nodular Lymphocyte-Predominant HL (NLPHL): Different entity. Features "popcorn" (L&H) cells which are CD20+ but CD15/30 negative. Indolent course.

Thrombocytopenia (Low Platelet Count)

• Causes: Decreased production (aplastic anemia), increased destruction (ITP), sequestration (hypersplenism).
• Clinical: Spontaneous bleeding occurs at counts < 20,000/mL. Presents as petechiae and purpura.
• Immune Thrombocytopenic Purpura (ITP): Autoimmune destruction of platelets. Marrow shows increased megakaryocytes as a compensatory response.

Qualitative Platelet Disorders

• Bernard-Soulier Syndrome: Defective adhesion due to deficiency of GpIb-IX (vWF receptor).
• Glanzmann's Thrombasthenia: Defective aggregation due to deficiency of GpIIb-IIIa (fibrinogen receptor).

Thrombotic Microangiopathies

• TTP & HUS: Serious conditions with widespread microthrombi formation, leading to thrombocytopenia and microangiopathic hemolytic anemia.
• TTP: Associated with neurologic defects and deficiency in ADAMTS13.
• HUS: Associated with renal failure and often follows E. coli infections.

von Willebrand Disease

• Description: Most common hereditary bleeding disorder.
• Defect: Deficiency of von Willebrand Factor (vWF), which impairs both platelet adhesion and stabilization of Factor VIII.
• Labs: Prolonged Bleeding Time. aPTT may be prolonged.

Hemophilias

• Description: X-linked recessive disorders.
• Hemophilia A: Deficiency of Factor VIII.
• Hemophilia B: Deficiency of Factor IX.
• Labs: Prolonged aPTT. Normal PT and Bleeding Time.
• Clinical: Deep bleeding into joints (hemarthrosis) and muscles.

• Pathogenesis: Widespread, systemic activation of coagulation, leading to widespread microthrombi.
• Consequence: This process consumes platelets and clotting factors, leading to a severe, paradoxical bleeding disorder.
• Triggers: Sepsis, major trauma, obstetric complications, malignancy.