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Topic 9

Part of the FMGE study roadmap. Botany topic pathol-009 of Botany.

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Hematopathology

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Hematopathology — Key Facts for FMGE Core concept: Understanding the differentiation of blood cells and the pathophysiology of anemia, leukemia, and bleeding disorders is essential High-yield point: Know the morphological differences between different types of anemia and the classification of leukemias ⚡ Exam tip: The blood picture (peripheral smear) is frequently tested in FMGE with clinical scenarios

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Hematopathology — FMGE Study Guide

Hematopoiesis

Bone Marrow

  • At birth: All bone marrow is active (red marrow)
  • Adult: Flat bones (pelvis, sternum, ribs), proximal ends of long bones
  • Red marrow → Yellow marrow (fat) with aging

Cell Lines

  • Common myeloid progenitor → erythrocytes, megakaryocytes (platelets), granulocytes, monocytes
  • Common lymphoid progenitor → lymphocytes, NK cells
  • Stem cell (pluripotent) → all lineages

Growth Factors

  • Erythropoietin (kidney): RBC production
  • G-CSF, GM-CSF: Neutrophil production
  • Thrombopoietin (liver): Platelet production
  • IL-3, IL-5: Eosinophil growth

Anemia

Definition

Hemoglobin <13 g/dL (men), <12 g/dL (women); Hematocrit <40% (men), <36% (women)

Classification by Morphology (MCV)

Microcytic (MCV <80 fL):

  • Iron deficiency anemia (IDA): Most common
  • Thalassemia: Target cells, elevated HbA2
  • Sideroblastic anemia: Ringed sideroblasts in bone marrow
  • Lead poisoning: Basophilic stippling, microcytic hypochromic

Normocytic (MCV 80-100 fL):

  • Anemia of chronic disease
  • Acute blood loss
  • Hemolytic anemia
  • Bone marrow failure (aplastic anemia, leukemia)
  • Renal failure (decreased EPO)

Macrocytic (MCV >100 fL):

  • Megaloblastic: B12/folate deficiency (hypersegmented neutrophils, oval macrocytes)
  • Non-megaloblastic: Liver disease, alcoholism, hypothyroidism, reticulocytosis

Iron Deficiency Anemia

Causes: Blood loss (most common in adults - GI bleeding, menorrhagia), decreased intake, increased demand (pregnancy), malabsorption Lab findings: Low ferritin (most specific), low serum iron, high TIBC, low transferrin saturation, low MCV, hypochromic microcytic cells

Peripheral smear: Pencil cells (elongated RBCs), anisocytosis, poikilocytosis

Megaloblastic Anemia

B12 deficiency: Neurological changes (subacute combined degeneration), glossitis, Howell-Jolly bodies Folate deficiency: No neurological changes (hydrocephalus? No - sorry, no neurological changes unlike B12) Blood picture: Hypersegmented neutrophils (6-lobed or more), oval macrocytes, pancytopenia

Hemolytic Anemia

Intrinsic (RBC defect):

  • Membrane defects: Hereditary spherocytosis (splenomegaly, spherocytes), paroxysmal nocturnal hemoglobinuria
  • Enzyme defects: G6PD deficiency (Heinz bodies, bite cells), pyruvate kinase deficiency
  • Hemoglobin defects: Sickle cell disease, thalassemia

Extrinsic (external cause):

  • Immune: Autoimmune hemolytic anemia (warm - IgG, or cold - IgM), hemolytic disease of newborn
  • Non-immune: Microangiopathic hemolytic anemia (MAHA) - TTP, HUS, DIC; infections; hypersplenism

Labs: ↑LDH, ↑indirect bilirubin, ↓haptoglobin, ↑RBC production (reticulocytosis)

Aplastic Anemia

  • Pancytopenia with hypocellular bone marrow
  • Causes: Chemicals (benzene), drugs (chloramphenicol), radiation, viruses (EBV, HIV), idiopathic (Fanconi anemia)
  • Presentation: Fatigue, infections, bleeding
  • Labs: Low reticulocytes, hypocellular marrow

Leukemia

Acute Leukemia

Blasts (>20%): Lymphoid or myeloid lineage

Acute Lymphoblastic Leukemia (ALL):

  • Most common in children (peak 2-5 years)
  • L1: Small homogeneous blasts
  • L2: Large heterogeneous blasts
  • L3: Burkitt-type (vac’uolated)
  • B-ALL (B-cell precursor): Most common in children; CD10+ (CALLA), TdT+
  • T-ALL: Mediastinal mass, adolescents
  • FAB classification: L1, L2, L3 (French-American-British)
  • Clinical: Bleeding, infections, bone pain, hepatosplenomegaly

Acute Myeloid Leukemia (AML):

  • Adults (median age 60)
  • Auer rods (pathognomonic) - pink needle-like inclusions in cytoplasm
  • FAB: M0-M7 based on lineage
  • AML M3 (APL): t(15;17), PML-RARA; DIC; treatment with ATRA (all-trans retinoic acid)
  • AML with maturation: Auer rods, myeloblasts >20%
  • Chloroma: Extramedullary tumor of AML
  • Lab: High WBC or low, blasts in peripheral smear, Auer rods

Chronic Leukemia

Chronic Myeloid Leukemia (CML):

  • t(9;22) Philadelphia chromosome - BCR-ABL fusion (constitutively active tyrosine kinase)
  • Chronic phase: Marked leukocytosis with full spectrum of myeloid cells (myelocyte, metamyelocyte, band, segmented), splenomegaly, low leukocyte alkaline phosphatase (LAP)
  • Blast crisis: Similar to acute leukemia
  • Treatment: Imatinib (Gleevec) - tyrosine kinase inhibitor
  • Philadelphia chromosome also in ALL

Chronic Lymphocytic Leukemia (CLL):

  • Most common leukemia in adults
  • Smudge cells (fragile lymphocytes that rupture)
  • CD5+, CD19+, CD20+ B cells
  • Richter transformation: To aggressive lymphoma
  • Hypogammaglobulinemia: Recurrent infections

Myelodysplastic Syndromes

  • Clonal stem cell disorders with ineffective hematopoiesis
  • Refractory anemia: One cell line affected, <5% blasts
  • RAEB (refractory anemia with excess blasts): 5-19% blasts
  • 5q- syndrome: Isolated del(5q), good response to lenalidomide
  • Cytopenias, hypercellular or hypocellular marrow with dysplastic changes
  • May progress to AML (30%)

Lymphoma

Hodgkin Lymphoma

  • Reed-Sternberg cells (RS): Large binucleated cells with prominent eosinophilic nucleoli (“owl-eye” appearance) in a reactive cellular background
  • CD15+, CD30+ (not CD45)
  • B symptoms: Fever, night sweats, weight loss >10%
  • Subtypes:
    • Nodular sclerosis (most common): Lacunar cells, collagen bands dividing node into nodules
    • Mixed cellularity, lymphocyte-rich, lymphocyte-depleted, nodular lymphocyte-predominant
  • Bimodal age: 15-35 years and >55 years
  • Staging (Ann Arbor): I-IV based on lymph node involvement + B symptoms

Non-Hodgkin Lymphoma

  • Clonal lymphoid proliferation
  • B-cell lymphomas: More common (85%)
  • T-cell lymphomas: 15%

Important types:

  • Burkitt lymphoma: t(8;14) c-myc translocation; “starry sky” pattern (tingible body macrophages); endemic (African jaw) and sporadic forms; associated with EBV
  • Diffuse large B-cell lymphoma: Most common NHL; aggressive but curable
  • Follicular lymphoma: t(14;18) BCL-2;indolent,Centrofollicular pattern; BCL-2+ (anti-apoptotic)
  • Mantle cell lymphoma: t(11;14) CCND1; aggressive
  • Mycosis fungoides: Cutaneous T-cell lymphoma; Sézary cells (cerebriform nuclei)
  • Anaplastic large cell lymphoma: ALK+ (t(2;5) NPM1-ALK)

Multiple Myeloma

  • Neoplastic plasma cell proliferation
  • CRAB criteria: Calcium elevation, Renal insufficiency, Anemia, Bone lesions (lytic lesions, osteoporosis)
  • M spike on serum protein electrophoresis (monoclonal protein)
  • Bence Jones protein (light chains in urine)
  • Lytic lesions: “Punched out” lesions without sclerotic rim
  • Plasma cells in bone marrow >10%
  • Associated with: Primary amyloidosis (AL type)

Myeloproliferative Neoplasms

  • Clonal proliferation of hematopoietic stem cells with overproduction of one or more cell lines

Polycythemia vera:

  • ↑RBC mass, ↑hematocrit
  • JAK2 mutation (V617F) in >95%
  • Splenomegaly, facial plethora, pruritus (after hot bath), thrombotic events
  • Low EPO (negative feedback)

Essential thrombocythemia:

  • Sustained platelets >450,000/μL
  • JAK2, CALR, or MPL mutations
  • May progress to myelofibrosis or AML

Primary myelofibrosis:

  • “Dry tap” on bone marrow aspiration (fibrosis)
  • Leukoerythroblastic picture (teardrop cells, nucleated RBCs, immature granulocytes)
  • Massive splenomegaly

Chronic Myeloid Leukemia (see above)

Bleeding Disorders

Thrombocytopenia

  • Platelets <150,000/μL
  • Causes: Decreased production (bone marrow suppression, infiltration), increased destruction (ITP, TTP, DIC, drugs), sequestration (splenomegaly)
  • ITP (Immune thrombocytopenic purpura): Autoantibodies against platelets; isolated thrombocytopenia; megakaryocytes present in bone marrow; response to steroids, IVIG, splenectomy

Coagulation Factor Deficiencies

Hemophilia A (Factor VIII deficiency):

  • X-linked recessive
  • Hemarthrosis (joint bleeds), muscle hematomas, prolonged aPTT
  • Normal PT

Hemophilia B (Factor IX deficiency):

  • Christmas disease
  • X-linked recessive
  • Same presentation as Hemophilia A

von Willebrand Disease:

  • Most common inherited bleeding disorder
  • vWF deficiency: Defective platelet adhesion
  • Mucocutaneous bleeding, menorrhagia, prolonged bleeding time
  • vWF antigen, ristocetin cofactor (reduced platelet agglutination with ristocetin)
  • Can have prolonged aPTT (vWF carries Factor VIII)

Disseminated Intravascular Coagulation (DIC)

  • Triggered by widespread activation of coagulation → consumption of clotting factors → bleeding
  • Causes: Sepsis (most common), obstetric complications (amniotic fluid embolism, placental abruption), malignancy, severe trauma
  • Lab findings: Low platelets, prolonged PT and aPTT, low fibrinogen, elevated D-dimer, schistocytes
  • Treatment: Treat underlying cause, supportive (FFP, cryoprecipitate, platelets)

Thrombotic Microangiopathies

TTP (Thrombotic Thrombocytopenic Purpura):

  • ADAMTS13 deficiency (metalloprotease that cleaves vWF)
  • Pentad: Microangiopathic hemolytic anemia (MAHA), thrombocytopenia, neurological symptoms, renal dysfunction, fever
  • Schistocytes on peripheral smear
  • Plasma exchange (plasmapheresis) is life-saving

HUS (Hemolytic Uremic Syndrome):

  • E. coli O157:H7 (Shiga toxin-producing) in children
  • Bloody diarrhea → HUS triad: MAHA, thrombocytopenia, acute kidney injury
  • Treatment: Supportive, avoid antibiotics

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