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Hematology Propaedeutics - Complete Study Guide for Practical Oral Exam

3rd Year Clinical Introduction | Focus: History-Taking & Physical Examination

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PART 1 - INTRODUCTION TO THE HEMATOLOGY CONSULTATION

1. Disorders of red blood cells (RBCs) - anemias, polycythemia
2. Disorders of white blood cells (WBCs) - leukemia, lymphoma, neutropenia
3. Disorders of hemostasis - bleeding disorders, thrombophilia, platelet disorders

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PART 2 - HISTORY-TAKING IN HEMATOLOGY

2.1 Opening and Chief Complaint

• Always introduce yourself, confirm the patient's identity, and ask open-ended: "What brings you in today?"
• Common chief complaints in hematology:
  • Fatigue, weakness, shortness of breath (anemia)
  • Abnormal bleeding or bruising (coagulopathy / thrombocytopenia)
  • Swollen glands / lumps in the neck, axilla, groin (lymphadenopathy)
  • Bone pain (multiple myeloma, leukemia)
  • Fever, night sweats, weight loss ("B symptoms" - lymphoma)
  • Recurrent infections (leukemia, immunodeficiency)

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2.2 History of Presenting Complaint (HPC) - Use the OLDCARTS Framework

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2.3 Symptoms of Anemia - Ask Specifically About:

• Fatigue and weakness - the most common but least specific symptom
• Dyspnea on exertion - patient gets breathless with activities they previously tolerated
• Palpitations / tachycardia - heart compensates by beating faster
• Dizziness, lightheadedness, syncope - reduced cerebral oxygenation
• Exertional chest pain - especially if the patient has underlying coronary artery disease or the anemia is severe
• Edema - decreased renal blood flow triggers neurohormonal activation (similar to heart failure mechanism), but unlike heart failure, cardiac output is actually HIGH in anemia
• Headache and difficulty concentrating - common, often overlooked
• Cold intolerance - peripheral vasoconstriction

Clinical pearl: Symptoms of hypovolemia (thirst, postural hypotension, rapid weak pulse) only occur in acute anemia from large blood loss - in chronic anemia, plasma volume expands to compensate.

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2.4 Symptoms of Bleeding Disorders - Ask About:

• Epistaxis (nosebleeds) - spontaneous or prolonged after minor trauma
• Gum bleeding
• Easy bruising - bruises appearing with minimal or no trauma
• Petechiae - patient may notice tiny red dots on legs
• Heavy menstrual periods (menorrhagia)
• Prolonged bleeding from cuts

• Hemarthrosis - bleeding into joints (classic for hemophilia)
• Muscle hematomas
• Prolonged bleeding after surgery, tooth extractions, injections
• Intracranial hemorrhage (rare, serious)

Key distinction: Platelet disorders cause immediate superficial bleeding (skin, mucous membranes). Coagulation disorders cause delayed deep bleeding (joints, muscles).

• Respiratory: hemoptysis, epistaxis
• Gastrointestinal: hematemesis (vomiting blood), melena (black tarry stools), hematochezia (fresh rectal blood)
• Genitourinary: hematuria, menorrhagia, abnormal pregnancies
• Skin: petechiae, ecchymoses

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2.5 Symptoms Suggesting Lymphoproliferative Disease (Lymphoma / Leukemia)

1. Fever - unexplained fever > 38°C
2. Night sweats - drenching, requiring change of clothes or sheets
3. Weight loss - unexplained loss of >10% body weight in 6 months

• Painless swollen lymph nodes - in the neck, armpits, or groin
• Pruritus (itching) - without obvious skin cause, classic in Hodgkin lymphoma
• Alcohol-induced pain at lymph node sites - pathognomonic for Hodgkin lymphoma (rare but high-yield)
• Recurrent or severe infections - suggests neutropenia or immune dysfunction (leukemia)
• Bone pain - leukemia infiltrating marrow, or multiple myeloma
• Abdominal fullness / early satiety - from splenomegaly

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2.6 Past Medical History (PMH)

• Chronic kidney disease - causes anemia of chronic disease (reduced erythropoietin)
• Liver disease - affects clotting factor production; causes thrombocytopenia from hypersplenism
• Inflammatory / autoimmune diseases (rheumatoid arthritis, lupus, IBD) - anemia of chronic inflammation; also autoimmune hemolytic anemia
• Hypothyroidism - causes normocytic anemia, macrocytosis
• Cancer - bone marrow infiltration causing pancytopenia
• Previous surgeries - especially gastrectomy (impairs B12 absorption) or bowel resection
• Previous blood transfusions - alloimmunization, transfusion reactions
• Previous episodes of DVT/PE - suggests thrombophilia

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2.7 Drug and Medication History

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2.8 Family History

• Sickle cell disease / sickle cell trait - autosomal recessive, common in Sub-Saharan African, Mediterranean, and Middle Eastern populations
• Thalassemia - autosomal recessive, common in Mediterranean, Middle Eastern, South Asian populations
• Hemophilia A & B - X-linked recessive (affects males, carrier females)
• Von Willebrand disease - autosomal dominant (most common inherited bleeding disorder)
• Hereditary spherocytosis - autosomal dominant hemolytic anemia
• G6PD deficiency - X-linked, triggers hemolytic episodes
• Familial polycythemia, hereditary thrombophilia (Factor V Leiden, prothrombin mutation)

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2.9 Social History

• Diet and nutrition: Vegetarian/vegan diet risks iron and B12 deficiency. Strict veganism: B12 deficiency (megaloblastic anemia). Poor nutrition: folate deficiency.
• Alcohol use: Causes macrocytosis, thrombocytopenia, and folate deficiency
• Occupation: Toxin/chemical exposure (benzene, radiation) - risk for aplastic anemia, leukemia
• Travel history: Malaria (hemolytic anemia), visceral leishmaniasis, schistosomiasis - all cause splenomegaly/anemia
• Ethnic/racial background: Guides suspicion for hereditary disorders (sickle cell, thalassemia, G6PD deficiency)
• Smoking: Associated with polycythemia

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2.10 Menstrual History (Female Patients)

• Regularity and frequency of periods
• Duration and heaviness of flow - menorrhagia is a major cause of iron-deficiency anemia in premenopausal women AND can be the presenting symptom of a bleeding disorder (e.g., von Willebrand disease)
• Number of pads/tampons used (>80 mL blood loss per cycle = menorrhagia)
• Pregnancy history

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2.11 Review of Systems (ROS) - Do Not Miss These

• Skin: Jaundice, pallor, petechiae, ecchymoses, pruritus, leg ulcers
• Eyes: Yellowing of sclera (jaundice from hemolysis)
• Mouth: Mouth sores, sore tongue
• Lymph nodes: Any lumps?
• Cardiorespiratory: Dyspnea, palpitations, chest pain
• GI: Abdominal pain, fullness, bowel changes, rectal bleeding
• Neurological: Numbness, tingling, weakness, balance problems (B12 deficiency)
• Musculoskeletal: Bone pain, joint swelling/bleeding

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PART 3 - PHYSICAL EXAMINATION IN HEMATOLOGY

3.1 General Inspection - First Impressions

• Pallor (pale skin suggesting anemia)
• Jaundice (yellow skin and sclerae suggesting hemolysis or liver disease)
• Cyanosis (blue discoloration - hypoxia, methemoglobinemia)
• Cachexia / weight loss (malignancy)
• General distress or fatigue

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3.2 Vital Signs

• Pulse rate: Tachycardia compensates for anemia (HR >100 bpm at rest suggests significant anemia)
• Blood pressure: Postural hypotension in acute blood loss
• Respiratory rate: Elevated with severe anemia
• Temperature: Fever can indicate infection (neutropenia), lymphoma, or hemolysis

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3.3 Skin Examination

How to distinguish petechiae from a rash: Press with a glass (diascopy). A rash blanches (blood pushed out). Petechiae do NOT blanch (extravasated blood does not move).

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3.4 Eye Examination

• Conjunctival pallor: The most reliable clinical sign of anemia
  • Examine the lower eyelid: pull it down and look at the inferior palpebral conjunctiva
  • Conjunctival rim pallor (LR+ 16.7): The normally bright red anterior rim of the inferior palpebral conjunctiva is the same pale pink color as the deeper posterior aspect - very specific for anemia
  • Palmar crease pallor (LR+ 7.9): Also highly useful - look at the lines of the palm; normally pink even when the hand is extended; if the palmar creases are white/pale, anemia is very likely
  • Facial pallor and nail bed pallor are less reliable (LR+ < 5)
• Scleral icterus (jaundice): Yellow coloration of the whites of the eyes - hemolysis or liver disease; best seen in natural daylight (fluorescent light masks yellow)
• Fundoscopy: Retinal hemorrhages, Roth spots (endocarditis, leukemia, severe anemia)

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3.5 Mouth and Oropharynx

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3.6 Lymph Node Examination

1. Submental and submandibular (under the chin)
2. Cervical - anterior and posterior chains
3. Occipital
4. Preauricular and postauricular
5. Supraclavicular (highly significant - Virchow's node on the left suggests GI malignancy)
6. Axillary
7. Epitrochlear (above the elbow)
8. Inguinal
9. Popliteal (behind the knee - often overlooked)

• Size (in cm - >1 cm in adults is generally pathological)
• Consistency: Soft (reactive/infectious), firm/rubbery (lymphoma), hard/rock-like (metastatic carcinoma)
• Tenderness: Tender = usually reactive/infectious. Painless = suspicious for lymphoma or malignancy
• Mobility: Mobile = benign. Fixed to underlying tissue = malignant
• Warmth and erythema: Suggests acute infection
• Location: Localized vs. generalized

• Localized tender nodes + infection signs = reactive lymphadenopathy
• Generalized lymphadenopathy = systemic illness (viral: EBV, CMV; bacterial; hematologic malignancy)
• Supraclavicular node is ALWAYS concerning - must be investigated

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3.7 Abdominal Examination - Spleen and Liver

Splenomegaly (Enlarged Spleen)

• Patient lies supine, comfortably relaxed
• Start palpation from the right iliac fossa (the right lower quadrant) - a massively enlarged spleen can extend far across the abdomen and you will miss it if you start in the left upper quadrant
• Move your hand toward the left upper quadrant on each inspiration - the spleen moves down with the diaphragm during inspiration
• Ask the patient to take deep breaths - the spleen is best felt on inspiration
• The spleen notch distinguishes it from the kidney

• Traube's space = the area over the left lower chest (8th-11th ribs in the anterior axillary line)
• Normally resonant (air in stomach and bowel)
• Dull percussion in Traube's space suggests splenomegaly

• Left upper quadrant fullness/pain, early satiety
• Cytopenia (hypersplenism trapping blood cells)
• In children: malaria, infectious mononucleosis (EBV), sickle cell

• Hematologic: Lymphoma, leukemia (especially CML - massive splenomegaly), hemolytic anemias, myeloproliferative disorders, thalassemia
• Infectious: EBV (glandular fever), malaria, visceral leishmaniasis, septicemia
• Portal hypertension: Liver cirrhosis, portal vein thrombosis
• Inflammatory: SLE, rheumatoid arthritis (Felty's syndrome)

Hepatomegaly

• Enlarged liver from infiltrative disease (lymphoma, leukemia), hepatitis, cirrhosis
• Examine from the right iliac fossa upward
• Measure the number of finger-breadths below the costal margin

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3.8 Cardiovascular Examination

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3.9 Neurological Examination

Subacute combined degeneration due to B12 deficiency is a classic exam favorite. Dorsal (posterior) and lateral columns of the spinal cord are demyelinated. Patient has impaired proprioception AND weakness.

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3.10 Musculoskeletal and Bone Examination

• Bone tenderness on palpation: Sternal tenderness (press firmly on the sternum) - suggests bone marrow infiltration in leukemia or multiple myeloma
• Joint swelling and deformity: Hemarthrosis in hemophilia - chronic joint disease from repeated bleeds (hemophilic arthropathy)
• Vertebral tenderness: Multiple myeloma can cause vertebral collapse

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3.11 Examination for Signs of Specific Disorders

Signs of Iron-Deficiency Anemia:

• Pallor (conjunctival, palmar crease)
• Koilonychia (spoon-shaped nails)
• Angular cheilitis
• Atrophic glossitis (smooth tongue)
• Dysphagia (Plummer-Vinson/Patterson-Kelly syndrome - rare)

Signs of B12/Folate Deficiency (Megaloblastic Anemia):

• Pallor with lemon-yellow tinge (mild jaundice from ineffective erythropoiesis)
• Smooth tongue (glossitis)
• Neurological signs (B12 only - folate does NOT cause neurological disease): loss of vibration, proprioception, ataxia

Signs of Hemolysis:

• Jaundice (scleral icterus)
• Pallor
• Splenomegaly (extramedullary hematopoiesis and RBC destruction)
• Dark urine (hemoglobinuria in intravascular hemolysis)

Signs of Leukemia:

• Pallor (anemia from marrow infiltration)
• Petechiae and ecchymoses (thrombocytopenia)
• Fever, recurrent infections (neutropenia)
• Lymphadenopathy
• Splenomegaly, hepatomegaly
• Gum hypertrophy (especially AML)
• Sternal tenderness
• Bone pain

Signs of Lymphoma:

• Painless lymphadenopathy (rubbery, non-tender nodes)
• B symptoms: fever, night sweats, weight loss
• Pruritus (especially Hodgkin)
• Splenomegaly, hepatomegaly
• Superior vena cava (SVC) syndrome (facial swelling, arm swelling) if mediastinal involvement

Signs of Multiple Myeloma:

• Bone pain, bone tenderness (vertebral collapse)
• Pallor (anemia)
• Recurrent infections (immunoparesis)
• Features of hypercalcemia: nausea, confusion, constipation, polyuria
• Peripheral neuropathy (paraprotein-related)

Signs of Bleeding Disorders:

• Petechiae, purpura, ecchymoses
• Hemarthrosis (joint swelling - hemophilia)
• Mucous membrane bleeding (gums, epistaxis)

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PART 4 - PUTTING IT TOGETHER: CLINICAL APPROACH

4.1 The Three-Question Framework

1. Is there evidence of anemia? (pallor, tachycardia, fatigue, flow murmur)
2. Is there evidence of a bleeding/clotting disorder? (petechiae, ecchymoses, hemarthrosis, thrombosis)
3. Is there evidence of lymphoproliferative/myeloproliferative disease? (lymphadenopathy, splenomegaly, B symptoms, bone pain)

4.2 The Clinical Significance of Pallor

• Conjunctival rim pallor: LR+ 16.7 - most useful sign
• Palmar crease pallor: LR+ 7.9 - second most useful
• Facial pallor / nail bed pallor: LR+ < 5 - less reliable
• No single physical sign rules out anemia
• Overall sensitivity and specificity of physical exam for anemia is ~70%

Practical tip for the oral exam: Always order a CBC if a patient has symptoms suggesting anemia, even if physical exam signs are absent. Do NOT rely solely on the physical exam.

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PART 5 - SUMMARY TABLE: SYMPTOMS AND THEIR HEMATOLOGIC INTERPRETATION

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PART 6 - PRACTICAL TIPS FOR THE ORAL EXAM

1. Structure your answer always in the same order: Chief complaint → HPC (OLDCARTS) → PMH → Medications → Family history → Social history → Review of systems → Physical examination
2. Always link the symptom to the mechanism: Don't just say "fatigue." Say "fatigue due to reduced oxygen delivery from anemia."
3. When examining, verbalize what you are doing and why: "I am starting palpation from the right iliac fossa because in massive splenomegaly the spleen can extend to the left lower quadrant."
4. Petechiae vs. rash: Use the glass test - petechiae don't blanch.
5. B symptoms are asked in every lymphoma case - if you forget to ask, the examiner will notice.
6. Sternal tenderness is a quick bedside test - always perform it if you suspect leukemia or myeloma.
7. Don't forget the neurological exam in any anemia case - B12 deficiency has combined blood and neuro findings.
8. Family history - always ask about hereditary blood disorders, especially if the patient is young.
9. Conjunctival pallor is your best tool for detecting anemia - never skip it.
10. The spleen moves on inspiration and has a notch - both features distinguish it from kidney or other left upper quadrant masses.

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All Hematological Disorders & Their Mechanisms

Complete Reference Guide - Based on Robbins Pathology, Harrison's & Goldman-Cecil Medicine

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MASTER CLASSIFICATION FRAMEWORK

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CATEGORY 1 - ANEMIAS

Two Broad Mechanisms:

1. Increased destruction / blood loss (hemolytic or hemorrhagic)
2. Decreased production (defective erythropoiesis)

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1.1 BLOOD LOSS ANEMIAS

A. Acute Blood Loss Anemia

B. Chronic Blood Loss Anemia

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1.2 HEMOLYTIC ANEMIAS (Increased RBC Destruction)

1.2.1 INHERITED HEMOLYTIC ANEMIAS

A. Hereditary Spherocytosis (HS)

• Loss of membrane proteins causes the RBC to lose membrane surface area relative to volume
• The RBC takes on a spherical shape instead of the normal biconcave disc
• Spherocytes are less deformable and cannot squeeze through the narrow splenic sinusoids
• They are trapped and destroyed in the spleen (extravascular hemolysis - hypersplenism)
• Result: hemolytic anemia + splenomegaly + jaundice

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B. G6PD Deficiency

• G6PD normally reduces NADP → NADPH
• NADPH is required to maintain reduced glutathione (GSH)
• Reduced glutathione is the main antioxidant that neutralizes hydrogen peroxide (H2O2) and other oxidants in RBCs
• Without G6PD → NADPH depleted → GSH depleted → oxidative stress damages hemoglobin
• Hemoglobin denatures and precipitates as Heinz bodies (rigid inclusions)
• Heinz bodies damage the membrane and get "pitted" out by the spleen
• Older RBCs are most vulnerable (they have less residual G6PD activity)

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C. Pyruvate Kinase (PK) Deficiency

• Mature RBCs rely entirely on anaerobic glycolysis (no mitochondria) for ATP production
• PK deficiency → impaired ATP generation → RBCs cannot maintain ion pumps (Na+/K+ ATPase)
• Cells dehydrate, become rigid, and are destroyed in the spleen
• Unlike G6PD deficiency, hemolysis is chronic (not episodic) because glycolysis is constitutively required

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D. Sickle Cell Disease

• Deoxygenated HbS polymerizes into long, rigid rods
• These rods distort the RBC into a sickle shape
• Sickling is initially reversible (re-oxygenation restores shape), but repeated cycles cause irreversible sickling
• Two pathological consequences:
  1. Hemolysis: Sickle cells are fragile and destroyed (intravascular + extravascular hemolysis), lifespan reduced to 20 days (normal: 120 days)
  2. Vaso-occlusion: Sickle cells are rigid and sticky; they obstruct small blood vessels, causing ischemia and infarction in multiple organs

• Bone: Painful crises (most common), avascular necrosis of femoral head
• Spleen: Repeated infarctions → autosplenectomy (by adulthood the spleen is fibrotic and non-functional) → susceptibility to encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae, Salmonella)
• Kidney: Papillary necrosis, hematuria, renal failure
• CNS: Stroke (10-15% of patients)
• Lung: Acute chest syndrome (life-threatening)
• Priapism
• Leg ulcers (medial/lateral malleoli - classic clinical sign)
• Dactylitis (hand-foot syndrome) - earliest manifestation in infants

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E. Thalassemias

• Insufficient β-chains → insufficient HbA (α2β2)
• Excess free α-globin chains accumulate - they are insoluble and precipitate
• Precipitated α-chains form inclusions that damage RBC membranes
• Erythroid precursors are destroyed in the bone marrow before they mature (ineffective erythropoiesis)
• This drives massive erythroid hyperplasia in the marrow → bone marrow expansion → bony deformities (facial bossing, "hair-on-end" skull X-ray)
• Also, erythroferrone released from expanded erythroid mass suppresses hepcidin → increased iron absorption → iron overload (hemochromatosis) even without transfusion

• β-thalassemia major (Cooley's anemia): Homozygous β0/β0. Severe anemia from infancy requiring regular transfusions. Hepatosplenomegaly, growth retardation, skull deformities. Death in teens without treatment.
• β-thalassemia intermedia: Moderate severity, transfusion-independent
• β-thalassemia minor (trait): Heterozygous carrier. Usually asymptomatic. Mild microcytic anemia. Important to distinguish from iron deficiency (HbA2 elevated to 4-8% on electrophoresis).

• 1 gene deleted: silent carrier (no anemia)
• 2 genes deleted: α-thalassemia trait (mild microcytosis, no/minimal anemia)
• 3 genes deleted: HbH disease - moderate hemolytic anemia, splenomegaly
• 4 genes deleted: Hydrops fetalis (Hb Bart's) - incompatible with life; death in utero or shortly after birth

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1.2.2 ACQUIRED HEMOLYTIC ANEMIAS

F. Paroxysmal Nocturnal Hemoglobinuria (PNH)

• GPI anchors normally attach complement-regulatory proteins (DAF/CD55 and CD59) to cell surfaces
• Without GPI anchors, complement regulatory proteins are absent from RBCs, platelets, and WBCs
• The complement system attacks unprotected RBCs → intravascular hemolysis (complement-mediated)
• Hemolysis is classically worse at night (blood becomes more acidic during sleep, activating complement)

• Hemolytic anemia (intravascular) with hemoglobinuria (dark morning urine)
• Thrombosis (major cause of death) - especially in unusual sites: hepatic veins (Budd-Chiari syndrome), cerebral veins
• Cytopenias

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G. Autoimmune Hemolytic Anemia (AIHA)

1. Warm AIHA (most common): IgG antibodies that react optimally at 37°C. RBCs coated with IgG are recognized by Fc receptors on splenic macrophages → extravascular hemolysis → spherocytes form as macrophages partially eat the membrane. Causes: idiopathic, SLE, CLL, drugs (methyldopa, penicillin).
2. Cold AIHA: IgM antibodies (cold agglutinins) react at <37°C (best at 4°C). IgM activates complement. At low temperatures (in extremities), complement is deposited → at warmer core temperature, C3b-coated RBCs are phagocytosed → hemolysis. Causes: Mycoplasma pneumoniae, EBV (infectious mononucleosis).

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H. Microangiopathic Hemolytic Anemia (MAHA)

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1.3 ANEMIAS OF DIMINISHED ERYTHROPOIESIS (Underproduction)

A. Megaloblastic Anemia

• DNA synthesis is impaired, but RNA and protein synthesis continue
• Cells grow large but cannot divide efficiently
• This nuclear-cytoplasmic asynchrony creates megaloblasts (abnormally large erythroid precursors with immature-looking nuclei)
• Many megaloblasts die in the marrow before release = ineffective erythropoiesis
• Those RBCs that do escape are large and oval (macro-ovalocytes)
• Neutrophils also show nuclear hypersegmentation (≥5 lobes)
• All rapidly dividing cells are affected (GI epithelium → mouth ulcers, glossitis, diarrhea)

i. Vitamin B12 Deficiency - Pernicious Anemia (PA)

• B12 is needed for myelin synthesis (via methylmalonyl-CoA pathway)
• Demyelination of posterior columns (dorsal) and lateral columns → loss of vibration sense + proprioception + spastic weakness + ataxia
• This is irreversible if not treated promptly

ii. Folate Deficiency

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B. Iron-Deficiency Anemia (IDA)

• Iron is essential for heme synthesis (the iron-containing part of hemoglobin)
• Depletion occurs in stages:
  1. Iron stores depleted (ferritin falls) - no anemia yet
  2. Serum iron falls, transferrin saturation falls to <15-20% - iron supply to erythropoiesis insufficient
  3. RBCs become hypochromic (pale) and microcytic (small) - classic IDA

• Koilonychia, angular cheilitis, atrophic glossitis
• Reduced immune function
• Pica (craving for non-food items - clay, ice)
• Plummer-Vinson syndrome (triad: IDA + dysphagia + esophageal webs)

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C. Anemia of Chronic Inflammation (ACI) / Anemia of Chronic Disease

• Binds to ferroportin (the only iron exporter from cells) and causes its degradation
• Traps iron inside macrophages and intestinal epithelial cells
• This sequesters iron away from erythroid precursors ("iron withholding" as an antimicrobial defense)
• Cytokines also directly suppress erythropoietin production and erythropoietic stem cell response

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D. Aplastic Anemia

1. Immune-mediated (most common): Stem cells are antigenically altered by drugs, infections, or environmental insults → activated Th1 cells produce cytokines (IFN-γ, TNF) → suppress and kill hematopoietic stem cells. Responds to immunosuppression in 60-70% of cases.
2. Intrinsic stem cell defect: Mutations in telomerase → premature senescence of stem cells. Stem cells with short telomeres express neoantigens → become targets for immune attack.

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E. Anemia of Renal Failure

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F. Myelophthisic Anemia

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G. Polycythemia (Excess RBCs - opposite of anemia)

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CATEGORY 2 - BLEEDING DISORDERS

1. Primary hemostasis: Platelet plug formation (platelet adhesion via vWF to collagen, then activation and aggregation)
2. Secondary hemostasis: Coagulation cascade → fibrin clot formation
3. Vessel wall integrity: Endothelium prevents exposure of procoagulant subendothelial matrix

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2.1 VESSEL WALL DISORDERS

Henoch-Schönlein Purpura (HSP)

Hereditary Hemorrhagic Telangiectasia (Rendu-Osler-Weber)

Perivascular Amyloidosis

Scurvy (Vitamin C deficiency)

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2.2 PLATELET DISORDERS

A. Thrombocytopenia - Reduced Platelet Number

• Drug-induced marrow suppression (alcohol, thiazides, chemotherapy)
• Infection (HIV, measles virus infecting megakaryocytes)
• B12/folate deficiency (megaloblastic suppression of all cell lines)
• Aplastic anemia
• Marrow replacement (leukemia, metastases)
• Myelodysplastic syndromes (ineffective hematopoiesis)

i. Immune Thrombocytopenic Purpura (ITP) - Chronic

ii. Acute ITP (in children)

iii. Drug-Induced Thrombocytopenia

• Heparin-induced thrombocytopenia (HIT): Heparin binds to platelet factor 4 (PF4) → new epitope formed → IgG antibodies against heparin-PF4 complexes → platelets activated and consumed paradoxically causing thrombosis (not just bleeding). Life-threatening.
• Other drugs (quinine, sulfonamides) act as haptens on platelet surface → immune destruction.

iv. Thrombotic Thrombocytopenic Purpura (TTP)

v. Hemolytic Uremic Syndrome (HUS)

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B. Platelet Function Disorders (Normal Count but Abnormal Function)

Glanzmann Thrombasthenia

Bernard-Soulier Syndrome

Drug-Induced Platelet Dysfunction

• Aspirin: Irreversibly inhibits COX-1 → no thromboxane A2 → reduced platelet activation. Effect lasts for platelet's lifetime (7-10 days).
• NSAIDs: Same mechanism, reversible.
• Clopidogrel: Irreversibly blocks P2Y12 (ADP receptor) on platelets.

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2.3 COAGULATION FACTOR DISORDERS

A. Hemophilia A (Factor VIII Deficiency)

B. Hemophilia B (Factor IX Deficiency - Christmas Disease)

C. Von Willebrand Disease (vWD) - Most Common Inherited Bleeding Disorder

1. Primary hemostasis: Bridges platelet GPIb receptors to exposed collagen in damaged vessel walls (platelet adhesion)
2. Secondary hemostasis: Carries and protects Factor VIII from degradation in plasma

• Type 1 (most common, 75%): Quantitative reduction in vWF - autosomal dominant, mild
• Type 2: Qualitative defect in vWF function
• Type 3: Complete absence of vWF - severe

D. Vitamin K Deficiency

E. Disseminated Intravascular Coagulation (DIC)

1. Release of tissue factor (TF) into the circulation: TF activates Factor VII → cascades through the coagulation system → widespread microvascular thrombus formation. Sources: placenta (obstetric catastrophes: abruptio placentae, amniotic fluid embolism), cancer cells (especially acute promyelocytic leukemia - AML M3 which releases a granule product with TF-like activity), trauma, burns, snake venom.
2. Widespread endothelial injury: Sepsis (gram-negative sepsis; TNF from immune response induces endothelial TF expression and downregulates thrombomodulin) → triggers coagulation cascade.

• Widespread clotting → consumption of platelets and coagulation factors (consumption coagulopathy)
• Depleted factors → hemorrhage from multiple sites
• Thrombi activate plasmin (fibrinolysis) → fibrin degradation products (D-dimers) form, which further impair normal clot formation

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CATEGORY 3 - WHITE BLOOD CELL (LEUKOCYTE) DISORDERS

3.1 REACTIVE (NON-NEOPLASTIC) LEUKOCYTE DISORDERS

Leukocytosis

• Neutrophilia: Bacterial infections, steroids, MI, burns
• Lymphocytosis: Viral infections (EBV, CMV, whooping cough)
• Eosinophilia: Allergic reactions, parasitic infections (helminths), drug reactions
• Monocytosis: Chronic infections (TB, subacute bacterial endocarditis)

Reactive Lymphadenitis

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3.2 NEOPLASTIC LEUKOCYTE DISORDERS

A. Leukemias

Acute Myeloid Leukemia (AML)

Acute Lymphoblastic Leukemia/Lymphoma (ALL)

Chronic Myeloid Leukemia (CML)

Chronic Lymphocytic Leukemia (CLL)

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B. Lymphomas

Hodgkin Lymphoma (HL)

• Nodular sclerosis (most common) - bands of fibrosis, lacunar cells, mediastinal mass in young women
• Mixed cellularity - more RS cells, EBV-associated, older adults
• Lymphocyte-rich
• Lymphocyte-depleted - worst prognosis

Non-Hodgkin Lymphoma (NHL)

• Chromosomal translocations juxtaposing oncogenes to immunoglobulin (Ig) gene promoters, which are constitutively active in B cells:
  • Follicular lymphoma: t(14;18) → BCL2 gene (anti-apoptotic protein) moved next to IgH promoter → BCL2 overexpressed → B cells cannot undergo apoptosis → accumulate as follicular-pattern lymphoma. Indolent but incurable.
  • Burkitt lymphoma: t(8;14) → MYC oncogene moved next to IgH promoter → massive cell proliferation. Extremely aggressive. Associated with EBV (especially endemic African form). "Starry sky" pattern on biopsy (macrophages engulfing apoptotic cells among sheets of blasts).
  • Mantle cell lymphoma: t(11;14) → cyclin D1 overexpressed → uncontrolled cell cycle progression.
  • Diffuse large B-cell lymphoma (DLBCL): Most common NHL, aggressive, heterogeneous mutations.
  • MALT lymphoma: Often driven by chronic antigenic stimulation (H. pylori gastritis → gastric MALT lymphoma; H. pylori eradication can cure early disease).

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3.3 PLASMA CELL DYSCRASIAS

Multiple Myeloma

• RANKL → activates osteoclasts → lytic bone lesions (punched-out lesions on X-ray), hypercalcemia, pathological fractures, bone pain
• IL-6 → promotes myeloma cell survival; also causes anemia (ACD mechanism)
• Crowd out normal marrow → pancytopenia (anemia, immunoparesis → infections)
• Bence-Jones proteins (free light chains) are filtered by kidneys → renal tubular damage → myeloma kidney

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CATEGORY 4 - MYELOPROLIFERATIVE / MYELODYSPLASTIC DISORDERS

4.1 Myeloproliferative Neoplasms (MPN) - Clonal Overproduction

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4.2 Myelodysplastic Syndromes (MDS)

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MASTER SUMMARY TABLE

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• Blood loss (acute vs. chronic)
• Hemolytic - inherited: Hereditary spherocytosis, G6PD deficiency, PK deficiency, Sickle cell disease, Beta & Alpha thalassemia
• Hemolytic - acquired: PNH, AIHA (warm & cold), MAHA
• Underproduction: Megaloblastic (B12/pernicious vs. folate), Iron deficiency, Anemia of chronic inflammation, Aplastic anemia, Renal anemia, Myelophthisic anemia
• Plus: Polycythemia vera (excess RBCs)

• Vessel wall: HSP, Hereditary hemorrhagic telangiectasia, Scurvy
• Platelet disorders: ITP (chronic & acute), HIT, TTP, HUS, Glanzmann, Bernard-Soulier, drug-induced
• Coagulation: Hemophilia A & B, vWD, Vitamin K deficiency, DIC

• AML, ALL, CML, CLL
• Hodgkin & Non-Hodgkin lymphoma (with specific translocations)
• Multiple myeloma

• PV, ET, Primary myelofibrosis, MDS

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Hematology Propaedeutics - Part 2: Laboratory Investigations & Interpretation

3rd Year Clinical Introduction | Detailed Explanations Format

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INTRODUCTION - Why Lab Tests in Hematology?

Step 1 → Complete Blood Count (CBC) with indices Step 2 → Peripheral Blood Smear Step 3 → Reticulocyte Count Step 4 → Disease-specific tests (iron studies, B12/folate, coagulation panel, hemolysis markers, bone marrow, etc.)

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PART 1 - THE COMPLETE BLOOD COUNT (CBC)

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1.1 RED BLOOD CELL PARAMETERS

Reference Ranges (Goldman-Cecil Medicine)

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How the Indices Are Calculated

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1.2 THE MOST IMPORTANT INDEX: MCV (Mean Corpuscular Volume)

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A. Microcytic Anemia (MCV < 81 fL) - Defective Hemoglobin Synthesis

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B. Normocytic Anemia (MCV 81-99 fL) - Mixed Group

• Acute blood loss (most common early, before iron depletes)
• Anemia of chronic inflammation (most common normocytic)
• Aplastic anemia
• Renal failure (insufficient erythropoietin)
• Hypothyroidism
• Early iron deficiency (before microcytosis develops)
• Sickle cell anemia (homozygous - cells vary in size with polychromasia)
• Myelophthisic anemia

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C. Macrocytic Anemia (MCV > 99 fL)

• Impaired DNA synthesis → cells grow but don't divide
• Classic cause: B12 deficiency or folate deficiency
• Smear shows: macro-ovalocytes + hypersegmented neutrophils (≥5 lobes) - pathognomonic
• MCV can reach 130-140 fL in severe cases

• Alcohol (direct toxin to marrow + folate depletion) - target cells and stomatocytes on smear
• Liver disease - target cells, stomatocytes
• Hypothyroidism
• Myelodysplastic syndromes (MDS) - dysplastic features
• Reticulocytosis (reticulocytes are large - macrocytosis indicates brisk hemolysis or blood loss recovery)
• Hydroxyurea (drug effect)

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1.3 RDW (Red Cell Distribution Width)

High-yield exam point: The combination of low MCV + high RDW strongly favors iron-deficiency anemia over thalassemia trait (which has low MCV + NORMAL RDW). This distinction is tested frequently.

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1.4 WHITE BLOOD CELL (WBC) PARAMETERS

• Leukocytosis: WBC > 11,000/μL
• Leukopenia: WBC < 4,000/μL
• Neutropenia: Absolute neutrophil count (ANC) < 1,500/μL; severe < 500/μL (high infection risk)
• Lymphocytopenia: Absolute lymphocyte count < 1,500/μL
• Left shift: Increased immature neutrophils (bands, metamyelocytes) in blood - indicates severe infection or bone marrow stress
• Leukemoid reaction: WBC > 50,000/μL, predominantly mature cells, reactive (not leukemia) - distinguish from CML by LAP score (leukocyte alkaline phosphatase: HIGH in leukemoid reaction, LOW in CML) and BCR-ABL testing

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1.5 PLATELET COUNT

Important: Always confirm thrombocytopenia on a peripheral blood smear before acting. Platelet clumping (pseudothrombocytopenia) can occur with EDTA anticoagulant in some patients, giving a falsely low automated count. The smear will show clumps of platelets.

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PART 2 - RETICULOCYTE COUNT AND THE RETICULOCYTE PRODUCTION INDEX (RPI)

What Are Reticulocytes?

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Why the Raw Percentage Is Misleading

Corrected Retic = Retic % × (Patient Hematocrit ÷ 42)

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Reticulocyte Production Index (RPI)

• RPI ≥ 2-3: Marrow is responding adequately → Hyperproductive anemia → hemolysis or blood loss (the marrow is working hard to compensate)
• RPI < 2: Marrow is NOT responding adequately → Hypoproductive anemia → underproduction (iron deficiency, aplastic anemia, B12/folate deficiency, renal failure, anemia of chronic disease)

This single calculation divides all anemias into two pathophysiologic groups and determines what tests you order next.

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PART 3 - PERIPHERAL BLOOD SMEAR

Why Review the Smear?

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3.1 Normal Appearance

• RBCs: biconcave discs, uniform size, central pallor = 1/3 of cell diameter
• Platelets: small granular fragments, no nucleus, abundant
• WBCs: nucleated, visible in their mature forms

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3.2 ABNORMAL RED CELL MORPHOLOGY - The Most Tested Area

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3.3 ABNORMAL WHITE CELL MORPHOLOGY

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3.4 PLATELET ABNORMALITIES ON SMEAR

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PART 4 - IRON STUDIES

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4.1 The Iron Metabolism Pathway (Background)

1. Dietary iron is absorbed in the duodenum (predominantly Fe²⁺)
2. Transported in blood bound to transferrin (Fe³⁺) - one molecule of transferrin carries two iron atoms
3. Stored in cells as ferritin (readily available) and hemosiderin (less available, overflow storage)
4. Used by the bone marrow to synthesize heme in RBCs
5. Hepcidin (produced by the liver) controls absorption and release from stores by degrading ferroportin (the only iron exporter)

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4.2 The Four Iron Tests

A. Serum Iron

• Low: Iron-deficiency anemia, anemia of chronic inflammation
• High: Iron overload (hemochromatosis), hemolysis, iron poisoning, thalassemia (iron not being used efficiently)

Caution: Serum iron has marked diurnal variation (higher in the morning) and varies with recent dietary intake. Never interpret serum iron alone - always combine with TIBC and ferritin.

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B. Total Iron-Binding Capacity (TIBC)

• High TIBC: Iron-deficiency (liver making more transferrin to grab what little iron there is; transferrin is mostly empty)
• Low TIBC: Anemia of chronic inflammation (liver downregulates transferrin production), iron overload, chronic liver disease, malnutrition

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C. Transferrin Saturation (TSAT)

• < 15-20%: Iron-restricted erythropoiesis (iron deficiency or functional iron deficiency)
• > 50%: Iron overload (hemochromatosis), hemolysis, excess intake

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D. Serum Ferritin

• Low ferritin (< 12-15 ng/mL): Diagnostic of iron deficiency - no other condition causes truly low ferritin. A low ferritin is pathognomonic.
• Normal ferritin: Does NOT rule out iron deficiency if ferritin is 15-70 ng/mL (equivocal range)
• High ferritin: Iron overload, anemia of chronic inflammation, liver disease, hemolysis, malignancy, infection. Ferritin is an acute-phase reactant - it rises with inflammation regardless of iron stores.

The key danger: In anemia of chronic inflammation, ferritin is HIGH (despite iron being functionally unavailable) because inflammation drives ferritin production. A normal or high ferritin does NOT rule out functional iron deficiency.

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4.3 Iron Profile Pattern Recognition - The Critical Table

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PART 5 - RETICULOCYTE COUNT IN DETAIL (AND RELATED TESTS)

Bone Marrow Response Assessment

For Hemolysis Specifically - The Hemolysis Panel:

Intravascular vs. Extravascular Hemolysis:

• Intravascular (cells burst in vessels: TTP, PNH, G6PD acute episode): Free Hb in blood → hemoglobinemia (pink plasma) + hemoglobinuria (dark urine). Haptoglobin very low/undetectable.
• Extravascular (cells phagocytosed in spleen: spherocytosis, warm AIHA): No free Hb in blood. Haptoglobin moderately low. Splenomegaly. Indirect bilirubin elevated.

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Direct Antiglobulin Test (DAT) / Direct Coombs Test

• DAT Positive (IgG): Warm AIHA, drug-induced immune hemolysis, hemolytic disease of the newborn
• DAT Positive (C3d/complement): Cold AIHA, PNH (partial)
• DAT Negative: Non-immune hemolysis (hereditary spherocytosis, G6PD, mechanical, PNH - use flow cytometry instead)

The Coombs test cannot tell you WHY the antibody is there; it only confirms immune-mediated hemolysis.

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PART 6 - VITAMIN B12 AND FOLATE TESTS

Serum B12 (Cobalamin)

• < 200 pg/mL: Definite deficiency
• 200-300 pg/mL: Low-normal (borderline - check methylmalonic acid and homocysteine to confirm)
• Causes of deficiency: pernicious anemia, veganism, gastrectomy, terminal ileum disease/resection, bacterial overgrowth

Serum Folate

• < 2 ng/mL: Deficient
• Causes: poor diet (alcohol, elderly), malabsorption, increased demand (pregnancy), drugs (methotrexate, trimethoprim, phenytoin)

Distinguishing B12 from Folate Deficiency:

High-yield: Methylmalonic acid (MMA) is elevated ONLY in B12 deficiency. In folate deficiency, MMA is normal. This is the definitive biochemical distinguisher.

Schilling Test (Historical - Rarely Done Now)

Intrinsic Factor Antibodies (for Pernicious Anemia)

• Anti-intrinsic factor antibodies (Type I blocking antibodies): Highly specific for pernicious anemia (if positive = PA); present in ~50-70% of PA patients
• Anti-parietal cell antibodies: More sensitive but less specific (also found in other autoimmune diseases)

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PART 7 - COAGULATION TESTS

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7.1 Prothrombin Time (PT) and INR

INR = (Patient PT ÷ Mean Normal PT)^ISI

• Warfarin use (inhibits Vitamin K recycling → low factors II, VII, IX, X)
• Vitamin K deficiency
• Liver disease (liver makes all clotting factors - II, V, VII, IX, X, fibrinogen)
• Factor VII deficiency (rare) - PT prolonged, PTT normal (VII only in extrinsic pathway)
• DIC (consumption of all factors)

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7.2 Partial Thromboplastin Time (PTT / aPTT)

• Hemophilia A (Factor VIII deficiency) - intrinsic pathway
• Hemophilia B (Factor IX deficiency) - intrinsic pathway
• Von Willebrand disease (vWF carries Factor VIII; low vWF → low Factor VIII → prolonged aPTT)
• Heparin therapy (heparin activates antithrombin which inactivates multiple factors)
• Lupus anticoagulant (antiphospholipid antibody - paradoxically prolongs PTT in vitro but causes thrombosis in vivo)
• DIC
• Factor XII deficiency (prolonged PTT but NO bleeding - XII is not needed for hemostasis in vivo)

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7.3 The Mixing Study

• Corrects to normal: The patient is missing a clotting factor (normal plasma supplies the missing factor). The diagnosis is factor deficiency (e.g., hemophilia).
• Does NOT correct (remains prolonged): The patient has an inhibitor (an antibody against a clotting factor that also inactivates the factor in the normal plasma). Examples: acquired hemophilia (anti-Factor VIII antibody), lupus anticoagulant.

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7.4 Thrombin Time (TT)

• Hypofibrinogenemia / afibrinogenemia
• Dysfibrinogenemia (structurally abnormal fibrinogen)
• Heparin (inactivates thrombin)
• Direct thrombin inhibitors (dabigatran, argatroban)
• High fibrin degradation products (in DIC - they interfere with fibrin polymerization)

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7.5 Fibrinogen

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7.6 D-Dimer

• DIC (pathological coagulation + fibrinolysis)
• Venous thromboembolism (DVT, PE) - sensitive screening test (high sensitivity, low specificity)
• Post-surgery, trauma, infection, pregnancy, malignancy

Key clinical use: D-dimer has a high negative predictive value for DVT/PE. A normal D-dimer effectively rules out DVT/PE in low-probability patients. A high D-dimer is not diagnostic (it is elevated in many conditions) but mandates further investigation (imaging).

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7.7 Diagnostic Pattern in Bleeding Disorders

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PART 8 - HEMOGLOBIN ELECTROPHORESIS

Normal Adult Hemoglobin Composition:

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PART 9 - ERYTHROCYTE SEDIMENTATION RATE (ESR) AND C-REACTIVE PROTEIN (CRP)

ESR (Erythrocyte Sedimentation Rate)

• Men: < 10-15 mm/hr (increases with age: roughly age ÷ 2 for men)
• Women: < 20-25 mm/hr (roughly (age + 10) ÷ 2 for women)

CRP (C-Reactive Protein)

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PART 10 - BONE MARROW EXAMINATION

10.1 What It Provides

1. Aspiration (smear of aspirated marrow cells): Evaluates individual cell morphology, gives differential cell counts, shows dysplastic changes, allows flow cytometry, cytogenetics, microbiological cultures.
2. Trephine biopsy (core of intact marrow tissue): Evaluates overall marrow architecture - cellularity, focal lesions (metastases, lymphoma, granulomas), fibrosis.

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10.2 Indications for Bone Marrow Examination

• Unexplained anemia with inconclusive peripheral studies
• Unexplained thrombocytopenia or leukopenia
• Pancytopenia (to distinguish aplastic anemia from leukemia from MDS)
• Suspected leukemia or lymphoma - staging and diagnosis
• Unexplained splenomegaly
• Fever of unknown origin (can identify granulomatous infections - TB, fungal)
• Dysproteinemia (myeloma staging - quantify plasma cell percentage)
• Monitoring chemotherapy response

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10.3 Site of Procedure

• Posterior superior iliac crest (most common, safest, can do both aspiration and biopsy)
• Sternum: Aspiration only in adults (never biopsy here - risk of cardiac tamponade)
• Anterior iliac crest: Alternative if posterior access is impossible
• Anterior tibia: Used in infants < 18 months

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10.4 What the Report Tells You

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10.5 Cytogenetics and Molecular Tests from Bone Marrow

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PART 11 - SPECIAL HEMATOLOGY TESTS (HIGH-YIELD EXAM TOPICS)

Flow Cytometry (Immunophenotyping)

• CLL: CD5+ (aberrant on B cells), CD19+, CD20 (dim), CD23+ - the combination is diagnostic
• AML vs ALL: Distinguishes by myeloid markers (CD13, CD33, MPO) vs lymphoid markers (CD10, CD19, CD20 for B-ALL; CD3, CD7 for T-ALL)
• PNH: Absence of CD55 (DAF) and CD59 on RBCs and granulocytes (both are GPI-anchored)

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Osmotic Fragility Test

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Ham Test (Acidified Serum Test)

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G6PD Assay

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Hb Electrophoresis vs. HPLC

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PART 12 - THE DIAGNOSTIC ALGORITHM

CBC with differential and platelet count
        |
        ├─── Anemia? ──→ Reticulocyte count
        |                       |
        |              High RPI (>2-3)              Low RPI (<2)
        |              HYPERPRODUCTIVE               HYPOPRODUCTIVE
        |              ↓                             ↓
        |              Hemolysis panel               MCV classification
        |              (LDH, haptoglobin,            ↓
        |              bilirubin, DAT)         Microcytic → Iron studies
        |              Smear (schistocytes?)   Normocytic → Check for systemic disease, EPO
        |                                      Macrocytic → B12/folate, smear, MDS workup
        |
        ├─── Thrombocytopenia? → Smear (rule out pseudothrombocytopenia)
        |                        → PT, PTT, fibrinogen, D-dimer (rule out DIC)
        |                        → DAT, platelet antibody (immune? ITP?)
        |
        ├─── Leukocytosis/Leukopenia? → Smear (blasts? atypical lymphocytes?)
        |                               → Bone marrow if blasts present
        |
        └─── Pancytopenia? → Bone marrow biopsy (aplastic anemia vs. leukemia vs. MDS)

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QUICK REFERENCE: LAB PATTERNS FOR COMMON CONDITIONS

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1. CBC - every parameter with reference ranges, formulas, and how to interpret each number
2. MCV classification - the master framework for all anemias (microcytic / normocytic / macrocytic) with full differential lists
3. RDW - how to use it to distinguish iron deficiency from thalassemia (key exam distinction)
4. WBC differential - what each cell elevation or reduction means
5. Platelet count - thresholds and clinical significance at each level
6. Reticulocyte count and RPI - why the raw percentage misleads you, how to correct it, and how to use it to divide all anemias into hyperproductive vs. hypoproductive
7. Peripheral blood smear - every abnormal cell morphology with its specific diagnosis (the most image-rich, exam-heavy topic)
8. Iron studies - all four parameters (serum iron, TIBC, TSAT, ferritin) explained mechanistically and as a pattern recognition table
9. Hemolysis panel - LDH, haptoglobin, bilirubin, Coombs test, and how to distinguish intravascular from extravascular hemolysis
10. B12 and folate testing - including the MMA test and how to distinguish the two
11. Coagulation tests - PT/INR, aPTT, TT, fibrinogen, D-dimer with full diagnostic pattern table for every bleeding disorder
12. Bone marrow examination - indications, sites, what each finding means, and the molecular/flow cytometry tests ordered from it

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Hematology Lab Investigations - All Disorders by Lab Finding & Mechanism

Complete Reference: Every Abnormal Result → Every Disorder It Diagnoses → Its Mechanism

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HOW TO USE THIS GUIDE

"You receive a CBC showing low MCV. What disorders does this represent, and what is the mechanism of each?"

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SECTION 1 - DISORDERS BY CBC ABNORMALITY

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1.A - LOW HEMOGLOBIN / ANEMIA

GROUP 1: MICROCYTIC ANEMIA (Low Hb + Low MCV < 81 fL)

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1. Iron-Deficiency Anemia (IDA)

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2. Anemia of Chronic Inflammation (ACI) / Anemia of Chronic Disease

Key distinction from IDA: Ferritin is low in IDA, high in ACI. TIBC is high in IDA, low in ACI.

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3. β-Thalassemia

• β-thalassemia major (β⁰/β⁰): severe transfusion-dependent anemia
• β-thalassemia intermedia: moderate, transfusion-independent
• β-thalassemia minor/trait (heterozygous): mild microcytosis, often asymptomatic

The RDW difference: In β-thalassemia trait, all RBCs are uniformly small → RDW is NORMAL. In IDA, cells vary in size as iron depletion progresses → RDW is HIGH. This is the key exam question.

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4. α-Thalassemia

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5. Sideroblastic Anemia

• Inherited: X-linked sideroblastic anemia (ALAS2 gene mutation)
• Acquired (MDS with ring sideroblasts): Clonal stem cell mutation (SF3B1 in 80-90%)
• Drug-induced: Isoniazid (inhibits pyridoxine/vitamin B6, which is a cofactor for ALAS2); chloramphenicol; alcohol; lead
• Lead poisoning: Lead inhibits multiple enzymes in the heme synthesis pathway (ALA dehydratase and ferrochelatase) → ring sideroblasts + basophilic stippling on smear (from inhibition of pyrimidine 5'-nucleotidase, causing RNA to accumulate)

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6. Copper Deficiency

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GROUP 2: NORMOCYTIC ANEMIA (Low Hb + Normal MCV 81-99 fL)

The key next step: Reticulocyte Production Index (RPI)

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7. Acute Blood Loss Anemia

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8. Warm Autoimmune Hemolytic Anemia (Warm AIHA)

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9. Cold Autoimmune Hemolytic Anemia (Cold AIHA)

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10. Hemolytic Disease of the Newborn (HDN)

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11. Microangiopathic Hemolytic Anemia (MAHA) - Multiple causes

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12. Hereditary Spherocytosis (HS)

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13. G6PD Deficiency

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14. Paroxysmal Nocturnal Hemoglobinuria (PNH)

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15. Aplastic Anemia

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16. Anemia of Renal Failure

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17. Hypothyroidism

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18. Anemia of Malignancy / Myelophthisic Anemia

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19. Pure Red Cell Aplasia

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GROUP 3: MACROCYTIC ANEMIA (Low Hb + High MCV > 99 fL)

20. Vitamin B12 Deficiency - Pernicious Anemia

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21. Folate Deficiency

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22. Drug-Induced Megaloblastic Anemia (without nutrient deficiency)

• Methotrexate, trimethoprim, pyrimethamine: Directly inhibit dihydrofolate reductase (DHFR) → folate cannot be converted to its active tetrahydrofolate form → identical to folate deficiency
• Hydroxyurea: Inhibits ribonucleotide reductase → blocks deoxyribonucleotide synthesis → impairs DNA synthesis → megaloblastic changes + striking macrocytosis
• Zidovudine (AZT): Chain terminator that impairs DNA synthesis in bone marrow
• 5-Fluorouracil (5-FU): Inhibits thymidylate synthase → no thymidine

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23. Alcoholism-Related Macrocytosis

1. Direct toxicity of ethanol on bone marrow erythroid precursors → vacuolated pronormoblasts → macrocytes
2. Folate depletion from poor diet + impaired intestinal absorption + increased folate catabolism
3. Liver disease → altered lipid composition of RBC membrane → target cells, stomatocytes, macrocytes (round, not oval - non-megaloblastic)
4. Thrombocytopenia from direct marrow suppression and hypersplenism

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24. Liver Disease Macrocytosis

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25. Myelodysplastic Syndrome (MDS)

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1.B - HIGH HEMOGLOBIN / ERYTHROCYTOSIS (HIGH MCV + HIGH RBC)

26. Polycythemia Vera (PV)

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27. Secondary Polycythemia

• Chronic hypoxemia: COPD, high altitude, cyanotic heart disease, sleep apnea → kidneys sense low O2 → EPO rises → more RBCs to carry O2
• High-affinity hemoglobin variants (Hb does not release O2 to tissues → tissue hypoxia → EPO)
• Carbon monoxide poisoning (CO binds Hb, reduces O2 delivery → secondary erythrocytosis)

• Renal cell carcinoma (tumor produces EPO)
• Hepatocellular carcinoma
• Cerebellar hemangioblastoma
• Renal cysts / hydronephrosis (compression of renal tissue → local hypoxia → EPO)
• Uterine leiomyoma
• Post-renal transplant erythrocytosis

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1.C - DISORDERS CAUSING ABNORMAL WBC COUNT

HIGH WBC (Leukocytosis)

28. Reactive Neutrophilia

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29. Leukemoid Reaction

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30. Infectious Mononucleosis (EBV)

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31. Chronic Myeloid Leukemia (CML)

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32. Chronic Lymphocytic Leukemia (CLL)

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33. Acute Leukemias (AML and ALL)

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LOW WBC (Leukopenia/Neutropenia)

34. Viral Infection-Related Neutropenia

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35. Drug-Induced Agranulocytosis

1. Immune-mediated: Drug or metabolite binds to neutrophil surface as a hapten → immune complex or drug-antibody complex triggers neutrophil destruction. Examples: clozapine, carbimazole, propylthiouracil, clindamycin, NSAIDs.
2. Direct myelotoxicity: Drug directly suppresses granulocyte progenitors in marrow. Examples: chemotherapy, carbamazepine, phenothiazines.

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36. Autoimmune Neutropenia

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37. Felty's Syndrome

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1.D - DISORDERS CAUSING ABNORMAL PLATELET COUNT

LOW PLATELETS (Thrombocytopenia)

38. Immune Thrombocytopenic Purpura (ITP) - Chronic

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39. Acute ITP (Post-Viral, Children)

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40. Heparin-Induced Thrombocytopenia (HIT)

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41. Thrombotic Thrombocytopenic Purpura (TTP)

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42. Hemolytic Uremic Syndrome (HUS)

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43. Disseminated Intravascular Coagulation (DIC) - Thrombocytopenia Component

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44. Hypersplenism

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HIGH PLATELETS (Thrombocytosis)

45. Reactive / Secondary Thrombocytosis

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46. Essential Thrombocythemia (ET)

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SECTION 2 - DISORDERS BY COAGULATION TEST ABNORMALITY

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2.A - PROLONGED PT ONLY (aPTT NORMAL)

47. Factor VII Deficiency (Isolated)

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48. Early Warfarin Therapy

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2.B - PROLONGED aPTT ONLY (PT NORMAL)

49. Hemophilia A (Factor VIII Deficiency)

• Severe: <1% FVIII activity (spontaneous bleeding into joints and muscles)
• Moderate: 1-5% (bleeding with minimal trauma)
• Mild: 5-40% (bleeding only with major trauma/surgery)

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50. Hemophilia B (Factor IX Deficiency - Christmas Disease)

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51. Von Willebrand Disease (vWD)

1. Bridges platelets to subendothelial collagen (via GPIb receptor on platelets) → primary hemostasis fails without vWF → mucocutaneous bleeding
2. Carries and protects Factor VIII in plasma from proteolytic degradation → low vWF → secondarily low FVIII → aPTT may be prolonged

• Type 1: Quantitative reduction (~75% of cases), autosomal dominant, mild
• Type 2: Qualitative dysfunction of vWF (several subtypes including 2A, 2B, 2M, 2N)
  • Type 2B: Gain-of-function mutation → vWF binds platelet GPIb spontaneously → platelet-vWF aggregates cleared → mild thrombocytopenia + loss of large vWF multimers
  • Type 2N: vWF cannot bind Factor VIII → very low FVIII → mimics mild Hemophilia A (but autosomal recessive)
• Type 3: Complete absence of vWF, severe

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52. Lupus Anticoagulant (Antiphospholipid Antibody Syndrome)

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53. Factor XII (Hageman Factor) Deficiency

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2.C - PROLONGED PT AND aPTT

54. Vitamin K Deficiency

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55. Liver Disease

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56. Disseminated Intravascular Coagulation (DIC) - Full Profile

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57. Acquired Hemophilia (Acquired Factor VIII Inhibitor)

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SECTION 3 - DISORDERS BY IRON STUDIES ABNORMALITY

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3.A - LOW SERUM IRON + HIGH TIBC + LOW FERRITIN

= Iron-Deficiency Anemia (most common worldwide anemia)

Remember: Low ferritin is the most sensitive and specific indicator of iron deficiency. No other condition causes truly low ferritin.

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3.B - LOW SERUM IRON + LOW TIBC + HIGH FERRITIN

= Anemia of Chronic Inflammation (ACI)

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3.C - HIGH SERUM IRON + HIGH FERRITIN + HIGH TSAT (>60%) + LOW TIBC

= Iron Overload / Hemochromatosis

58. Hereditary Hemochromatosis (HH)

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59. Transfusional Iron Overload (Secondary Hemochromatosis)

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3.D - HIGH SERUM IRON + HIGH FERRITIN + RING SIDEROBLASTS ON MARROW

= Sideroblastic Anemia

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SECTION 4 - DISORDERS BY HEMOLYSIS PANEL ABNORMALITY

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4.A - ELEVATED LDH + LOW HAPTOGLOBIN + ELEVATED INDIRECT BILIRUBIN + ELEVATED RETICULOCYTES

= Hemolysis (any cause)

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4.B - ELEVATED INDIRECT BILIRUBIN ONLY (Normal LDH, Normal Haptoglobin)

60. Gilbert's Syndrome

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SECTION 5 - DISORDERS BY PERIPHERAL BLOOD SMEAR FINDING

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61. Spherocytes - Mechanism

• Hereditary spherocytosis: Defective cytoskeletal proteins (spectrin/ankyrin) → membrane vesiculation → progressive membrane loss
• AIHA (warm): IgG-coated RBCs → splenic macrophages partially phagocytose membrane → spherocyte residue

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62. Schistocytes (Helmet Cells) - Mechanism

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63. Sickle Cells - Mechanism

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64. Target Cells (Codocytes) - Mechanism

• Less hemoglobin per cell (IDA, thalassemia)
• More cholesterol in cell membrane (liver disease)
• HbC disease (HbC crystalizes → membrane reorganizes)

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65. Teardrop Cells (Dacrocytes) - Mechanism

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66. Basophilic Stippling - Mechanism

• Lead poisoning inhibits pyrimidine 5'-nucleotidase → RNA not degraded → aggregates as stippling
• Thalassemia (ribosomal RNA accumulates in cells producing excess globin)

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67. Howell-Jolly Bodies - Mechanism

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68. Rouleaux - Mechanism

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69. Hypersegmented Neutrophils - Mechanism

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70. Auer Rods - Mechanism

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71. Smudge Cells - Mechanism

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SECTION 6 - DISORDERS BY ESR/CRP ABNORMALITY

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6.A - VERY HIGH ESR (>100 mm/hr)

72. Multiple Myeloma

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73. Waldenström's Macroglobulinemia

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6.B - LOW ESR

74. Polycythemia Vera (PV)

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MASTER DIAGNOSTIC TABLE: LAB FINDING → DISORDER → MECHANISM

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• Microcytic anemias (6 disorders): IDA, anemia of chronic inflammation, β and α thalassemia, sideroblastic anemia, copper deficiency
• Normocytic anemias - high RPI group (hemolytic): acute blood loss, warm AIHA, cold AIHA, hemolytic disease of newborn, all 6 causes of MAHA (TTP, HUS, DIC, HELLP, malignant hypertension, prosthetic valve), HS, G6PD, PNH
• Normocytic anemias - low RPI group (underproductive): aplastic anemia, renal anemia, hypothyroidism, myelophthisic anemia, pure red cell aplasia
• Macrocytic anemias (6 disorders): B12 deficiency, folate deficiency, drug-induced megaloblastosis, alcohol, liver disease, MDS
• High Hb/erythrocytosis: polycythemia vera, all causes of secondary polycythemia
• WBC disorders: reactive neutrophilia, leukemoid reaction, EBV mononucleosis, CML, CLL, AML, ALL, viral neutropenia, drug-induced agranulocytosis, autoimmune neutropenia, Felty syndrome
• Platelet disorders: ITP, acute ITP, HIT, TTP, HUS, DIC, hypersplenism, reactive thrombocytosis, essential thrombocythemia