---

Complete Exam Answer Guide - Blood Disorders

---

1. Classification of Anemia (Causes)

• Excessive loss - bleeding
• Destruction - hemolysis
• Deficient production - nutritional deficiency or bone marrow failure

---

2. Lab Values You Must Know

• Low MCV = microcytic cells (e.g., iron deficiency, thalassemia)
• High MCV = macrocytic cells (e.g., megaloblastic anemia)
• Low MCHC = hypochromic (pale cells, less Hgb per cell - iron deficiency)
• Normal MCHC + high MCV = megaloblastic (big but not over-filled with Hgb)

• Decreases with: anemia, blood loss, hemodilution
• Increases with: polycythemia, dehydration
• Clinical significance: measures the proportion of blood volume occupied by RBCs; a low Hct directly reflects reduced oxygen-carrying capacity

---

3. Iron Deficiency Anemia - Pathogenesis & Lab Findings

• Dietary deficiency
• Loss of iron through bleeding (GI bleeding, menstruation)
• Increased demands (toddlers, adolescents, pregnant women)

• Low Hgb / Hct
• Decreased serum iron and ferritin (stored iron)
• Decreased MCHC and MCV (microcytic, hypochromic)
• Poikilocytosis (irregular shapes) and anisocytosis (unequal sizes)

• Pallor, fatigue, dyspnea, tachycardia
• Brittle hair/nails, spoon-shaped nails (koilonychia)
• Smooth tongue, cheilosis (mouth corner sores)
• Dysphagia, pica, decreased acid secretion
• In infants: poor cognitive, motor, and emotional development

---

4. Megaloblastic Anemia - Why Do Cells Become Large?

• Immature nuclei
• Flimsy membranes
• Oval shape
• Very short life span (weeks instead of 120 days)

• B12 is a cofactor for DNA synthesis AND nuclear maturation
• Also prevents abnormal fatty acid incorporation into neuronal lipids - deficiency predisposes to myelin breakdown, explaining the neurological symptoms
• Cause: dietary deficiency (rare) OR pernicious anemia (immunological destruction of gastric mucosa, blocking B12 binding to intrinsic factor)
• Clinical: anemia + glossitis + neurological signs (paresthesias, loss of vibratory sense, spastic ataxia, dementia)
• Labs: low serum B12, increased MCV, normal MCHC

• Folic acid required for DNA synthesis and RBC maturation
• Causes: malnutrition (elderly, alcoholism), malabsorption (celiac disease), drugs (methotrexate, anticonvulsants, triamterene), pregnancy (demand increases 5-10 fold - linked to neural tube defects)
• No neurological symptoms (unlike B12 deficiency)

---

5. Anemia of Chronic Disease (= Anemia of Chronic Inflammation)

1. Blocks iron release from macrophages/reticuloendothelial cells
2. Reduces iron absorption from the gut
3. Traps iron in storage, making it unavailable for RBC production

• Shortened RBC lifespan
• Blunted response to erythropoietin
• Low serum iron (iron sequestered by RES)

---

6. Hereditary Spherocytosis

• Spherocytes are rigid and cannot deform to squeeze through the splenic sinusoids
• The spleen traps and destroys them (extravascular hemolysis)
• Result: shortened RBC lifespan, chronic hemolytic anemia
• The spleen enlarges (splenomegaly) from the increased workload
• Increased bilirubin from RBC breakdown causes jaundice and pigment gallstones
• Bone marrow compensates with increased erythropoiesis (increased reticulocyte count)

---

7. Blood Loss Anemia - Acute vs. Chronic

• Causes circulatory shock and collapse
• Loss of intravascular volume is the immediate threat
• Fall in RBC count, Hct, Hgb is caused by hemodilution (plasma volume maintained, cells diluted)
• Cell type: normocytic, normochromic (cells are normal in size and color - just fewer of them)

• Causes: GI bleeding, menstrual disorders
• Asymptomatic until Hgb falls below 8 g/dL
• The body slowly depletes iron stores trying to keep up with ongoing losses
• Eventually iron deficiency develops
• Cell type: microcytic, hypochromic (small, pale cells due to iron depletion)

---

8. Sickle Cell Anemia

• Inherited disorder with abnormal hemoglobin S (HbS) - recessive inheritance
• Sickle cell trait = heterozygote (1 HbS gene); Sickle cell disease = homozygote (2 HbS genes)
• Under low oxygen conditions, HbS polymerizes into rigid rods, distorting the RBC into a sickle shape

1. Chronic hemolytic anemia
2. Blood vessel occlusion (vaso-occlusion)
3. Susceptibility to infection (functional asplenia)

• Sickled cells are rigid and sticky
• They block small blood vessels
• Blockage causes tissue hypoxia (ischemia)
• Pain occurs in abdomen, chest, bones, and joints
• Chronic vascular damage affects liver, spleen, heart, kidneys, retina

• Atypical pneumonia due to pulmonary infarction (blocked vessels in the lung)
• This is the most serious complication causing chest pain specifically

---

9. Hemolytic Anemia

• Intrinsic - hereditary defects in the RBC itself (e.g., hereditary spherocytosis, sickle cell, G6PD)
• Extrinsic - immune mechanisms, mechanical trauma, infections

• Intravascular - RBCs destroyed inside blood vessels (mechanical injury, transfusion reactions, toxins) → hemoglobinemia, hemoglobinuria, hemosiderinuria
• Extravascular - abnormal RBC shapes trigger phagocytosis by spleen and liver → jaundice and pigment gallstones

• Warm-reacting antibodies (IgG, 37°C) → spherocytosis, splenic destruction
• Cold-reacting antibodies (IgM, 4°C) → agglutination, complement activation, Raynaud's
• Diagnosis: Coombs test

---

10. Aplastic Anemia

• High-dose radiation
• Chemicals and toxins
• Viral complications (hepatitis, mononucleosis, AIDS)
• Idiopathic

---

11. Thrombocytopenia - Causes & Mechanisms

1. Impaired (decreased) platelet production

• Bone marrow biopsy shows: lack of megakaryocytes (the platelet-producing cells are gone)
• Causes:
  • Aplastic anemia (stem cell failure) - pancytopenia
  • Bone marrow depression (radiation, chemotherapy)
  • Chronic alcoholism
  • Drugs (thiazide diuretics, gold, phenylbutazone, certain antibiotics)
  • Dietary deficiencies (folate, B12 - needed for DNA synthesis)
  • Bone marrow infiltration by malignant cells (leukemia, cancer)
  • Viral infections (EBV, HIV)

2. Increased destruction of platelets

• Bone marrow biopsy shows: normal megakaryocytes (they are producing platelets, but platelets are being destroyed)
• Most common type
• ITP (Immune Thrombocytopenic Purpura):
  • Autoimmune disorder
  • Antibodies target the platelet GPIIb/IIIa membrane complex
  • Platelet-antibody complexes phagocytosed and destroyed by macrophages in the spleen
  • Acute ITP: children, follows viral illness, complete remission
  • Chronic ITP: adults (women 20-50), remissions and exacerbations
• Drug-induced: Drugs act as haptens forming immune complexes that destroy platelets via complement. Over 1500 drugs implicated; most common = heparin, antimalarials, sulfa antibiotics
• HIT (Heparin-Induced Thrombocytopenia): Antibodies to heparin:PF4 complex activate platelets causing aggregation and thrombosis (paradoxically causes clotting, not just bleeding)

3. Splenic sequestration

• Splenomegaly causes hypersplenism
• Enlarged spleen traps excessive numbers of platelets (and other blood cells)
• Also causes anemia and leukopenia

---

12. Primary vs. Secondary Hemostasis

---

13. How Bleeding Disorders Manifest on the Skin

• Petechiae - flat, pinpoint, non-blanching red/purple spots; almost exclusively seen in platelet deficiency
• Purpura - petechiae occurring in groups or patches; often itchy
• Ecchymosis (bruises) - blood escaping into tissue; typical of coagulation (clotting factor) disorders
• Hematoma - collection of blood trapped in soft tissue; typical of coagulation disorders

---

14. How Platelets Are Activated

1. Vessel injury exposes subendothelial collagen
2. von Willebrand factor (vWF) - produced by endothelial cells and megakaryocytes - bridges the collagen to platelet GPIb receptors (adhesion)
3. Platelet activation triggers the cyclooxygenase (COX) pathway, producing Thromboxane A2 (TXA2) inside platelets
4. TXA2 induces platelet aggregation and vasoconstriction
5. The opposing force is Prostacyclin (produced by endothelial cells) - inhibits platelet aggregation and causes vasodilation
6. Activated platelets change shape and release granules, recruiting more platelets (secondary aggregation)

---

15. Types of Bilirubin / Jaundice

• Premature destruction of RBCs releases excess bilirubin (hyperbilirubinemia)
• The PPT specifically lists: premature destruction of RBC → hyperbilirubinemia, jaundice, pigment gallstones

---

16. Von Willebrand Factor (vWF) - Which Cell Produces It?

• vWF is produced by endothelial cells (also stored in platelet alpha-granules/megakaryocytes)
• vWF circulates in plasma complexed with Factor VIII
• Function: mediates platelet adhesion to damaged subendothelium; carries and protects Factor VIII

---

17. Erythropoietin - Function

• Produced by the kidney in response to decreased O2 levels (hypoxia)
• Stimulates bone marrow to increase RBC production
• In chronic kidney disease: kidney damage reduces erythropoietin production → blunted bone marrow response → anemia
• Treatment: short-term erythropoietin therapy (e.g., EPO injections)

---

---

Predicted Exam Questions + Model Answers

Thinking like your Patho professor

---

SECTION 1: RED BLOOD CELLS & ANEMIA

---

1. Excessive loss - acute GI bleeding
2. Destruction (hemolysis) - hereditary spherocytosis, sickle cell disease
3. Deficient production - iron deficiency, aplastic anemia, megaloblastic anemia

---

• Pallor - anemia causes redistribution of blood away from cutaneous tissues (skin, mucous membranes, nail beds, conjunctiva) to vital organs
• Fatigue and weakness - reduced hemoglobin means less oxygen delivery to tissues (tissue hypoxia)
• Tachycardia and palpitations - the heart compensates for low oxygen delivery by increasing cardiac output (beating faster to circulate whatever Hgb is present more rapidly)

---

---

---

---

• Macrophages cannot release stored iron back into circulation
• Intestinal cells cannot absorb dietary iron
• Iron becomes trapped, unavailable for RBC production

---

• Erythropoietin (EPO) is a glycoprotein hormone
• Made by peritubular cells of the kidney (interstitial cells)
• Stimulus: decreased O2 levels (hypoxia) detected by the kidney
• Function: travels to bone marrow and stimulates stem cells to increase RBC production
• In chronic kidney disease: damaged kidney tissue produces less EPO → blunted bone marrow response → normocytic, normochromic anemia with low reticulocyte count
• This is the reason anemia of chronic kidney disease is treated with EPO injections (erythropoietin therapy)

---

---

---

---

---

SECTION 2: HEREDITARY SPHEROCYTOSIS & HEMOLYTIC ANEMIAS

---

1. Defective spectrin/ankyrin causes the membrane to be unstable
2. The RBC loses membrane fragments over time
3. Without enough membrane, the cell rounds up into a sphere (spherocyte) - it cannot maintain the biconcave shape
4. Spherocytes are rigid - they cannot deform to squeeze through the narrow slits of the splenic sinusoids
5. The spleen traps and destroys them (extravascular hemolysis)
6. Result: shortened RBC lifespan, chronic hemolytic anemia, splenomegaly, jaundice

---

• Cause: mechanical injury (defective heart valves, turbulent flow), transfusion reactions, toxins
• Hgb spills directly into blood → hemoglobinemia, hemoglobinuria (red/brown urine), hemosiderinuria

• Cause: any condition that alters RBC shape (spherocytosis, sickle cell, antibody-coated cells)
• Produces jaundice and pigment gallstones (bilirubin accumulates)
• Splenomegaly from overwork

---

SECTION 3: SICKLE CELL ANEMIA

---

• Rigid (cannot deform)
• Sticky (adheres to vessel walls)
• Fragile (short lifespan of 10-20 days instead of 120)

---

---

SECTION 4: BLEEDING DISORDERS & PLATELETS

---

• Decreased production: Bone marrow biopsy shows absence or reduction of megakaryocytes - the cells that produce platelets are not present, so platelets cannot be made. Causes include aplastic anemia, chemotherapy, radiation, viral infections, folate/B12 deficiency.
• Increased destruction: Bone marrow biopsy shows normal or increased megakaryocytes - the marrow is producing platelets normally and even compensating, but platelets are being destroyed peripherally faster than they are made. Causes include ITP, drug-induced thrombocytopenia, HIT, TTP.

---

1. Autoimmune - the body produces antibodies against the platelet surface protein GPIIb/IIIa
2. Antibody-coated platelets are recognized by macrophages in the spleen
3. Macrophages phagocytose and destroy the platelet-antibody complexes
4. Platelet count falls → mucocutaneous bleeding (petechiae, purpura, epistaxis, menorrhagia)

---

• Bleeding side effect: Without TXA2, platelets cannot aggregate normally → primary hemostasis impaired → bleeding tendency. The effect lasts the entire platelet lifespan (8-9 days) because platelets have no nucleus and cannot synthesize new COX.
• Cardiovascular benefit: Reducing platelet aggregation prevents pathological clots from forming in already-narrowed coronary arteries → reduces risk of MI and stroke.

---

• vWF is a large glycoprotein produced by endothelial cells (and stored in platelet alpha-granules/megakaryocytes)
• It circulates in plasma complexed with Factor VIII, protecting it from degradation
• In vessel injury, vWF acts as a bridge: it binds exposed subendothelial collagen on one end and platelet surface receptors (GPIb) on the other, anchoring platelets to the wound site

• vWF and Factor VIII levels are decreased or absent
• Platelet adhesion fails (primary hemostasis defect)
• Factor VIII is also low (since vWF normally carries it), so secondary hemostasis is also partially impaired
• Result: bleeding that manifests as epistaxis, easy bruising, GI bleeding, menorrhagia
• Hemarthrosis is rare (distinguishes it from hemophilia)

---

---

• Abnormally large vWF multimers accumulate in the blood
• These large multimers spontaneously bind and activate platelets without any vessel injury
• Large platelet-rich thrombi form in the small blood vessels throughout the body (heart, kidney, brain)
• Platelets are consumed in forming all these thrombi → thrombocytopenia
• RBCs physically fragment as they try to pass through clot-obstructed vessels → microangiopathic hemolytic anemia

---

1. Chronic kidney disease damages the peritubular interstitial cells of the kidney
2. These cells are the primary producers of erythropoietin (EPO)
3. With fewer functional kidney cells, EPO production is reduced
4. Low EPO means the bone marrow receives an inadequate stimulus to produce RBCs
5. RBC production falls → normocytic, normochromic anemia with low reticulocyte count
6. Simultaneously, the chronic inflammatory state raises hepcidin → iron sequestration → low serum iron available for any RBC production that does occur
7. Treatment: EPO injections restore the missing hormonal signal to the bone marrow; iron supplementation addresses the hepcidin-mediated iron block

---

---

---

Q1: Difference Between Primary and Secondary Hemostasis

---

PRIMARY HEMOSTASIS - The Platelet Plug

1. Vessel injury exposes subendothelial collagen
2. von Willebrand factor (vWF) - produced by endothelial cells - acts as a bridge between the collagen and platelet surface receptors (GPIb)
3. Platelets adhere to the injury site
4. Platelets become activated - they change shape, release granules, and produce Thromboxane A2 via the COX pathway
5. More platelets are recruited and aggregate together
6. A soft, temporary platelet plug forms - this is primary hemostasis

• Platelet disorders or von Willebrand disease
• Bleeding is mucocutaneous - skin and mucous membranes
• Manifests as petechiae, purpura, epistaxis (nosebleeds), menorrhagia, GI bleeding
• Petechiae are almost exclusively seen in platelet deficiency

---

SECONDARY HEMOSTASIS - The Fibrin Clot

1. The coagulation cascade is activated (intrinsic and extrinsic pathways)
2. A series of clotting factors activate each other in sequence
3. The final result: fibrinogen is converted to fibrin
4. Fibrin threads weave through and around the platelet plug, creating a hard, stable clot

• Coagulation factor defects (e.g., Hemophilia A = Factor VIII deficiency, Hemophilia B = Factor IX deficiency)
• Bleeding is deep tissue - muscles, joints, soft tissue
• Manifests as ecchymosis (bruises), hematomas, hemarthrosis (bleeding into joints), prolonged GI/urinary tract bleeding, intracranial bleeds

---

Side-by-Side Comparison

---

---

Q2: Chronic Inflammation → Kidney → Which Hormone? What Does It Do?

---

The Hormone: Erythropoietin (EPO)

---

How Chronic Inflammation Affects It

• The cells responsible for producing EPO are lost or dysfunctional
• EPO production drops
• The bone marrow does not receive the signal to make RBCs
• Result: normocytic, normochromic anemia with a low reticulocyte count

---

Function of Erythropoietin (exactly what she wants)

1. Stimulates bone marrow stem cells to proliferate and differentiate into red blood cell precursors
2. Increases the rate of RBC production - more reticulocytes are released into blood
3. Speeds up maturation of RBC precursors in the bone marrow
4. Acts as the body's oxygen sensor feedback loop - low O2 → kidney makes EPO → more RBCs → more O2 carried → EPO production decreases

---

Clinical Consequence + Treatment

• Chronic kidney disease = low EPO = low RBC production = anemia
• Treatment: exogenous EPO injections (e.g., epoetin alfa) to replace the missing hormone signal
• Also: iron supplementation and blood transfusions as needed

---

---

COMPLETE NOTES: RED BLOOD CELLS & BLOOD DISORDERS

Compiled from all PPTs and PDFs

---

PART 1: NORMAL RBC - STRUCTURE & LIFE CYCLE

What is a Normal RBC?

• Biconcave disc shape - this increases the surface area for oxygen diffusion (more surface area = more efficient gas exchange)
• Normocytic - average diameter is 7-8 micrometres
• Normochromic - normal pinkish color with a central pale area that takes up 1/3 of the cell's diameter
• Has a complex cytoskeleton made of proteins called spectrin and ankyrin - these give the cell its flexible shape and allow it to squeeze through tiny capillaries

What is inside an RBC?

• Hemoglobin - made of 2 polypeptide chains, each with a globin protein and a heme group
• Heme surrounds an iron atom - this iron is what actually carries oxygen
• One Hgb molecule carries 4 oxygen molecules (one per iron atom)

RBC Life Cycle

1. Stem cells in the bone marrow develop into reticulocytes
2. Reticulocytes are released into blood where they mature into full erythrocytes in 24-48 hours
3. RBCs live for approximately 120 days
4. After 120 days, old RBCs are destroyed in the spleen, liver, and bone marrow
5. The heme portion breaks down into bilirubin → liver picks it up → conjugates it → excretes in bile

What controls RBC production?

---

PART 2: LABORATORY TESTS - THE FULL BLOOD COUNT (FBC/CBC)

How to Use MCV to Classify Anemia:

• MCV < 80 fL = Microcytic (small cells) → think: Iron deficiency, thalassemia, chronic disease
• MCV 80-100 fL = Normocytic (normal cells) → think: Acute blood loss, hemolysis, chronic disease
• MCV > 100 fL = Macrocytic (large cells) → think: B12 deficiency, folate deficiency, alcohol

How to Use MCHC to Classify Color:

• Low MCHC = Hypochromic (pale cells, less Hgb per cell) → Iron deficiency
• Normal MCHC = Normochromic → Most anemias
• High MCHC = Hyperchromic → Spherocytosis (cells appear darker, no central pallor)

The Reticulocyte Count - Why It Matters:

• Normal = 0.5-2% of RBCs
• Raised reticulocyte count (>3%) = marrow is responding properly → means RBCs are being destroyed/lost in the periphery (hemolysis, blood loss)
• Low reticulocyte count (<3%) = marrow is NOT responding = the problem is in the marrow (underproduction)

---

PART 3: RBC MORPHOLOGY ABNORMALITIES

Variations in SIZE (Anisocytosis)

• Microcytes (MCV <80 fL) - small cells → iron deficiency, thalassemia
• Macrocytes (MCV >100 fL) - large cells → megaloblastic anemia, alcohol
• Normocytes (MCV 80-100 fL) - normal

Variations in SHAPE (Poikilocytosis)

Variations in COLOR

• Hypochromic - pale cell, enlarged central pallor → iron deficiency, thalassemia (low Hgb inside)
• Hyperchromic - dark cell, no central pallor → spherocytes (too much Hgb per surface area)
• Polychromatic (Polychromic) - grayish-blue color → immature RBCs (reticulocytes) still have RNA → seen in hemolysis, blood loss, treatment response

Variations in CONTENT (Inclusions)

---

PART 4: ANEMIA - DETAILED NOTES ON EACH TYPE

Definition of Anemia

• Hb < 13.5 g/dL in males
• Hb < 12.5 g/dL in females

General Manifestations of Anemia

• Pallor - blood redistributed away from skin, mucous membranes, conjunctiva, nail beds
• Fatigue and weakness - tissue hypoxia
• Dyspnea - body tries to get more O2 by breathing faster
• Tachycardia and palpitations - heart compensates by pumping faster
• Headache and light-headedness - brain hypoxia
• Angina - especially if there is pre-existing coronary artery disease

---

A. MICROCYTIC ANEMIAS (MCV < 80 fL)

---

1. IRON DEFICIENCY ANEMIA

• Dietary deficiency (inadequate iron intake)
• Blood loss - most common: GI bleeding (ulcers, cancer), menstrual disorders
• Increased demand - toddlers, adolescents, pregnant women, women of childbearing age

• Low Hgb and Hct
• Low serum iron (not enough iron in blood)
• Low ferritin (depleted iron stores - this is the earliest sign)
• Decreased MCHC and MCV
• Poikilocytosis (varied shapes) and anisocytosis (varied sizes) on smear
• Pencil cells, target cells on smear

• Pallor, fatigue, dyspnea, tachycardia (from anemia)
• Koilonychia - spoon-shaped nails (concave nails)
• Brittle hair and nails
• Glossitis - smooth, beefy red tongue
• Cheilosis - cracks/sores at corners of the mouth
• Dysphagia (difficulty swallowing)
• Pica - craving for non-food items (ice, dirt, clay)
• Decreased stomach acid secretion
• In infants: poor cognitive, motor, and emotional development

---

2. ANEMIA OF CHRONIC DISEASE (ACD)

• Cytokines shorten RBC lifespan
• Cytokines blunt the bone marrow's response to EPO
• EPO production may be reduced (especially if kidneys are affected)
• The goal of trapping iron is actually to starve bacteria of iron (bacteria need iron to survive) - it's an immune defense mechanism that unfortunately also starves RBC production

• Low serum iron (iron is sequestered)
• High or normal ferritin (iron stores are FULL - iron is trapped there, not released) ← key difference from iron deficiency
• Decreased TIBC (total iron binding capacity - less transferrin made)
• Normocytic, normochromic usually; can be mildly microcytic
• Low reticulocyte count

---

3. SIDEROBLASTIC ANEMIA (mentioned in PPT 1)

---

4. THALASSEMIA

Beta-Thalassemia

• AKA Cooley's or Mediterranean anemia
• Found in: Greek, southern Italian, African, and African-American populations
• Caused by a point mutation in the beta-globin gene
• Thalassemia minor (heterozygous - 1 normal gene, 1 mutant) - mild/no symptoms
• Thalassemia major (homozygous - 2 mutant genes) - severe
• Pathophysiology: Inadequate HbA formation → hemolysis of abnormal RBCs → compensatory increase in EPO → bone marrow hyperplasia trying to compensate
• Clinical manifestations (major):
  • "Chipmunk facies" - expansion of facial bones from marrow hyperplasia
  • Bone growth impairment, osteoporosis/osteopenia, fractures
  • Splenomegaly and hepatomegaly (from excess RBC destruction)
  • Iron accumulation in heart, liver, endocrine organs (from chronic transfusions)
• Treatment: Regular blood transfusions (major); stem cell transplant

Alpha-Thalassemia

• Most common in Asians (also Africans)
• Caused by gene deletion of alpha-globin genes (4 total genes)

---

B. MACROCYTIC ANEMIA (MCV > 100 fL)

5. MEGALOBLASTIC ANEMIA

---

B12 (Cobalamin) Deficiency

• Folate circulates as methyltetrahydrofolate (methyl-THF)
• B12 accepts the methyl group from methyl-THF, freeing THF to participate in DNA synthesis
• Without B12, folate stays "trapped" as methyl-THF and cannot help make DNA precursors
• B12 also has a SECOND function: it is a cofactor preventing abnormal fatty acids from entering neuronal cell membranes. Without it, myelin breaks down → neurological symptoms

• Dietary deficiency - rare; B12 is found in all animal products
• Pernicious anemia - most important cause: autoimmune destruction of gastric parietal cells → loss of intrinsic factor (IF) → B12 cannot be absorbed in the terminal ileum (IF is the escort that carries B12 to its absorption site)

• Moderate-severe anemia
• Mild jaundice (from RBC destruction)
• Glossitis (smooth, red tongue)
• Anorexia, diarrhea
• Neurological signs (not seen in folate deficiency):
  • Symmetric paresthesias of feet and fingers
  • Loss of vibratory sense and position sense
  • Spastic ataxia
  • Dementia, neuropsychiatric changes

• Abnormally low serum B12
• Increased MCV, normal MCHC
• Parietal cell antibodies and intrinsic factor antibodies (in pernicious anemia)

---

Folate Deficiency

• Malnutrition (common in elderly and alcoholics)
• Malabsorption (celiac disease, other GI disorders)
• Drugs that block folate metabolism: methotrexate (cancer/immunosuppression), anticonvulsants, triamterene (diuretic)
• Pregnancy - demand increases 5-10 fold (critical link to neural tube defects if deficient)

---

C. NORMOCYTIC ANEMIAS (MCV 80-100 fL)

6. BLOOD LOSS ANEMIA

Acute Blood Loss

• Rapid hemorrhage → circulatory shock and collapse
• Immediate problem is loss of intravascular volume, not RBC count
• The fall in RBC count, Hct, and Hgb is initially from hemodilution (plasma volume is maintained while cells are diluted)
• Blood smear: normocytic, normochromic (the cells that remain are normal - there are just fewer of them)

Chronic Blood Loss

• Causes: slow GI bleeding, menstrual disorders
• Patient is asymptomatic until Hgb falls below 8 g/dL
• Over time, iron stores become depleted trying to replace lost RBCs
• Eventually becomes microcytic, hypochromic (iron deficiency develops)

---

7. HEMOLYTIC ANEMIAS

• High reticulocyte count (marrow trying to compensate)
• Elevated bilirubin (from Hgb breakdown) → jaundice
• Splenomegaly
• Pigment gallstones

---

Hereditary Spherocytosis

• Genetic defect in RBC membrane proteins: spectrin or ankyrin
• Defective membrane cannot maintain the biconcave shape
• RBC loses membrane fragments over time → becomes spherical (spherocyte)
• Spherocytes are rigid - cannot deform to squeeze through splenic sinusoids
• Spleen traps and destroys them (extravascular hemolysis)
• Result: chronic hemolytic anemia, splenomegaly, jaundice, pigment gallstones

---

Sickle Cell Anemia

• Single point mutation: glutamate → valine at position 6 of beta-globin chain
• Produces hemoglobin S (HbS)
• Under low O2, HbS polymerizes into rigid rods → cell deforms into sickle shape

• Autosomal recessive
• Sickle cell trait (heterozygote - 1 HbS gene) - usually asymptomatic
• Sickle cell disease (homozygote - 2 HbS genes) - full disease

1. Chronic hemolytic anemia - sickled cells are fragile, lifespan 10-20 days
2. Vaso-occlusion - sickled cells are rigid and sticky, block small vessels
3. Susceptibility to infection - repeated splenic infarctions → functional asplenia → no defense against encapsulated bacteria (S. pneumoniae, H. influenzae)

• Vaso-occlusive pain crisis - tissue hypoxia in abdomen, chest, bones, joints
• Acute chest syndrome - pulmonary infarction → atypical pneumonia-like picture with chest pain, fever, respiratory distress (most dangerous complication)
• Chronic damage to liver, spleen, heart, kidneys, retina

---

Acquired Hemolytic Anemia (Immunohemolytic)

• IgG antibodies react with RBC membrane antigens
• Cause spherocytosis (membrane damage) → phagocytic destruction in spleen and reticuloendothelial system

• IgM binds RBCs → agglutination + complement activation
• Symptoms from vascular obstruction in cold-exposed areas: ears, fingers, toes (Raynaud's phenomenon)

---

Intravascular vs Extravascular Hemolysis

---

8. APLASTIC ANEMIA

• High-dose radiation
• Chemicals and toxins suppressing hematopoiesis
• Viral hepatitis, mononucleosis, AIDS
• Idiopathic

• Low RBCs → weakness, fatigue, pallor
• Low platelets → petechiae, ecchymoses, bleeding from nose/gums/vagina/GI tract
• Low WBCs → infections

---

PART 5: BLEEDING DISORDERS - HEMOSTASIS

Normal Hemostasis

Primary Hemostasis = Platelet Plug

Secondary Hemostasis = Fibrin Clot (Coagulation Cascade)

Primary vs Secondary Hemostasis - Side by Side

---

Skin Signs of Bleeding Disorders

• Petechiae - flat, pinpoint (<2mm), non-blanching red/purple spots; almost exclusively in platelet disorders
• Purpura - petechiae in groups or patches; often itchy
• Ecchymosis (bruise) - blood escaping into skin tissue; typical of coagulation (clotting factor) disorders
• Hematoma - collection of blood trapped in soft tissue; typical of coagulation disorders
• Hemarthrosis - bleeding into joints (knees, ankles, elbows); hallmark of hemophilia

---

Thrombocytopenia

Three Mechanisms:

1. Decreased Production

• Bone marrow biopsy: absence of megakaryocytes
• Causes: aplastic anemia, radiation/chemotherapy, chronic alcoholism, drugs (thiazide diuretics, gold, some antibiotics), folate/B12 deficiency (DNA synthesis impaired), bone marrow infiltration (leukemia, cancer), viral infections (EBV, HIV)

2. Increased Destruction

• Bone marrow biopsy: normal or increased megakaryocytes (making platelets fine, but they are destroyed peripherally)

• Autoimmune - antibodies against platelet GPIIb/IIIa surface complex
• Platelet-antibody complexes destroyed by macrophages in the spleen
• Acute ITP: children under 6, follows viral illness by ~2 weeks, complete remission
• Chronic ITP: adults (women aged 20-50), remissions and exacerbations

• Over 1500 medications can cause it
• Drugs act as haptens → form immune complexes → complement-mediated platelet destruction
• Platelet count falls 7+ days after starting a drug (time needed to mount immune response)
• Platelet count rises rapidly after stopping the drug
• Most common: heparin, antimalarial drugs, sulfa antibiotics

• Most common drug-induced cause
• Paradox: causes thrombocytopenia BUT increased risk of thrombosis (not just bleeding)
• Mechanism: antibodies against heparin:PF4 complex → antibodies activate platelets → platelet aggregation → clot formation in arteries and veins
• DVT and pulmonary embolus are common; arterial thrombosis causes limb ischemia, MI, stroke

• Rare but serious
• Deficiency of ADAMTS13 enzyme (inherited or acquired antibodies against it)
• ADAMTS13 normally cleaves large vWF multimers into smaller pieces
• Without it → abnormally large vWF multimers accumulate → spontaneous platelet aggregation in small vessels throughout body → platelets consumed (thrombocytopenia) → RBCs physically fragment passing through clot-obstructed vessels (schistocytes on smear - microangiopathic hemolytic anemia)

1. Thrombocytopenia
2. Hemolytic anemia
3. Thrombotic vascular occlusions
4. Fever
5. Neurological abnormalities (hallucinations, bizarre behavior, seizures)

3. Splenic Sequestration

• Splenomegaly → hypersplenism (overactive spleen)
• Enlarged spleen traps excessive RBCs, platelets, and WBCs
• Causes anemia + thrombocytopenia + leukopenia

---

Platelet Function Disorders

• Irreversibly inhibits cyclooxygenase (COX) → blocks Thromboxane A2 synthesis
• Platelets cannot make new COX (no nucleus) → effect lasts entire platelet lifespan (8-9 days)
• NSAIDs also block COX but the effect is reversible (lasts duration of drug action)
• Clinical use: 81 mg daily reduces risk of heart attack and stroke

---

Coagulation Disorders

Von Willebrand Disease

• Most common hereditary bleeding disorder (affects 1% of population)
• Affects both males and females equally (unlike hemophilia)
• More evident in females due to menorrhagia

• vWF and Factor VIII circulate complexed together
• vWF deficiency → (1) impaired platelet adhesion (primary hemostasis fails) AND (2) Factor VIII is also low because vWF normally carries and protects it (secondary hemostasis also partially impaired)

---

Hemophilias

---

Vitamin K Deficiency

• Vitamin K required for synthesis of clotting factors II, VII, IX, and X
• Found in green leafy vegetables; also synthesized by gut bacteria
• Causes: parenteral nutrition + antibiotics (destroys gut flora), malabsorption
• In newborns: routine Vitamin K injection given because breast milk is low in Vitamin K and neonates have sterile guts

---

DIC (Disseminated Intravascular Coagulation)

1. Endothelial or tissue injury (most commonly from sepsis - gram-negative LPS; also major trauma)
2. Coagulation cascade is massively activated
3. Widespread clot formation in small vessels throughout body
4. Clotting factors and platelets are consumed in making all these clots (consumption coagulopathy)
5. Now there are no clotting factors or platelets left → the patient bleeds from everywhere

---

Polycythemia (Increased RBCs)

Primary Polycythemia (Polycythemia Vera)

• Neoplastic disease of bone marrow pluripotent cells → uncontrolled increase in ALL cell lines (RBCs, WBCs, platelets)
• Primarily men, median age 62
• Manifestations: splenomegaly, hypertension, headache, dizziness, dusky redness/cyanosis, itching, thromboembolism, hemorrhage
• Treatment: reduce blood viscosity via phlebotomy, low-dose aspirin, hydroxyurea

Secondary Polycythemia

• Physiologic increase in EPO as compensatory response to hypoxia
• Causes: high altitudes, chronic heart/lung disease, smoking, EPO-secreting tumors, hydronephrosis, renal cysts
• Treatment: relieve hypoxia; low-flow oxygen for COPD

---

PART 6: BILIRUBIN & JAUNDICE

Normal Bilirubin Pathway:

Types of Bilirubin:

Neonatal Jaundice (Hyperbilirubinemia of Newborn)

• 60% of term and 80% of preterm neonates develop jaundice in the first week of life
• Cause: immature liver cannot conjugate bilirubin fast enough
• Most resolves within 1 week without treatment

Hemolytic Disease of Newborn (Erythroblastosis Fetalis)

• Rh-negative mother previously sensitized to Rh-positive blood → forms anti-Rh antibodies
• In subsequent Rh-positive pregnancies → antibodies cross placenta → attack fetal RBCs → hemolysis
• Fetus develops splenomegaly, hepatomegaly → impaired liver → low albumin → massive edema (hydrops fetalis)
• Treatment/Prevention: Rh immune globulin injection into Rh-negative mother within 72 hours of delivery (prevents sensitization)

---

QUICK REFERENCE: ANEMIA COMPARISON TABLE

---