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