1. Why is p53 called the “guardian of the genome”?
   p53 is activated by DNA damage, oncogene activation, and cellular stress. It prevents damaged DNA from being passed to daughter cells by causing:
   • Cell-cycle arrest at G1/S through p21, allowing DNA repair
   • DNA repair programs
   • Senescence if damage persists
   • Apoptosis if damage is irreparable
     Loss of p53 therefore permits survival and division of genetically abnormal cells.
2. Why is ATP depletion the hallmark of reversible cell injury?
   ATP is required for ion pumps, protein synthesis, membrane maintenance, and cellular metabolism. Early ATP depletion causes:
   • Na+/K+-ATPase failure, leading to Na+ and water influx and cell swelling
   • Shift to anaerobic glycolysis, causing lactic acidosis and decreased intracellular pH
   • Ribosomal detachment from rough ER, causing reduced protein synthesis
     These changes can reverse if oxygen supply and ATP production recover. However, severe or sustained ATP depletion progresses to irreversible membrane and mitochondrial injury.
3. Why is RAS called a proto-oncogene?
   A proto-oncogene is a normal gene that promotes controlled cell growth or survival. RAS normally transmits growth-factor signals from membrane receptors to the nucleus. When mutated, RAS becomes locked in its active GTP-bound state, continuously signaling proliferation even without growth-factor stimulation. Thus, the normal proto-oncogene RAS becomes an activated oncogene.
4. Why is Virchow's triad important in thrombosis?
   It summarizes the three major pathogenic influences that predispose to thrombosis:
   • Endothelial injury
   • Abnormal blood flow, stasis or turbulence
   • Hypercoagulability
     It helps identify the cause and clinical setting of venous and arterial thrombi. For example, stasis is particularly important in deep-vein thrombosis, while endothelial injury and turbulence are prominent in arterial thrombosis.
5. Why does AML-M3 commonly cause DIC?
   Acute promyelocytic leukemia, APL or AML-M3, contains abnormal promyelocytes with granules that release potent procoagulant substances, including tissue-factor-like activity and cancer procoagulant. This triggers widespread coagulation, consumes platelets and clotting factors, and causes disseminated intravascular coagulation (DIC). APL cells also promote fibrinolysis, contributing to severe bleeding. DIC may worsen when leukemic cells lyse, as described in the Merck AML review.
6. Why does pancreatitis cause fat necrosis?
   Damaged pancreatic acinar cells release lipase into pancreatic and peripancreatic tissues. Lipase hydrolyzes triglycerides in adipocytes into free fatty acids. These free fatty acids combine with calcium to form insoluble calcium soaps, called saponification. Grossly this produces chalky-white foci of enzymatic fat necrosis.
7. Why is type I hypersensitivity called immediate hypersensitivity?
   In a previously sensitized person, re-exposure to an allergen cross-links allergen-specific IgE bound to mast cells and basophils. This causes rapid degranulation and release of histamine and other mediators within minutes. Hence, reactions such as anaphylaxis, urticaria, allergic rhinitis, and some forms of asthma are termed immediate hypersensitivity. A later inflammatory phase can occur hours afterward.
8. Why does C5a cause chemotaxis?
   C5a is a complement-derived chemoattractant, or anaphylatoxin. It binds C5a receptors on neutrophils, monocytes, and other leukocytes, activating intracellular signaling that directs their migration along a concentration gradient toward the site where complement has been activated. It also activates leukocytes and increases endothelial adhesion.
9. Why does hereditary spherocytosis show increased osmotic fragility?
   Defects in membrane proteins such as spectrin, ankyrin, band 3, or protein 4.2 cause progressive membrane loss. RBCs become spherical and have a reduced surface-area-to-volume ratio. Unlike normal biconcave cells, spherocytes cannot expand much when placed in hypotonic fluid. They therefore lyse at a relatively higher saline concentration, producing increased osmotic fragility.
10. Why is MCV increased in megaloblastic anemia?
    Vitamin B12 or folate deficiency impairs thymidine synthesis and therefore DNA replication. Nuclear maturation and cell division are delayed, while cytoplasmic growth continues relatively normally. Erythroid precursors undergo fewer divisions and emerge as large RBCs, causing macrocytosis and increased MCV. The smear commonly shows macro-ovalocytes and hypersegmented neutrophils.
11. Why does iron-deficiency anemia show increased TIBC?
    TIBC mainly reflects circulating transferrin, the iron-binding transport protein. In iron deficiency, the liver increases transferrin production to capture and transport the limited available iron. Therefore:

• Serum iron decreases
• Transferrin/TIBC increases
• Transferrin saturation decreases
• Ferritin decreases

1. Why is LAP/NAP low in CML but high in leukemoid reaction?
   Leukocyte alkaline phosphatase, also called neutrophil alkaline phosphatase, reflects enzyme activity in mature neutrophils.

• In CML, neutrophils are part of a clonal neoplastic myeloid proliferation and have low LAP activity.
• In a leukemoid reaction, neutrophils are reactive cells responding to infection, inflammation, or stress and show increased LAP activity.
  Thus, low LAP historically supported CML, while high LAP supported a reactive leukemoid reaction. Molecular testing for BCR::ABL1 is now the decisive test for CML.

1. Why does myocardial infarction produce coagulative necrosis?
   Myocardial infarction is ischemic injury in a solid organ. Ischemia denatures structural proteins and enzymes, which inhibits proteolysis of dead cells. Tissue architecture therefore remains temporarily preserved, producing coagulative necrosis.
   Exception: ischemic injury in the brain causes liquefactive, not coagulative, necrosis.
2. Why does dystrophic calcification occur despite normal Ca²⁺?
   Dystrophic calcification occurs in dead, dying, or chronically damaged tissue, such as atherosclerotic plaques, old caseous tuberculosis lesions, damaged heart valves, and areas of fat necrosis. Local tissue injury provides phospholipids and other nucleation sites that bind calcium, enabling calcium phosphate deposition even though serum calcium and phosphate are normal.
   This differs from metastatic calcification, which occurs in otherwise normal tissues because of hypercalcemia or disturbed calcium-phosphate metabolism.

AML-M3 and DIC

1. Leukemic promyelocytes contain granules rich in tissue factor/thromboplastin-like material and cancer procoagulant.
2. Release of these substances activates the coagulation cascade throughout the circulation.
3. This produces widespread fibrin microthrombi and causes consumption of platelets and clotting factors, resulting in consumptive coagulopathy (DIC).
4. APL cells also overexpress annexin II, which promotes conversion of plasminogen to plasmin and causes excessive fibrinolysis.
5. Therefore, the patient develops severe bleeding, with thrombocytopenia, prolonged PT/aPTT, low fibrinogen, and raised D-dimer. Cell lysis may aggravate the coagulopathy.