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• Hematology and Oncology are closely connected to immunology
• Master different types of anaemia
• Be comfortable interpreting blood smears
• Focus on mechanisms and adverse effects of oncologic drugs, not clinical uses
• Solid tumors are covered in their respective organ system chapters

Fetal Erythropoiesis

• Fetal erythropoiesis occurs in the yolk sac (3-8 weeks), liver (6 weeks-birth), spleen (10-28 weeks), and bone marrow (18 weeks to adult)
• The young liver synthesizes blood

Hemoglobin Development

• Embryonic globins: ζ and ɛ
• Fetal hemoglobin (HbF) = α2γ2
• Adult hemoglobin (HbA₁) = α2β2
• From fetal to adult hemoglobin: Alpha always; gamma goes, becomes beta
• HbF has higher affinity for O2 due to less avid binding of 2,3-BPG, allowing HbF to extract O2 from maternal hemoglobin (HbA₁ and HbA₂) across the placenta HbA₂ (α2δ2) is a form of adult hemoglobin present in small amounts

Blood Groups

• Hemolytic disease of the fetus and newborn is called erythroblastosis fetalis
• Rh hemolytic disease occurs when a Rh-negative pregnant patient has a Rh-positive fetus
• First pregnancy: patient exposed to fetal blood (often during delivery) → formation of maternal anti-D IgG
• Subsequent pregnancies: anti-D IgGcrosses placenta → attacks fetal and newborn RBCs → hemolysis
• Presentation of Rh hemolytic disease includes hydrops fetalis, jaundice shortly after birth, and kernicterus
• Prevent Rh hemolytic disease by administration of anti-D IgG to Rh-negative pregnant patients during the third trimester and early postpartum period (if fetus is Rh-positive) to prevent maternal anti-D IgG production
• ABO hemolytic disease occurs when a type O pregnant patient has a type A or B fetus
• Preexisting pregnant patient anti-A and/or anti-B IgG antibodies cross the placenta → attack fetal and newborn RBCs → hemolysis
• Presentation of ABO hemolytic disease includes mild jaundice in the neonate within 24 hours of birth; unlike Rh hemolytic disease, can occur in firstborn babies and is usually less severe
• Treatment for hemolytic disease include phototherapy or exchange transfusion

Hematopoiesis

• Hematopoiesis is the formation of blood cells

Neutrophils

• Act in acute inflammatory response and are phagocytic
• The Multilobed nucleus is labeled A
• Specific granules contain leukocyte alkaline phosphatase (LAP), collagenase, lysozyme, and lactoferrin
• Azurophilic granules (lysososomes) contain proteinases, acid phosphatase, myeloperoxidase, and β-glucuronidase
• Inflammatory states (e.g. bacterial infection) cause neutrophilia and changes in neutrophil morphology, such as left shift, toxic granulation (dark blue, coarse granules), Döhle bodies (light blue, peripheral inclusions), and cytoplasmic vacuoles
• Neutrophil chemotactic agents: C5a, IL-8, LTB4, 5-HETE (leukotriene precursor), kallikrein, platelet-activating factor, N-formylmethionine (bacterial proteins)
• Hypersegmented neutrophils (nucleus with 6+ lobes) are seen in vitamin B₁₂/folate deficiency
• Left shift is where neutrophil precursors (e.g. band cells, metamyelocytes) are in peripheral blood, which reflects states ↑ myeloid proliferation (e.g. inflammation, CML)
• Leukoerythroblastic reaction is left shift accompanied by immature RBCs; suggests bone marrow infiltration (e.g. myelofibrosis, metastasis)

Erythrocytes

• Carry O₂ to tissues and CO₂ to lungs
• Anucleate and lack organelles with large surface area-to-volume ratio for rapid gas exchange
• Life span of ~120 days in adults; 60-90 days in neonates
• Membranes contain Cl-/HCO₃ antiporter, which allow RBCs to export HCO₃ and transport CO₂ from the periphery to the lungs for elimination

Erythrocyte Terminology

• Erythro = red; cyte = cell
• Erythrocytosis = polycythemia = ↑ Hct
• Anisocytosis = varying sizes
• Poikilocytosis = varying shapes
• Reticulocyte = immature RBC; reflects erythroid proliferation
• Bluish color (polychromasia) on Wright-Giemsa stain of reticulocytes represents residual ribosomal RNA

Monocytes

• Are found in blood and differentiate into macrophages in tissues
• Have a large, kidney-shaped nucleus with extensive "frosted glass" cytoplasm
• One nucleus (mono) and a cyte = cell

Macrophages

• Are a type of antigen-presenting cell, which Phagocytose bacteria, cellular debris, and ageing RBCs
• Have a long life in tissues and differentiate from circulating blood monocytes
• Is activated by IFN-γ and can function as antigen-presenting cell via MHC II
• Also engage in antibody-dependent cellular cytotoxicity
• Important cellular component of granulomas (eg, TB, sarcoidosis), where they may fuse to form giant cells
• Lipid A from bacterial LPS binds CD14 on macrophages to initiate septic shock

Dendritic Cells

• Function as a link between innate and adaptive immune systems (e.g., via T-cell stimulation)
• Express MHC class II and Fc Receptors on the surface
• Can present exogenous antigens on MHC class I (cross-presentation)

Eosinophils

• Defend Against Helminthic Infections (Major Basic Protein)
• Bilobate Nucleus.
• Packed with Large Eosinophilic Granules of Uniform Size
• Highly Phagocytic for Antigen-Antibody Complexes.
• Produce histaminase, Major Basic Protein (MBP, a helminthotoxin), eosinophil peroxidase, eosinophil cationic protein, and eosinophil-derived neurotoxin
• Eosin = pink dye; philic = loving. Causes of eosinophilia (PACMAN Eats):
• Parasites
• Asthma
• Chronic Adrenal Insufficiency
• Myeloproliferative Disorders
• Allergic Processes
• Neoplasia (eg, Hodgkin Lymphoma)

Basophils

• Mediate Allergic Reaction.
• Densely Basophilic granules contain Heparin (Anticoagulant) and Histamine (Vasodilator) as well as Leukotrienes synthesized and released on demand.
• Basophilic - Stains Readily With Basic Stains.
• Basophilia is uncommon, but can be a sign of Myeloproliferative Disorders, Particularly CML.

Mast cells

• Mediate local tissue allergic reactions and contain basophilic granules
• Originate From Same Precursor as Basophils But Are Not the Same Cell Type
• Can bind the Fc portion of IgE to membrane
• Involved in Type I Hypersensitivity reactions as cell trauma, C3a and C5a, Surface IgE cross- Linking by antigen (IgE Receptor Aggregation) Degranulation, and Release of Histamine, Heparin, Tryptase, and Eosinophil Chemotactic Factors
• Cromolyn Sodium Prevents Mast Cell Degranulation (Used for Asthma Prophylaxis)
• Vancomycin, Opioids, and Radiocontrast Dye Can Elicit IgE-Independent Mast Cell Degranulation.
• Mastocytosis Rare.
• Proliferation of Mast Cells in Skin and/or Extracutaneous Organs Associated With C-KIT Mutations and ↑ Serum Tryptase

Lymphocytes

• Refer to B cells, T cells, and natural killer (NK) cells.
• B cells and T cells mediate adaptive immunity.
• NK cells are part of the innate immune response.
• Small Amount of Pale Cytoplasm

Natural Killer Cells

• Important In Innate Immunity, Especially Against Intracellular Pathogens.
• NK cells are Larger then B and T cell, with Distinctive Cytoplasmic Lytic Granules that Contain Perforin and Granzymes
• When cells are released and act on target to induce apoptosis.
• Distinguish between healthy and infected cells by identifying cell surface proteins induced by cell stress, malignant transformation, or microbial infections
• Induce Apoptosis and virally infected cells in which these molecules are downregulated.

B Cells

• Mediate Humoral Immune Response
• Originate from Stem Cells In Bone Marrow and Mature in Marrow Migrate to Peripheral Lymphoid Tissue
• When it encounters antigen, B cells differentiate into Plasma Cells (which produce antibodies) and Memory cells.
• Can Function As an APC.
• B = Bone Marrow

T Cells

• Mediate Cellular Immune Response.
• Originate from Stem Cells in Bone Marrow
• Differentiate into Cytotoxic T-Cells and Helper T-Cells.
• cd28 is necessary for T-Cell activation.

Rule of 8: (CD4 x MHCII) = 8 (CD8 x MHCII) = 8 T= Thymus. and B cells must recognize antigen

Plasma Cells

• Produce large amounts of antibody specific to a particular antigen.
• Undergo eccentric nucleus, RER, and well-developed Golgi apparatus
• Found in bone marrow and normally do not circulate in peripheral blood.
• Multiple myeloma is a plasma cell dyscrasia

Hemoglobin Electrophoresis

• During gel electrophoresis, hemoglobin migrates from the negatively charged cathode to the positively charged anode
• HbA migrates the farthest, followed by HbF, HbS, and HbC
• This is because the missense mutations in HbS and HbC replace glutamic acid with valine (neutral) and lysine respectively, making HbC and HbS more positively
• charged than HbA
• A Fat Santa Claus can't (cathode) go far

Antiglobulin Test

• Also called Coombs test
• Detects the Presence of Antibodies Against Circulating RBCs
• In Direct Antiglobulin Test Anti-Human Globulin (Coombs Reagent) added to Patient's RBCs; RBCs Agglutinate if RBCs are coated with Anti-RBC Abs Which is Used for AIHA Diagnosis
• In Indirect Antiglobulin Test, Normal RBCs added to Patient's Serum

Platelet plug formation (primary hemostasis)

• Temporary Plug Stops Bleeding; Unstable, Easily Dislodged
• ADP helps platelets adhere to endothelium

Thrombogenesis

• Weibel Palade's body are formed by the endothelial cells which release ADP & Calcium and TXA2
• In ADP Deficiency von Willebrand's disease and in Bernard Soulier Syndrome both deficiencies occur
• For COX, deficiency Glanzmann thrombasthenia and Ristocetin occurs

Aspirin: Irreversibly Inhibits Cyclooxygenase, Thereby Inhibiting TXA, Synthesis

• Aspirin irreversibly Inhibits COX

Coagulation and kinin pathway

• PT Extrinsic Pathways :11,V,V11,X
• PTT Intrinsic Pathway All Other Factors

Vitamin -K dependent Coagulation

• Reduces Synthesis Factor 11, V11, 1X, X
• Factors 279 and 10.
• Given with vitamin k in severe bleeding

Iron Deficiency & Study

• evolutionary Reasoning- Pathogens used for Circulating Iron
• body Adapted and stored within to Prevent Pathogens

Microcytic Anemia

• (MCV"<80fl)
• Iron Deficiency
• Anemia
• lead

A-Thalassemia & A Glybin

 - gene deletions on chromosome 16 Glybin synthysis

Lead Poisoning

• Anemia & Inhibts Ferrochelatase and ALA
• poisoning and treatment : Succimer EDTA *
• drops wrist and foot and colic
• Lead Exposure High
• B Thalassmia B Globins

Sideroblastic Anemia

• Defect Alasynthesis
• Blood iron, Normal1 & *Fe ferritin : Ring Siderbalsts with Iron.
• B - given with Iron

Macrocytic anemias:

• (MCV"100n)
• Description*

Impaired DNA synthesis Causes B12 Deficiency or malabsorption from Chron's or Gastectomy

• Homocysteine*

megaloblastic. Findings & B12

_Normal MetylmialoniACid - B12 Deficiency _Involvements in Neurologic.

• OroticAciduria*
• Children cant convert orticacid with defect in UMP
• no hiper amonia *Treatment: "uridinmonophosphate
• Nonmegloblasticanemia-liver or alcohol
• Diamondblackfanmia- Rapsid onset anemia *

Normocytic, normochromic anemias

• anemia* are classified Hemolytic vs Nonhemolytic . The hemolysis classified ,by intrinsic vs erinxsiv to RBC .
• Disease Extrvasesula
• Anemic from iron .
  • Failure or destruction of hematopiotic Stem cells suchas a: Radiation :

1. **FINDINGS IRON : low
2. TIB-A: High High
3. **Ferritin High 3

Intrinsic hemolytic anemias

• Primarily autosomal dominant -defects in RBC such as band 3,protein . Spherocysosi
• small and Round RBCs with no central pallor .surface area dehydration- prematur Removalhemolyis Splenegaly, Pigmented gallstones.labs"1fragyily
• Paraxysmall Hemgobinura* .
• Aquited PM* ,complied hemohlysis -cd55-50 on Alowcytomerty .
• treatment* - eculizumab (targets terminal C-Protein (S -Linked recevise *6ap0 defects**and stress and hemolysus) -
• Back PAIN Hemgloin*
• Labs -G6PD may be normal +heinzbodys stressmakes me eat bites

Extrinsic hemolytic anemias

• AutoimmuneHemolyticAnemis - - normocytis is - warm 064- Chronic +cold acute warm is good
• Druduced hemolytic -most conmnorny - antibody mediated.
• microangapathuc* schizxytes
• Hemolytic Anemia. destruction of RBC eg

Leucopenias

• Neutropenia ,. Sepsis , Post Infection Drug Anemias Lymphopenia: HIV , Di George, SCID.S. I.R . cosinopenia: Cushing syndoime. Steriods

Hemesynthsis, Porphyria & lead , lead posining

• Porphyria and lead poisoning cause similr -

1 Lead Poising : Ferochetalase, ALA accumulates in : Protophrin, ALA = Blood -Microcytic Anima kids get lead paint get mental deterioration. ALAPop

• Acute intemitten Porphyria*: deficiate in Porphorbiogn deaminase
• Accumulates porphobing - in Urine : Symtoms 4 P Treatment : Hemming

3. Porphoria curanea Tarda: Cutanceaus photosensitity Alcohol Treatment: Flebotomy-

• PT detects function in exrinisc pathwy Factor .INR - patlent Pt Control more than 1 = proolonyed -most test for Watfarin
• PTT - in trinsic pathway

Coaglutation disorders

• A Hernofily , Factor V11 &
• Vitamik + Factors V1and Protiein +C

Plate Dysfunstion

• D15DRDERS All have I Bleeding time
• Benard boulster,
• Gplb - platelet to
• 19 defersive adhesion agragahon . Blood smear- no Plateal et Clumying
• 1 platelet count GUCORTOCOD
• Rema Pailut- to

Hereditary Thomdilitis

Autocanal dominant in hypercoagutable Authrondin deficiency - renal syndrome

• Factor V. Protheombin and
• de friciency

Mised platlet coaguation &

Von Willbraid Diease : D111sminated- Widespread clotting factor activation. + Trombi , + Hemorrages. Sepsis Tranfusion, Stroke etc

Tumore Lyse:

Release *Of K Hyperkalemea -*Reale Phosphate-Hyperphaphatemea -A1lopaical , Resburiase-Hyponcalcimuea

• Heparin* activates . Antiithrombin is short half life. Bleading 1-2 + T+ Hype2: Platelets (Platele factor removed by spleen. . L MW Used in renal. Warfarin Vitanik. Protien CS with effects. -

Anticogulan Reverses

• Hepan * Protare Sulfade' Waforn VilamiK . Drbyta Monocronal Antidody

• Antiplatelets: All work y agregahng playlets

• Aspiran***

• Plopudrel , Prajrel, ticagrelor:* All for platelets

• Trombolitics:*

• Aitelolasc*. Reteplase & Tecectolase & cleaves thrombin and + PT & +PT" all in for platelets Tumore Lyse Cyde bleaching and intertulates and prevents with dactimycin. Doxruicin is + and aduese .and alkin and + cyles . antimatabolites

Antitumor Antibiotics/ Mech

• All cyrce nono specific

Blea

• Tessicular, 14 lymphoma and Free radicals + lungs
• dacturomyciu* wilms and prevants RN
• *Anthracycliner

All cyes Specific

• Thioulues - Arthitus 16 MP
• Myrele supprenion: and 6Mp with allouinal with toxycity
• Cyabine- chain termination. and Myle suppression

4. Flu- and thyminal synthisis 1" OMP AND myesio and diarahce.

• ALL IN S/ G 2 Phases and deyrades
• Anti Cancer Small Inhibtors ,Alestinab. Crizetinip-ALK & EGFR
• Imateril & Ruxoliimib- LFT & *A" *Pabosidils P04 & BRAK, RASH FAGUE Ami fostine & Dexrez - tetrathyrde Alkylating Agent All Cycle Nono Specific

Busullan, Tears the morrow Lungs and Hypero. -1- Cyclofos and Nitronreas (A

• Lymhoma : and brain tumour & Microtuble Inhibites - Paclituxul and Taxis Taxaniz Stabilize Society

Cyta Toxity - Vinaristine neurpothic, Blmycin : Lung & Cysclophramide. Myle S - P-O: (S & C.I.)