Platelet Activation and Hypersensitivity

Hematology and Oncology

• Immunology is closely linked to hematology.
• Types of anemias should be mastered.
• Blood smears should be interpreted with ease.
• Focus on mechanisms and adverse effects of oncologic drugs instead of clinical uses.
• Solid tumors are covered in their respective organ system chapters.

Fetal Erythropoiesis

• In the yolk sac, fetal erythropoiesis occurs during weeks 3–8.
• Occurs in the liver from 6 weeks until birth.
• Spleen: happens between 10–28 weeks.
• Bone marrow handles it from week 18 until adulthood.
• Young livers produce blood.

Hemoglobin Development

• Embryonic hemoglobins: ζ and ɛ.
• HbF (Fetal hemoglobin) = α2γ2.
• Adult hemoglobin (HbA₁) = α2β2.
• HbF has a higher affinity for O₂.
• There is less avid binding of 2,3-BPG.
• Oxygen can be extracted from maternal hemoglobin (HbA₁ and HbA₂) across placenta.
• HbA₂ (α₂δ₂) is a form of adult hemoglobin, but only a small amount is present.
• Alpha is constant between fetal and adult forms, gamma becomes beta.

Blood Groups

• Blood groups are classified by ABO classification.
• Blood groups are classified by Rh classification.
• The antigens on RBC surface are A, B, A&B, or NONE.
• The antibodies are Anti-B, Anti-A, Anti-A and Anti-B, or None, or Anti-D
• Compatible RBC types to receive: A and O can receive from A, B, and O can receive from B, AB, A, B, and O can receive from AB, and O can only receive from O
• Rh + can receive from Rh
• To donate to: A can donate to A and AB, B can donate to B and AB, AB can only donate AB, O can to AB, A, B, and O
• Rh⊕ can donate to Rh⊕ and Rh- can donate to Rh

Hemolytic Disease

• Hemolytic disease: erythroblastosis fetalis
• Rh hemolytic happens from Rh negative pregnant patients with a Rh positive fetus.
• Patient exposed to fetal blood first pregnancy and maternal anti-D IgG forms often during delivery
• Subesquent pregnancies: hemolysis occurs from Anti-D IgG crossing placenta and attacking fetal and newborn RBCs .
• Results in hydrops fetalis, jaundice shortly after birth, and kernicterus
• Given by administration of anti-D IgG to prevent treatment, and is given in the third trimester during pregnancy as well as the early postpartum if the fetus is Rh positive.

ABO hemolytic disease

• Type O pregnant patient; type A or B fetus.
• Preexisting pregnant patient anti-A and/or anti-B IgG antibodies cross the placenta.
• Antibodies attack fetal and newborn RBCs → hemolysis.
• Causes mild jaundice in the neonate within 24 hours of birth. and can occur in first born unlike Rh hemolytic disease
• Phototherapy or exchange transfusions

Hematopoiesis

• Hematopoiesis: The process of forming blood cells from the multipotent stem cell which differentiates into both myeloid stem cells and lymphoid stem cells
• Erythropoiesis: the development of erythrocytes from erythroblasts
• Thrombopoiesis: the development of thrombocytes from megakaryoblasts
• Granulocytopoiesis: the development of granulocytes from myelobasts ending in the granulocytes, eosinophils, basophils, and neutrophils
• Monocytopoiesis: the development of monocites from monoblasts
• Lymphopoiesis: the development of lymphocytes from lymphoblasts including B cells, T cells, NK cells, Plasma cells, T-helper cells, T-cytotoxic cells

Neutrophils

• Neutrophils: Phagocytic, acute inflammatory response cells.
• Specific granules contain leukocyte alkaline phosphatase (LAP), collagenase, lysozyme, and lactoferrin.
• Azurophilic granules (lysosomes) contain proteinases, acid phosphatase, myeloperoxidase, and ẞ-glucuronidase.
• Inflammatory states cause neutrophilia and changes in neutrophil morphology, like left shift, toxic granulation, Döhle bodies, and cytoplasmic vacuoles.
• Chemoattractants for neutrophils are C5a, IL-8, LTB4, 5-HETE, kallikrein, platelet-activating factor, and N-formylmethionine (bacterial proteins).
• Hypersegmented neutrophils (nucleus has 6+ lobes): vitamin B₁₂/folate deficiency.
• Left shift: ↑ neutrophil precursors (eg, band cells, metamyelocytes) in peripheral blood, which results in states of ↑ myeloid proliferation like inflammation, CML)
• Leukoerythroblastic reaction: left shift and immature RBCs, implying bone marrow infiltration (eg, myelofibrosis, metastasis).

Erythrocytes

• They carry oxygen and carbon dioxide.
• Anucleate and lack organelles. Biconcave.
• Large surface area-to-volume ratio.
• Life span of ~120 days (adults) or 60-90 days (neonates).
• Energy source: glucose (90% glycolysis, 10% HMP shunt).
• Membranes contain Cl-/HCO₃ antiporter.
• Allows RBCs to export HCO₃.
• Allows RBCs transport CO₂ from periphery to lungs.
• Erythro = red and cyte = cell.
• Erythrocytosis = polycythemia = ↑ Hct.
• Anisocytosis: varying sizes.
• Poikilocytosis: varying shapes.
• Reticulocyte: immature RBC, reflects erythroid proliferation.
• Bluish color (polychromasia) via Wright-Giemsa stain signifies leftover ribosomal RNA.

Platelets (Thrombocytes)

• Involved in 1º hemostasis.
• Anucleate, small cytoplasmic fragments are derived from megakaryocytes.
• Platelet lifespan is 8–10 days When endothelial injury activates, aggregate with other platelets and interact with fibrinogen to form platelet plug.
• Contain dense granules (Ca²⁺, ADP, Serotonin, Histamine) and α granules (vWF, fibrinogen, fibronectin, platelet factor 4).
• Roughly 1/3 of platelet pool is stored in the spleen.
• Thrombocytopenia or platelet function = petechiae.
• For vWF, Receptor: GpIb.
• For Fibrinogen, Receptor: GpIIb/IIIa.
• Thrombopoietin stimulates megakaryocyte proliferation.
• Alfa granules contain vWF, fibrinogen, fibronectin, platelet factor four

Monocytes

• In the blood and differentiate into macrophages in tissues.
• Large and kidney-shaped.
• Has an abundance of frosted glass cytoplasm.
• Mono = one / nucleus; cyte = cell

Macrophages

• A type of antigen-presenting cell.
• Phagocytose bacteria, cellular debris, and senescent RBCs.
• Activated by IFN-γ.
• Act as antigen-presenting cell via MHC II
• Engage in antibody-dependent cellular cytotoxicity.
• Cellular components of granulomas.
• May fuse to form giant cells.
• macro = large
• phage = eater
• Lipid A binds CD14 on macrophages.

Dendritic Cells

• Highly phagocytic antigen-presenting cells (APCs), and the link between innate and adaptive immune systems.
• Express MHC class II and Fc receptors on surface.
• Can present exogenous antigens on MHC class I.
• Important for cross-presentation

Eosinophils

• Defend against helminthic infections (major basic protein).
• Have a bilobate nucleus.
• Packed with large eosinophilic granules of uniform size.
• Produce histaminase, major basic protein (MBP, a helminthotoxin), eosinophil peroxidase, eosinophil cationic protein, and eosinophil-derived neurotoxin.
• Eosin = pink dye, philic = loving. and parasitic infections

Causes for Eosinophilia include PACMAN Eats

• Parasites
• Asthma
• Chronic adrenal insufficiency
• Myeloproliferative disorders
• Allergic processes
• Neoplasia like Hodgkin Lymphoma and related granulomatosis

Basophils

• They mediate allergic reaction.
• Contain heparin (anticoagulant) and histamine (vasodilator).
• Basophilic-stains readily with basic stains and rare

Mast Cells

• Mediate allergic reaction in local tissue.
• 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.
• Activation from tissue trauma, C3a and C5a, surface IgE cross-linking by antigen
• Leads to degranulation and release of histamine, heparin, tryptase, eosinophil chemotactic factors.
• Cromolyn sodium Prevents mast cell degranulation (asthma prophylaxis)

Lymphocytes

• 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.
• Staining nucleus and cytoplasm.

Natural Killer Cells

• NK cells especially important in the innate immune response
• larger than B and T cells, with distinctive cytoplasmic lytic granules (containing perforin and granzymes) NK cells induce apoptosis (natural killer) in cells lacking class I MHC, like virally infected where the molecules are downregulated.

B Cells

• Mediate a humoral immune response.
• Originate from stem cells in bone marrow and mature there.
• Migrate to peripheral lymphoid tissue.
• When antigen is encountered = Antibodies + memory cells.
• Function as APC
• Can differentiate into plasma cells

T Cells

• Mediate cellular immune response.
• Originate in bone marrow, mature in thymus.
• Differentiate to cytotoxic T cells(MHC I), helper T cells(MHC II), regulatory T cells. Costimulatory needed Most circulating lymphocytes are T cells.
• T = thymus
• CD4+ helper T cells: primary target of HIV

Plasma Cells

• Produce great amounts of antibody for all antigens.
• eccentric nucleus, abundant RER and well-developed Golgi
• In bone marrow but no circulation in peripheral blood

Hemoglobin Electrophoresis

• Detect abnormal hemoglobins
• During gel electrophoresis, hemoglobin migrates from the negatively charged cathode to the positively charged anode.
• The missense mutations in HbS replaces glutamic acid with valine (neutral) and in HbC replaces glutamic acid with lysine +

The rate of migration is as follows

• HbA migrates the farthest, followed by HbF, HbS, and HbC.
• A Fat Santa Claus can't go far.

Antiglobulin Test

• Coombs test
• Detects the presence of antibodies vs circulating RBCs.
• Direct antiglobulin test: anti-human globulin (Coombs reagent) added to patient's RBCs and will agglutinate with with anti-RBC Abs for AIHA diagnosis
• Can identify AlHA from RBCs via direct test
• Indirect antiglobulin test: normal RBCs added to patient's serum, presence of serum will be the addition Anti-RBCs with Coombs reagent

Platelet Plug Formation (primary hemostasis)

• Temporary plug stops bleeding, unstable, and will easily be eroded
• In coagulation cascade after secondary hemostasis
• There is both tissue injury and damage
• Transient Vasoconstriction occurs and then there is platelet adhesion after exposure
• Platelets undergo change that have fibrinogen and binds
• Coagulation cascade begins with Von Willebrand binding
• Pro and anti aggregation factors occur

Thrombogenesis

• It creates a fibrin mesh insoluble to stop formation and inhibit TXA2
• If not Von Willebrand then desmopressin
• Gpllb deficiency vs Gpllla insertion of fibrinogen and platelet coagulation
• Von Willebrand carries and protects VIII
• VWF caries and protects factor VIII
• Factors made gr8 cars (volksWagen)

Coagulation and Kinin Pathways

• The intrinsic and common pathway are monitored by PT, reflecting activity of factors 1, II, V, VII, and X as 13
• PTT reflects activity of factors except VII and XIII during common pathways
• C1 esterase inhibitor is hereditary angioedema

Vitamin K-Dependent Coagulopathy

• Procoagulation activates reduction Vitamin K that carboxylates factors involved in procoagulation
• When reduced, there will be Y and carboxyglutamic acid (Vitamin dependent)
• Anti-procoagulation does the inverse
• Warfarin inhibits and Vitamin K is depleted
• Heparin enhances antithrombin action

Red Blood Cell Morphology Review

• Acanthocytes: spur cells in liver diesase
• Echinocytes: burr cells
• Dacrocytes: Teardrop cells due to bone marrow
• Schistocytes: Fragmented Helmet
• Degmacytes: Bite cells
• Elliptocytes: Hereditary

Red Blood Cell Morphology Review Continued

• Spherocytes: Without central pallor
• Macro ovalocytes:
• target cells: Halt
• Sickle cells for sickle cell anemia

RBC Inclusions

• Bone marrow iron granules
• basophilic stippling
• howell jolly bodies
• Hinz bodies

Anemias

• Microcytic: MCH less than
• Normocytic: MCH 80-100
• Macrocytic: MCH greater than 100
• There is no defective goblin chain
• Iron deficiency is major

Microcytic Hypochromic Anemias

• MCV < 80 fL due to malnutrition, absorption disorders, and lead poisoning
• Can result in fatigue, the Plummer vision syndrome, Spoon nails and glossitis if extreme
• A Thalassemia can be a silent carrier if not fatal

Microcytic, hypochromic anemias (continued)

• Beta globin synthesis requires chromosome 11 with defects that create synthesis
• Symptoms include anemia, cells being targeted, and other globin chains causing sickness
• Lead inhibits ALAD and causes synthesis

Macrocytic Anemias

• Impairs both the nucleus and cytoplasm
• Vitamin deficiency, and medications (eg, hydroxyurea, phenytoin, methotrexate, sulfa drugs)
• Folate vs cobalamin
• Orotic aciduria
• Non Megaloblastic Anemia

Normocytic, Normochromic Anemias

• Blood vessels carry intrinsic and extravascular
• Anemia or chronic diseases
• Aplastic crisis which is when volume is reduced from radiation

Intrinsic Hemolytic Anemias

• Hereditary is a cause of spherocytosis
• paroxysmal nocturnal from stemcell
• G6PD deficiency with oxidative stress
• sickel cell is abnormal, and HbC has has hemolysis due to its acid form

Extrinsic Hemolytic Anemias

• auto immune caused drug induced problems
• TTP, DIC, and others of RBCS become damaged
• infections from parasites

Leukopenias from Neutropenia

• Reduced count from Sepsis, drugs, radiation/genetics
• Lymphopenia reduced from Di George, AIDS and radiation
• Eosinopenia from glucocorticoids

Heme Synthesis

• Acute and chronic lead poisoning
• Porphobilinogen =ALA

Lead Poisioning

• Ferrochelatase and aminolevulinate leads to substrate buildup and the rest of porphyrins
• Can cause anemia, GI issues, mental deteroriation and peripheral neuropathy.
• Chelation is best for treatment,
• Most high in old houses as a occupational risk and to children

Hemophilia

• Involves bleeding after trauma or surgery which includes the easy bruising to joint areas
• General coagulation defects and the bleeding is normal
• This is mostly from vitamin deificiancy from factors and protein S
• bleeding

Platelet Disorders

• Platelet Disorders often cause microhemorhages that can lead to bleeding time
• Bernard-Soulier is reduced at Gplb and is autosomally recessive with Big Platelets and is reduces VWF
• Glanzmann causes autsomal reduction
• thrombocytopenia causes increased destruction by Macrophages , with increased megakarocytes
• uermic dysfuction has increased toxins

Mixed ThromboPhilias

• Von willebrand
• Disseminated

Polycythemia

• Relative, appropriate absolute, and Inappropriate
• In relative there is red cell mass in polycythemia vera

Chromosomal Translocations

• The Ig heavy chain genes on chromosome 14 are constitutively expressed.
• When other genes (eg, c-myc and BCL-2) are translocated
• next to this heavy chain gene region, they are
• overexpressed.

Cancer

• Treatment comes with a variety of agents
• Cancer therapy cell cylce is always in interphase

Key Chemotoxicities

• Cisplatin is ototoxic
• Vincristine, vinca alloids cause paresthesia neuropathies
• Bleomycin and Busulfan cause pulmonary fibrosis, due to free radical
• DOXOs, ruby/anthracyclines cause cardiotoxicity
• Trastuzumab affects HRT2,

Nonspecific common toxicities of cytotoxic chemos

• Immunosupression Neutropenia
• Anemia
• Thrombocytopenida
• G.I effects, Nausea , vomitting, mucositis , and Alopecia.

Explore platelet activation pathways, receptor functions (ADP, GpIIb/IIIa), and related disorders like Bernard-Soulier syndrome and Glanzmann thrombasthenia. Understand drug mechanisms (aspirin) and hypersensitivity reactions involving basophils and mast cells.