Hematology and Oncology - First Aid Flashcards by Juan Suazo

Blood Cells:

carry O₂ to tissues and CO₂ to lungs
anucleate and lack organelles
biconcave with large surface area-to-volume ratio for rapid gas exchange
life span of 120 days
source of energy is glucose (90% used in glycolysis, 10% used in HMP shunt)
membranes contain Cl⁻/HCO₃⁻ antiporter, which allow export of HCO₃⁻ and transport CO₂ from the periphery to the lungs for elimination

Erythrocytes

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Erythrocytes:

polycythemia
↑ Hct

Erythrocytosis

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Erythrocytes:

varying sizes

Anisocytosis

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Erythrocytes:

varying shapes

Poikilocytosis

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Erythrocytes:

immature RBC
reflects erythroid proliferation

Reticulocyte

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Erythrocytes:

Bluish color (polychromasia) on Wright-Giemsa
stain of reticulocytes represents \_\_\_\_\_.

residual ribosomal RNA

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Blood Cells:

involved in 1° hemostasis
small cytoplasmic fragments derived from megakaryocytes
life span of 8–10 days
when activated by endothelial injury, aggregate with other _____ and interact with fibrinogen to form platelet plug
contain dense granules (ADP, Ca²⁺) and α granules (vWF, fibrinogen, fibronectin)
approximately 1⁄3 is stored in the spleen

Thrombocytes (Platelets)

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Thrombocytopenia or ↓ platelet function results in _____.

petechiae

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Thrombocytes (Platelets):

vWF Receptor

GpIb

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Thrombocytes (Platelets):

Fibrinogen Receptor

GpIIb/IIIa

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Thrombopoietin stimulates _____.

megakaryocyte proliferation

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Leukocytes are divided into granulocytes (neutrophils, eosinophils, basophils, mast cells) and mononuclear cells (monocytes, lymphocytes). WBC differential counts from highest to lowest are _____.

Neutrophils Like Making Everything Better.

Neutrophils (~ 60%)
Lymphocytes (~ 30%)
Monocytes (~ 6%)
Eosinophils (~ 3%)
Basophils (~ 1%)

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Leukocytes:

Granulocytes

Neutrophils
Eosinophils
Basophils
Mast Cells

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Leukocytes:

Mononuclear Cells

Monocytes
Lymphocytes

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Blood Cells:

acute inflammatory response cells
numbers ↑ in bacterial infections
phagocytic
multilobed nucleus
specific granules contain leukocyte alkaline phosphatase (LAP), collagenase, lysozyme, and lactoferrin
azurophilic granules (lysosomes) contain proteinases, acid phosphatase, myeloperoxidase, and β-glucuronidase
hypersegmented _____ (nucleus has 6+ lobes) are seen in vitamin B12/ folate deficiency
↑ band cells (immature _____) reflect states of ↑ myeloid proliferation (bacterial infections, CML)

Neutrophils

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Important Neutrophil Chemotactic Agents

C5a
IL-8
LTB4
Kallikrein
Platelet-Activating Factor

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Blood Cells:

found in blood
differentiate into macrophages in tissues
large, kidney-shaped nucleus
extensive “frosted glass” cytoplasm

Monocytes

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Blood Cells:

phagocytose bacteria, cellular debris, and senescent RBCs
long life in tissues
differentiate from circulating blood monocytes
activated by γ-interferon
can function as antigen-presenting cell via MHC II
name differs in each tissue type (eg. Kupffer cells in liver, histiocytes in connective tissue, Langerhans cells in skin, osteoclasts in bone, microglial cells in brain)
important component of granuloma formation (eg. TB, sarcoidosis)
Lipid A from bacterial LPS binds CD14 on _____ to initiate septic shock

Macrophages

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Macrophages:

liver

Kupffer Cells

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Macrophages:

connective tissue

Histiocytes

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Macrophages:

skin

Langerhans Cells

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Macrophages:

bone

Osteoclasts

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Macrophages:

brain

Microglial Cells

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Blood Cells:

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), _____ peroxidase, _____ cationic protein, and _____-derived neurotoxin

Eosinophils

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Causes of Eosinophilia

**PACCMAN**: * **P**arasites * **A**sthma * **C**hurg-Strauss Syndrome * **C**hronic Adrenal Insufficiency * **M**yeloproliferative Disorders * **A**llergic Processes * **N**eoplasia (eg. Hodgkin Lymphoma)

Blood Cells: * mediate allergic reaction * densely basophilic granules contain heparin (anticoagulant) and histamine (vasodilator) * leukotrienes synthesized and released on demand * stains readily with basic stains

Basophils

Blood Cells: * mediate allergic reaction in local tissues * contain basophilic granules and originate from the same precursor as basophils but are not the same cell type * can bind the Fc portion of IgE to membrane * activated by tissue trauma, C3a and C5a, surface IgE crosslinking by antigen (IgE receptor aggregation) → degranulation → release of histamine, heparin, tryptase, and eosinophil chemotactic factors * type I hypersensitivity reactions * cromolyn sodium prevents degranulation (used for asthma prophylaxis)

Mast Cells

Blood Cells: * highly phagocytic antigen-presenting cells (APCs) * function as link between innate and adaptive immune systems * express MHC class II and Fc receptors on surface * called Langerhans cell in the skin

Dendritic Cells

Blood Cells: * refer to B cells, T cells, and NK cells * B cells and T cells mediate adaptive immunity * NK cells are part of the innate immune response * round, densely staining nucleus with small amount of pale cytoplasm

Lymphocytes

Blood Cells: * part of humoral immune response * originate from stem cells in bone marrow and matures in marrow * migrate to peripheral lymphoid tissue (follicles of lymph nodes, white pulp of spleen, unencapsulated lymphoid tissue) * when antigen is encountered, _____ differentiate into plasma cells (which produce antibodies) and memory cells * can function as an APC

B Cells **B** = **B**one marrow

Blood Cells: * mediate cellular immune response * originate from stem cells in the bone marrow, but mature in the thymus * differentiate into cytotoxic _____ (express CD8, recognize MHC I), helper _____ (express CD4, recognize MHC II), and regulatory \_\_\_\_\_ * CD28 (costimulatory signal) necessary for activation * most circulating lymphocytes (80%) * CD4+ helper _____ are the primary target of HIV

T Cells **T** = **T**hymus Rule of 8: * MHC II × CD4 = 8 * MHC I × CD8 = 8

Blood Cells: * produce large amounts of antibody specific to a particular antigen * “clock-face” chromatin distribution and eccentric nucleus, abundant RER, and well-developed Golgi apparatus * found in bone marrow and normally do not circulate in peripheral blood * multiple myeloma is a _____ cancer

Plasma Cells

Fetal Erythropoiesis

**Y**oung **L**iver **S**ynthesizes **B**lood. * **Y**olk sac (3–8 weeks) * **L**iver (6 weeks–birth) * **S**pleen (10–28 weeks) * **B**one marrow (18 weeks to adult)

Hemoglobin Development

Embryonic Globins: ζ and ε fetal → adult hemoglobin: **A**lpha **A**lways; **G**amma **G**oes, **B**ecomes **B**eta * Fetal Hemoglobin (HbF) = α2γ2 * Adult Hemoglobin (HbA1) = α2β2 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 newborn is also known as \_\_\_\_\_.

Erythroblastosis Fetalis

Rh HDN: Interaction

* Rh ⊝ mothers * Rh ⊕ fetus

Rh HDN: Mechanism

* First Pregnancy: * mother exposed to fetal blood (often during delivery) → formation of maternal anti-D IgG * Subsequent Pregnancies: * anti-D IgG crosses the placenta → HDN in the fetus

Rh HDN: Presentation

* jaundice shortly after birth * kernicterus * hydrops fetalis

Rh HDN: Treatment

* Prevent by administration of anti-D IgG to Rh ⊝ pregnant women during third trimester and early postpartum period (if fetus tests ⊕ for Rh). * Prevents maternal anti-D IgG production.

ABO HDN: Interaction

* Type O mothers * Type A or B fetus

ABO HDN: Mechanism

Pre-existing maternal anti-A and/or anti-B IgG antibodies cross placenta → HDN in the fetus.

ABO HDN: Presentation

* mild jaundice in the neonate within 24 hours of birth * usually less severe than Rh HDN

ABO HDN: Treatment

* phototherapy * exchange transfusion

Hemoglobin Electrophoresis

* On a gel, hemoglobin migrates from the negatively charged cathode to the positively charged anode. * Hb**A** migrates the farthest, followed by Hb**F**, Hb**S**, and Hb**C**. * This is because the missense mutations in HbS and HbC replace glutamic acid ⊝ with valine (neutral) and lysine ⊕, respectively, impacting the net protein charge. **A** **F**at **S**anta **C**laus

Coagulation and Kinin Pathways

Coagulation Cascade Components: Procoagulation

* Vitamin K Deficiency: ↓ synthesis of factors II, VII, IX, X, protein C, protein S * Warfarin inhibits vitamin K epoxide reductase. Vitamin K administration can potentially reverse inhibitory effect of warfarin on clotting factor synthesis. FFP or PCC administration reverses action of warfarin immediately and can be given with vitamin K in cases of severe bleeding. * Neonates lack enteric bacteria, which produce vitamin K. Early administration of vitamin K overcomes neonatal deficiency/coagulopathy. * Factor VII—shortest half life * Factor II—longest half life **v**olks**W**agen **F**actories make gr**8** cars. * **vWF** carries/protects factor **VIII**

Coagulation Cascade Components: Anticoagulation

* Antithrombin inhibits activated forms of factors II, VII, IX, X, XI, XII. * Heparin enhances the activity of Antithrombin. * Targets of Antithrombin: * Thrombin * Factor Xa * Factor V Leiden mutation produces a factor V resistant to inhibition by activated protein C. * tPA is used clinically as a thrombolytic.

Platelet Plug Formation | (Primary Hemostasis)

Thrombogenesis

* Formation of insoluble fibrin mesh. * Aspirin irreversibly inhibits cyclooxygenase, thereby inhibiting TXA2 synthesis. * Clopidogrel, prasugrel, and ticlopidine inhibit ADP-induced expression of GpIIb/IIIa by irreversibly blocking P2Y12 receptor. * Abciximab, eptifibatide, and tirofiban inhibit GpIIb/IIIa directly. * Ristocetin activates vWF to bind GpIb. * Failure of aggregation with ristocetin assay occurs in von Willebrand disease and Bernard-Soulier syndrome.

Pathologic RBC Forms: * liver disease * abetalipoproteinemia (states of cholesterol dysregulation) * spiny appearance

Acanthocytes | (“Spur Cells”)

Pathologic RBC Forms: * Sideroblastic Anemias: * lead poisoning * myelodysplastic syndromes * thalassemias * seen primarily in peripheral smear, vs. ringed sideroblasts seen in bone marrow * aggregation of residual ribosomes

Basophilic Stippling

Pathologic RBC Forms: * bone marrow infiltration (eg. myelofibrosis) * thalassemias

Dacrocytes RBC “sheds a **tear**” because it’s mechanically squeezed out of its home in the bone marrow. | (“Teardrop Cells”)

Pathologic RBC Forms: G6PD deficiency

Degmacytes | (“Bite Cells”)

Pathologic RBC Forms: * end-stage renal disease * liver disease * pyruvate kinase deficiency * different from acanthocyte; its * projections are more uniform and * smaller.

Echinocytes | (“Burr Cells”)

Pathologic RBC Forms: * hereditary elliptocytosis * usually asymptomatic * caused by mutation in genes encoding RBC membrane proteins (eg. spectrin)

Elliptocytes

Pathologic RBC Forms: megaloblastic anemia (also hypersegmented PMNs)

Macro-Ovalocytes

Pathologic RBC Forms: * sideroblastic anemia * excess iron in mitochondria * seen in bone marrow with special staining (Prussian blue), vs. basophilic stippling in peripheral smear

Ringed Sideroblasts

Pathologic RBC Forms: * Microangiopathic Hemolytic Anemias: * DIC * TTP/HUS * HELLP syndrome * mechanical hemolysis (eg. heart valve prosthesis) * fragmented RBCs (eg. helmet cells)

Schistocytes

Pathologic RBC Forms: * sickle cell anemia * sickling occurs with dehydration, deoxygenation, and at high altitud

Sickle Cells

Pathologic RBC Forms: K K Hereditary spherocytosis, drug- and infection-induced hemolytic anemia. Small, spherical cells without central pallor.

Spherocytes

Pathologic RBC Forms: * HbC disease * asplenia * liver disease * thalassemia

Target Cells “**HALT**,” said the hunter to his **target**. * **H**bC disease * **A**splenia * **L**iver disease * **T**halassemia

RBC Abnormalities: * seen in G6PD deficiency * oxidation of Hb -SH groups to -S—S- → Hb precipitation, with subsequent phagocytic damage to RBC membrane bite cells.

Heinz Bodies (Hb)

RBC Abnormalities: Howell-Jolly bodies B B Seen in patients with functional hyposplenia or asplenia. Basophilic nuclear remnants found in RBCs. Howell-Jolly bodies are normally removed from RBCs by splenic macrophages.

Anemias

Microcytic, Hypochromic Anemias

MCV \< 80 fL * Defective Heme Synthesis: * iron deficiency (late) * lead poisoning * sideroblastic anemia * anemia of chronic disease * Defective Globin Chain: * thalassemias

Anemias: * microcytic, hypochromic * ↓ iron due to chronic bleeding (eg. GI loss, menorrhagia), malnutrition, absorption disorders, GI surgery (eg. gastrectomy), or ↑ demand (eg. pregnancy) → ↓ final step in heme synthesis * Labs: * ↓ iron * ↑ TIBC * ↓ ferritin * ↑ free erythrocyte protoporphyrin * ↑ RDW * ↑ central pallor * Symptoms: * fatigue * conjunctival pallor * pica (consumption of nonfood substances) * spoon nails (koilonychia) * May manifest as glossitis, cheilosis, or Plummer-Vinson syndrome (triad of iron deficiency anemia, esophageal webs, and dysphagia).

Iron Deficiency

\_\_\_\_\_ is the triad of iron deficiency anemia, esophageal webs, and dysphagia.

Plummer-Vinson Syndrome

Anemias: * microcytic, hypochromic * α-globin gene deletions → ↓ α-globin synthesis * cis deletion (deletions occur on same chromosome) prevalent in Asian populations * trans deletion (deletions occur on separate chromosomes) prevalent in African populations * normal is αα/αα

α-Thalassemia

α-Thalassemia: * 1 deleted α-globin gene (α α/α –) * no anemia (silent carrier)

α-Thalassemia Minima

α-Thalassemia: * 2 deleted α-globin genes * (α –/α –; trans) * (α α/– –; cis) * mild microcytic, hypochromic anemia * cis deletion may worsen outcome for the carrier’s offspring

α-Thalassemia Minor

α-Thalassemia: * 3 deleted α-globin genes (– –/– α) * excess β-globin forms β4 * moderate to severe microcytic hypochromic anemia

Hemoglobin H Disease (HbH)

α-Thalassemia: * 4 deleted α-globin genes (– –/– –) * no α-globin * excess γ-globin forms γ4 * hydrops fetalis * incompatible with life

Hemoglobin Barts Disease (Hb Barts)

Anemias: * microcytic, hypochromic * point mutations in splice sites and promoter sequences → ↓ β-globin synthesis * prevalent in Mediterranean populations

β-Thalassemia

β-Thalassemia: * heterozygote * β chain is underproduced * usually asymptomatic * diagnosis confirmed by ↑ HbA2 (\> 3.5%) on electrophoresi

β-Thalassemia Minor

β-Thalassemia: * homozygote * β chain is absent → severe microcytic, hypochromic anemia with target cells and increased anisopoikilocytosis requiring blood transfusion (2° hemochromatosis) * marrow expansion (“crew cut” on skull x-ray) → skeletal deformities * “chipmunk” facies * extramedullary hematopoiesis → hepatosplenomegaly * ↑ risk of parvovirus B19–induced aplastic crisis * ↑ HbF (α2γ2), HbA2 (α2δ2) * HbF is protective in the infant and disease becomes symptomatic only after 6 months, when fetal hemoglobin declines

β-Thalassemia Major

β-Thalassemia: mild to moderate sickle cell disease depending on amount of β-globin production

HbS/β-Thalassemia Heterozygote

Anemias: * microcytic, hypochromic * inhibits ferrochelatase and ALA dehydratase → ↓ heme synthesis and ↑ RBC protoporphyrin * also inhibits rRNA degradation → RBCs retain aggregates of rRNA (basophilic stippling) * Succimer used for chelation for kids * exposure risk ↑ in old houses with chipped paint

Lead Poisoning

Symptoms of Lead Poisoning

**LEAD**: * **L**ead **L**ines on gingivae (Burton lines) and on metaphyses of long bones on x-ray * **E**ncephalopathy and **E**rythrocyte basophilic stippling * **A**bdominal colic and sideroblastic **A**nemia * **D**rops—wrist and foot drop, **D**imercaprol and EDTA are 1st line of treatment

Anemias: * microcytic, hypochromic * Causes: * genetic (eg. X-linked defect in ALA synthase gene) * acquired (myelodysplastic syndromes) * reversible (alcohol is most common; also lead, vitamin B6 deficiency, copper deficiency, isoniazid, chloramphenicol). * Lab findings: * ↑ iron * normal/↓ TIBC * ↑ferritin * ringed sideroblasts (with iron-laden, Prussian blue–stained mitochondria) seen in bone marrow * peripheral blood smear—basophilic stipplin of RBCs * Treatment: * Pyridoxine (B6, cofactor for ALA synthase)

Sideroblastic Anemia

Macrocytic Anemias

MCV \> 100 fL * Megaloblastic (Nuclear Defects): * Defective DNA Synthesis: * folate deficiency * vitamin B12 deficiency * orotic aciduria * Defective DNA Repair: * •Fanconi anemia * Nonmegaloblastic * Diamond-Blackfan anemia * liver disease * alcoholism

Anemias: * macrocytic * impaired DNA synthesis → maturation of nucleus of precursor cells in bone marrow delayed relative to maturation of cytoplasm * RBC macrocytosis, hypersegmented neutrophils, glossitis

Megaloblastic Anemia

Anemias: * macrocytic * megaloblastic * Causes: * malnutrition (eg. alcoholics) * malabsorption * drugs (eg. methotrexate, trimethoprim, phenytoin) * ↑ requirement (eg. hemolytic anemia, pregnancy) * ↑ homocysteine, normal methylmalonic acid * no neurologic symptoms (vs. B12 deficiency)

Folate Deficiency

Anemias: * macrocytic * megaloblastic * Causes: * pernicious anemia * malabsorption (eg. Crohn disease) * gastrectomy * insufficient intake (eg. veganism) * *Diphyllobothrium latum* (fish tapeworm) * ↑ homocysteine, ↑ methylmalonic acid * Neurologic Symptoms: * reversible dementia * subacute combined degeneration (due to involvement of B12 in fatty acid pathways and myelin synthesis)—spinocerebellar tract, lateral corticospinal tract, dorsal column dysfunction * historically diagnosed with the Schilling test, a 4-stage test that determines if the cause is dietary insufficiency vs. malabsorption * anemia 2° to insufficient intake may take several years to develop due to liver’s ability to store B12 (as opposed to folate deficiency)

Vitamin B12 (Cobalamin) Deficiency

Anemias: * macrocytic * megaloblastic * inability to convert orotic acid to UMP (de novo pyrimidine synthesis pathway) because of defect in UMP synthase * autosomal recessive * presents in children as failure to thrive, developmental delay, and megaloblastic anemia refractory to folate and B12 * no hyperammonemia (vs. ornithine transcarbamylase deficiency—↑ orotic acid with hyperammonemia) * orotic acid in urine * Treatment: * uridine monophosphate * uridine triacetate * both bypass mutated enzyme

Orotic Aciduria

Anemias: * macrocytic * DNA synthesis is unimpaired * Causes: * alcoholism * liver disease * RBC macrocytosis without hypersegmented neutrophils

Nonmegaloblastic Anemia

Anemias: * macrocytic * nonmegaloblastic * rapid-onset anemia within 1st year of life due to intrinsic defect in erythroid progenitor cells * ↑ % HbF (but ↓ total Hb) * short stature, craniofacial abnormalities, and upper extremity malformations (triphalangeal thumbs) in up to 50% of cases

Diamond-Blackfan Anemia

Normocytic, Hemolytic Anemias

MCV 80–100 fL, reticulocyte count \> 2%: * Intrinsic: * Membrane Defects: * hereditary spherocytosis * paroxysmal nocturnal hemoglobinuria * Enzyme Deficiencies: * G6PD deficiency * pyruvate kinase deficiency * Hemoglobinopathies: * sickle cell anemia * HbC disease * Extrinsic: * autoimmune * microangiopathic * macroangiopathic * infections

Normocytic, Nonhemolytic Anemias

MCV 80–100 fL, reticulocyte count ≤ 2%: * iron deficiency (early) * anemia of chronic disease * aplastic anemia * chronic kidney disease

Anemias: * classified as nonhemolytic or hemolytic * the hemolytic anemias are further classified according to the cause of the hemolysis (intrinsic vs. extrinsic to the RBC) and by the location of the hemolysis (intravascular vs. extravascular) * hemolysis can lead to increases in LDH, reticulocytes, unconjugated bilirubin, urobilinogen in urine

Normocytic, Normochromic Anemia

Anemias: * ↓ haptoglobin * ↑ schistocytes on blood smear * characteristic hemoglobinuria, hemosiderinuria, and urobilinogen in urine * may also see ↑ unconjugated bilirubin * notable causes are mechanical hemolysis (eg. prosthetic valve), paroxysmal nocturnal hemoglobinuria, microangiopathic hemolytic anemias

Intravascular Hemolysis

Anemias: * macrophages in spleen clear RBCs * spherocytes in peripheral smear (most commonly hereditary spherocytosis and autoimmune hemolytic anemia), no hemoglobinuria/hemosiderinuria * can present with urobilinogen in urine

Extravascular Hemolysis

Anemias: * nonhemolytic, normocytic * inflammation → ↑ hepcidin (released by liver, binds ferroportin on intestinal mucosal cells and macrophages, thus inhibiting iron transport) → ↓ release of iron from macrophages and ↓ iron absorption from gut * associated with conditions such as rheumatoid arthritis, SLE, neoplastic disorders, and chronic kidney disease * ↓ iron, ↓ TIBC, ↑ ferritin * normocytic, but can become microcytic * Treatment: * address underlying cause of inflammation * judicious use of blood transfusion * consider erythropoiesis-stimulating agents such as EPO (eg. in chronic kidney disease)

Anemia of Chronic Disease

Anemias: * nonhemolytic, normocytic * caused by failure or destruction of myeloid stem cells * ↓ reticulocyte count, ↑ EPO * pancytopenia characterized by anemia, leukopenia, and thrombocytopenia * normal cell morphology, but hypocellular bone marrow with fatty infiltration (dry bone * marrow tap) * Symptoms: fatigue, malaise, pallor, purpura, mucosal bleeding, petechiae, infection * Treatment: * withdrawal of offending agent * immunosuppressive regimens (eg. antithymocyte globulin, cyclosporine) * bone marrow allograft * RBC/platelet transfusion * bone marrow stimulation (eg. GM-CSF)

Aplastic Anemia

Cuases of Aplastic Anemia

* Radiation and Drugs (eg. benzene, chloramphenicol, alkylating agents, antimetabolites) * Viral Agents (EBV, HIV, hepatitis viruses) * Fanconi Anemia (DNA repair defect causing bone marrow failure; macrocytosis may be seen on CBC); also short stature, ↑ incidence of tumors/leukemia, café-au-lai spots, thumb/radial defects * Idiopathic (immune mediated, 1° stem cell defect); may follow acute hepatitis

Anemias: * intrinsic hemolytic anemia * extravascular hemolysis due to defect in proteins interacting with RBC membrane skeleton and plasma membrane (eg. ankyrin, band 3, protein 4.2, spectrin) * mostly autosomal dominant inheritance * results in small, round RBCs with less surface area and no central pallor (↑ MCHC) → premature removal by spleen * splenomegaly, aplastic crisis (parvovirus B19 infection) * Labs: * ↑ fragility in osmotic fragility test * normal to ↓ MCV with abundance of cells * Treatment: splenectomy

Hereditary Spherocytosis

Anemias: * intrinsic hemolytic anemia * most common enzymatic disorder of RBCs * causes extravascular and intravascular hemolysis * X-linked recessive * defect in G6PD → ↓ reduced glutathione → ↑ RBC susceptibility to oxidant stress * hemolytic anemia following oxidant stress (eg. sulfa drugs, antimalarials, infections, fava beans) * back pain, hemoglobinuria a few days after oxidant stress * Labs: blood smear shows RBCs with Heinz bodies and bite cells

G6PD Deficiency “**Stress** makes me eat **bite**s of **fava beans** with **Heinz** ketchup.”

Anemias: * intrinsic hemolytic anemia * autosomal recessive pyruvate kinase defect → ↓ ATP → rigid RBCs → extravascular hemolysis * increases levels of 2,3-BPG → ↓ hemoglobin affinity for O₂ * hemolytic anemia in a newborn

Pyruvate Kinase Deficiency

Anemias: * intrinsic hemolytic anemia * ↑ complement-mediated intravascular RBC lysis (acquired mutation in PIGA gene → impaired synthesis of GPI anchor for decay-accelerating factor [DAF/CD55] and membrane inhibitor of reactive lysis [MIRL/CD59] that protects RBC membrane from complement) * acquired mutation in a hematopoietic stem cell * ↑ incidence of acute leukemias * associated with aplastic anemia * Triad: * Coombs ⊝ hemolytic anemia * pancytopenia * venous thrombosis * red or pink urine (from hemoglobinuria) * Labs: CD55/59 ⊝ RBCs on flow cytometry * Treatment: Eculizumab (inhibits terminal complement formation)

Paroxysmal Nocturnal Hemoglobinuria

Anemias: * intrinsic hemolytic anemia * HbS point mutation causes a single amino acid replacement in β chain (substitution of glutamic acid with valine) * causes extravascular and intravascular hemolysis * Pathogenesis: low O₂, high altitude, or acidosis precipitates sickling (deoxygenated HbS polymerizes) → anemia, vaso-occlusive disease. * newborns are initially asymptomatic because of ↑ HbF and ↓ HbS * heterozygotes (sickle cell trait) also have resistance to malaria * 8% of African Americans carry an HbS allele. * crescent-shaped RBCs * “crew cut” on skull x-ray due to marrow expansion from ↑ erythropoiesis (also seen in thalassemias) * Diagnosis: hemoglobin electrophoresis * Treatment: hydroxyurea (↑ HbF), hydration

Sickle Cell Anemia

Sickle Cell Anemia Complications

* aplastic crisis (due to parvovirus B19) * autosplenectomy (Howell-Jolly bodies) → ↑ risk of infection by encapsulated organisms (eg. *S. pneumoniae*) * splenic infarct/sequestration crisis * *Salmonella* osteomyelitis * painful crises (vaso-occlusive): dactylitis (painful swelling of hands/feet), priapism,acute chest syndrome, avascular necrosis, stroke * sickling in renal medulla (↓ Po₂) → renal papillary necrosis → microhematuria

Anemias: * intrinsic hemolytic anemia * glutamic acid–to–lysine mutation in β-globin * causes extravascular hemolysis * patients with HbSC (1 of each mutant gene) have milder disease than HbSS patients * blood smear in homozygotes: hemoglobin crystals inside RBCs, target cells

HbC Disease glutamic acid–to–ly**C**ine, hemoglobin **C**rystals

Anemias: * extrinsic hemolytic anemia * _Warm (IgG)_ * __chronic anemia seen in SLE and CLL and with certain drugs (eg. α-methyldopa) * _Cold (IgM and complement)_ * __acute anemia triggered by cold; seen in CLL, *Mycoplasma pneumoniae* infections, and infectious mononucleosis * RBC agglutinates may cause painful, blue fingers and toes with cold exposure * many are idiopathic * usually Coombs ⊕

Autoimmune Hemolytic Anemia **Warm** weather is **G**reat, **cold** weather is **MMM**iserable. * **Warm**—Ig**G** * **Cold** * ****Ig**M** and Complement * ***M**ycoplasma pneumoniae* * Infectious **M**ononucleosis

Coombs Test

* Direct Coombs Test * anti-Ig antibody (Coombs reagent) added to patient’s RBCs * RBCs agglutinate if RBCs are coated with Ig * Indirect Coombs Test * normal RBCs added to patient’s serum * If serum has anti-RBC surface Ig, RBCs agglutinate when Coombs reagent added

Anemias: * extrinsic hemolytic anemia * RBCs are damaged when passing through obstructed or narrowed vessel lumina * seen in DIC, TTP/HUS, SLE, HELLP syndrome, and hypertensive emergency * schistocytes (eg. “helmet cells”) are seen on peripheral blood smear due to mechanical destruction (schisto = to split) of RBCs

Microangiopathic Anemia

Anemias: * extrinsic hemolytic anemia * prosthetic heart valves and aortic stenosis may cause hemolytic anemia 2° to mechanical destruction of RBCs * schistocytes on peripheral blood smear

Macroangiopathic Anemia

Anemias: * extrinsic hemolytic anemia * ↑ destruction of RBCs (eg. malaria, *Babesia*)

Infections

Interpretation of Iron Studies

Leukopenias

Left Shift

* ↑ neutrophil precursors, such as band cells and metamyelocytes, in peripheral blood. * Usually seen with neutrophilia in the acute response to infection or inflammation. * Called **Leukoerythroblastic Reaction** when left shift is seen with immature RBCs. * Occurs with severe anemia (physiologic response) or marrow response (eg. fibrosis, tumor taking up space in marrow). * A left shift is a shift to a more immature cell in the maturation process.

The _____ are hereditary or acquired conditions of defective heme synthesis that lead to the accumulation of heme precursors. Lead inhibits specific enzymes needed in heme synthesis, leading to a similar condition.

Porphyrias

Porphyrias: * Affected Enzymes: * Ferrochelatase * ALA dehydratase * Accumulated Substrate: * Protoporphyrin * ALA (blood) * Symptoms: * microcytic anemia (basophilic stippling in peripheral smear, ringed sideroblasts in bone marrow) * GI and kidney disease * Children—exposure to paint → mental deterioration * Adults—environmental exposure (eg. batteries, ammunition) → headache, memory loss, demyelination

Lead Poisoning

Porphyrias: * Affected Enzymes: * Porphobilinogen Deaminase—previously known as Uroporphyrinogen I Synthase (autosomal dominant mutation) * Accumulated Substrate: * Porphobilinogen * ALA * Symptoms: * painful abdomen * port wine–colored urine * polyneuropathy * psychological disturbances * precipitated by drugs (eg. cytochrome P-450 inducers), alcohol, and starvation * Treatment: * Hemin and Glucose, which inhibit ALA synthase

Acute Intermittent Porphyria Symptoms (**5 P**’s): * **P**ainful abdomen * **P**ort wine–colored urine * **P**olyneuropathy * **P**sychological disturbances * **P**recipitated by drugs (eg. cytochrome P-450 inducers), alcohol, and starvation

Porphyrias: * Affected Enzymes: * Uroporphyrinogen Decarboxylase (autosomal dominant mutation) * Accumulated Substrate: * Uroporphyrin (teacolored urine) * Symptoms: * blistering cutaneous photosensitivity and hyperpigmentation * most common porphyria * exacerbated with alcohol consumption * associated with hepatitis C

Porphyria Cutanea Tarda

Heme Synthesis

Iron Poisoning

* High mortality rate with accidental ingestion by children (adult iron tablets may look like candy). * Mechanism: * cell death due to peroxidation of membrane lipids. * Signs and Symptoms: * nausea, vomiting, gastric bleeding, lethargy, scarring leading to GI obstruction * Treatment: * Chelation (eg. IV Deferoxamine, oral Deferasirox) * Dialysis

Coagulation Tests: tests function of common and extrinsic pathway (factors I, II, V, VII, and X)

Coagulation Tests: * calculated from PT * 1 = normal, \> 1 = prolonged * most common test used to follow patients on Warfarin

INR (International Normalized Ratio)

Coagulation Tests: tests function of common and intrinsic pathway (all factors except VII and XIII)

PTT

\_\_\_\_\_ can be due to clotting factor deficiencies or acquired inhibitors. Diagnosed with a mixing study, in which normal plasma is added to patient’s plasma. Clotting factor deficiencies should correct (the PT or PTT returns to within the appropriate normal range), whereas factor inhibitors will not correct.

Coagulation Disorders

Coagulation Disorders: * intrinsic pathway coagulation defect (↑ PTT). * A: deficiency of factor VIII; X-linked recessive. * B: deficiency of factor IX; X-linked recessive. * C: deficiency of factor XI; autosomal recessive. * hemorrhage—hemarthroses (bleeding into joints, eg. knee), easy bruising, bleeding after trauma or surgery (eg. dental procedures) * Treatment: * Desmopressin + Factor VIII concentrate (A) * Factor IX concentrate (B) * Factor XI concentrate (C)

Hemophilia A, B, or C

Coagulation Disorders: * ↑ PT and PTT * general coagulation defect * bleeding time normal * ↓ activity of factors II, VII, IX, X, protein C, protein S

Vitamin K Deficiency

Defects in platelet plug formation causes \_\_\_\_\_.

↑ bleeding time (BT)

Platelet abnormalities cause \_\_\_\_\_.

* microhemorrhage * mucous membrane bleeding * epistaxis * petechiae * purpura * ↑ bleeding time * possibly decreased platelet count (PC)

Platelet Disorders: * –/↓ PT * ↑ PTT * defect in platelet plug formation * large platelets * ↓ GpIb → defect in platelet-to-vWF adhesion * abnormal ristocetin test that does not correct with mixing studies

Bernard-Soulier Syndrome

Platelet Disorders: * – PT * ↑ PTT * defect in platelet integrin αIIbβ3 (GpIIb/IIIa) → defect in platelet-to-platelet aggregation, and therefore platelet plug formation * blood smear shows no platelet clumping

Glanzmann Thrombasthenia

Platelet Disorders: * ↓ PT * ↑ PTT * characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure * typically seen in children, accompanied by diarrhea and commonly caused by Shiga-like toxin of enterohemorrhagic E coli (EHEC) (eg. O157:H7) * in adults, does not present with diarrhea; EHEC infection not required * same spectrum as TTP, with a similar clinical presentation and same initial treatment of plasmapheresis

Hemolytic-Uremic Syndrome

Platelet Disorders: * ↓ PT * ↑ PTT * Anti-GpIIb/IIIa antibodies → splenic macrophage consumption of platelet‑antibody complex * may be 1° (idiopathic) or 2° to autoimmune disorder, viral illness, malignancy, or drug reaction * ↑ megakaryocytes on bone marrow biopsy * Treatment: * Steroids * IVIG * Rituximab or splenectomy for refractory disease

Immune Thrombocytopenia

Platelet Disorders: * ↓ PT * ↑ PTT * Inhibition or deficiency of ADAMTS 13 (vWF metalloprotease) → ↓ degradation of vWF multimers. * Pathogenesis: * ↑ large vWF multimers → ↑ platelet adhesion → ↑ platelet aggregation and thrombosis * Labs: * schistocytes * ↑ LDH * normal coagulation parameters * Symptoms: * pentad of fever * microangiopathic hemolytic anemia * thrombocytopenia * renal failure * neurologic symptoms * Treatment: * Plasmapheresis * Steroids

Thrombotic Thrombocytopenic Purpura **FAT RN**: * **F**ever * microangiopathic hemolytic **A**nemia * **T**hrombocytopenia * **R**enal failure * **N**eurologic symptoms

Mixed Platelet and Coagulation Disorders: * ↑ BT * —/↑ PTT * intrinsic pathway coagulation defect: ↓ vWF → ↑ PTT (vWF acts to carry/protect factor VIII) * defect in platelet plug formation: ↓ vWF → defect in platelet-to-vWF adhesion * autosomal dominant * mild but most common inherited bleeding disorder * no platelet aggregation with ristocetin cofactor assay * Treatment: * Desmopressin, which releases vWF stored in endothelium

von Willebrand Disease

Mixed Platelet and Coagulation Disorders: * ↓ PC * ↑ BT * ↑ PT * ↑ PTT * widespread activation of clotting → deficiency in clotting factors → bleeding state * Causes: * sepsis (gram ⊝) * trauma * obstetric complications * acute pancreatitis * malignancy * nephrotic syndrome * transfusion * Labs: * schistocytes * ↑ fibrin degradation products (d-dimers) * ↓ fibrinogen * ↓ factors V and VIII

Disseminated Intravascular Coagulation **STOP** **M**aking **N**ew **T**hrombi. * **S**epsis (gram ⊝) * **T**rauma * **O**bstetric complications * acute **P**ancreatitis * **M**alignancy * **N**ephrotic syndrome * **T**ransfusion

Hereditary Thrombosis Syndromes leading to Hypercoagulability: * inherited deficiency of antithrombin * has no direct effect on the PT, PTT, or thrombin time but diminishes the increase in PTT following heparin administration * can also be acquired * renal failure/nephrotic syndrome → antithrombin loss in urine → ↓ inhibition of factors IIa and Xa

Antithrombin Deficiency

Hereditary Thrombosis Syndromes leading to Hypercoagulability: * production of mutant factor V (G → A DNA point mutation → Arg506Gln mutation near the cleavage site) that is resistant to degradation by activated protein C * most common cause of inherited hypercoagulability in Caucasians * complications include DVT, cerebral vein thromboses, recurrent pregnancy loss

Factor V Leiden

Hereditary Thrombosis Syndromes leading to Hypercoagulability: * ↓ ability to inactivate factors Va and VIIIa * ↑ risk of thrombotic skin necrosis with hemorrhage after administration of warfarin

Protein C or S Deficiency Together, protein C **C**ancels, and protein S **S**tops, coagulation.

Hereditary Thrombosis Syndromes leading to Hypercoagulability: mutation in 3′ untranslated region → ↑ production of prothrombin → ↑ plasma levels and venous clots

Prothrombin Gene Mutation

Blood Transfusion Therapy: * ↑ Hb and O₂ carrying capacity * used for acute blood loss and severe anemia

Packed RBCs

Blood Transfusion Therapy: * ↑ platelet count (↑ ∼ 5000/mm3/unit) * stop significant bleeding (thrombocytopenia, qualitative platelet defects)

Platelets

Blood Transfusion Therapy: * ↑ coagulation factor levels * FFP contains all coagulation factors and plasma proteins * PCC generally contains factors II, VII, IX, and X, as well as protein C and S * used for DIC, cirrhosis, and immediate anticoagulation reversal

Fresh Frozen Plasma/Prothrombin Complex Concentrate

Blood Transfusion Therapy: * contains fibrinogen, factor VIII, factor XIII, vWF, and fibronectin * used for coagulation factor deficiencies involving fibrinogen and factor VIII

Cryoprecipitate

Blood Transfusion Risks

* Infection Transmission (low) * Transfusion Reactions * Iron Overload (may lead to 2° hemochromatosis) * Hypocalcemia (citrate is a Ca²⁺ chelator) * Hyperkalemia (RBCs may lyse in old blood units)

\_\_\_\_\_ is a lymphoid or myeloid neoplasm with widespread involvement of bone marrow. Tumor cells are usually found in peripheral blood.

Leukemia

\_\_\_\_\_ is a discrete tumor mass arising from lymph nodes. Presentations often blur definitions.

Lymphoma

Lymphomas: * may present with constitutional (“B”) signs/symptoms: low-grade fever, night sweats, weight loss * localized, single group of nodes * contiguous spread (stage is strongest predictor of prognosis) * overall prognosis is better * Reed-Sternberg cells * Bimodal Distribution: * young adulthood * \> 55 years * more common in men except for nodular sclerosing type * associated with EBV

Hodgkin

Lymphomas: * may present with constitutional (“B”) signs/symptoms: low-grade fever, night sweats, weight loss * multiple lymph nodes involved * extranodal involvement is common * noncontiguous spread * majority involve B cells; a few are of T-cell lineage * can occur in children and adults * may be associated with HIV and autoimmune diseases

Non-Hodgkin

Hodgkin lymphoma contains \_\_\_\_\_, distinctive tumor giant cells which are binucleate or bilobed with the 2 halves as mirror images (“owl eyes”).

Reed-Sternberg Cells 2 owl eyes × **15** = **30** RS cells are CD**15**+ and CD**30**+ B-cell origin.

Hodgkin Lymphoma: most common

Nodular Sclerosis

Hodgkin Lymphoma: best prognosis

Lymphocyte Rich

Hodgkin Lymphoma: * eosinophilia * seen in immunocompromised patients

Mixed Cellularity

Hodgkin Lymphoma: seen in immunocompromised patients

Lymphocyte Depleted

Non-Hodgkin Lymphoma: * mature B cells * adolescents or young adults * t(8;14)—translocation of c-myc (8) and heavy-chain Ig (14) * “starry sky” appearance, sheets of lymphocytes with interspersed “tingible body” macrophages * associated with EBV * jaw lesion in endemic form in Africa * pelvis or abdomen lesion in sporadic form

Burkitt Lymphoma

Non-Hodgkin Lymphoma: * mature B cells * usually older adults, but 20% in children * alterations in Bcl-2 and Bcl-6 * most common type of non-Hodgkin lymphoma in adults

Diffuse Large B-Cell Lymphoma

Non-Hodgkin Lymphoma: * mature B cells * adults * t(14;18)—translocation of heavy-chain Ig (14) and BCL-2 (18) * indolent course * Bcl-2 inhibits apoptosis * presents with painless “waxing and waning” lymphadenopathy

Follicular Lymphoma

Non-Hodgkin Lymphoma: * mature B cells * adult males * t(11;14)—translocation of cyclin D1 (11) and heavy-chain Ig (14), CD 5+ * very aggressive * patients typically present with late-stage disease

Mantle Cell Lymphoma

Non-Hodgkin Lymphoma: * mature B cells * adults * t(11;18) * associated with chronic inflammation (eg. Sjögren syndrome, chronic gastritis [MALT lymphoma])

Marginal Zone Lymphoma

Non-Hodgkin Lymphoma: * mature B cells * adults * most commonly * associated with HIV/AIDS * pathogenesis involves EBV infection * considered an AIDS-defining illness * variable presentation: confusion, memory loss, seizures * mass lesion(s) (may be ring-enhancing in immunocompromised patient) on MRI * needs to be distinguished from toxoplasmosis via CSF analysis or other lab tests

Primary Central Nervous System Lymphoma

Non-Hodgkin Lymphoma: * mature T cells * adults * caused by HTLV (associated with IV drug abuse) * adults present with cutaneous lesions * common in Japan, West Africa, and the Caribbean * lytic bone lesions * hypercalcemi

Adult T-Cell Lymphoma

Non-Hodgkin Lymphoma: * mature T cells * adults * skin patches/plaques (cutaneous T-cell lymphoma) * characterized by atypical CD4+ cells with “cerebriform” nuclei and intraepidermal neoplastic cell aggregates (Pautrier microabscess)

Mycosis Fungoides/Sézary Syndrome

Hematologic Pathologies: * monoclonal plasma cell (“fried egg” appearance) cancer that arises in the marrow and produces large amounts of IgG (55%) or IgA (25%) * bone marrow \> 10% monoclonal plasma cells * most common 1° tumor arising within bone in people \> 40–50 years old * numerous plasma cells with “clock‑face” chromatin and intracytoplasmic inclusions containing immunoglobulin

Multiple Myeloma **CRAB**: * Hyper**C**alcemia * **R**enal involvement * **A**nemia * **B**one lytic lesions/**B**ack pain **M**onoclonal **M** protein spike

Multiple Myeloma is associated with \_\_\_\_\_

* ↑ susceptibility to infection * primary amyloidosis (AL) * punched-out lytic bone lesions on x-ray * M spike on serum protein electrophoresis * Ig light chains in urine (Bence Jones protein) * Rouleaux formation (RBCs stacked like poker chips in blood smear)

Hematologic Pathologies: * monoclonal expansion of plasma cells (bone marrow \< 10% monoclonal plasma cells) * asymptomatic * may lead to multiple myeloma * no CRAB findings * patients develop multiple myeloma at a rate of 1–2% per year

Monoclonal Gammopathy of Undetermined Significance (MGUS) No **CRAB** findings. * Hyper**C**alcemia * **R**enal involvement * **A**nemia * **B**one lytic lesions/**B**ack pain

Hematologic Pathologies: * should be distinguished from Multiple Myeloma * M spike = IgM → hyperviscosity syndrome (eg. blurred vision, Raynaud phenomenon) * no CRAB findings

Waldenström Macroglobulinemia No **CRAB** findings. * Hyper**C**alcemia * **R**enal involvement * **A**nemia * **B**one lytic lesions/**B**ack pain

Hematologic Pathologies: * stem-cell disorders involving ineffective hematopoiesis → defects in cell maturation of nonlymphoid lineages * caused by de novo mutations or environmental exposure (eg. radiation, benzene, chemotherapy) * risk of transformation to AML

Myelodysplastic Syndromes

Hematologic Pathologies: * neutrophils with bilobed (“duet”) nuclei * typically seen after chemotherapy

Pseudo-Pelger-Huet Anomaly

Hematologic Pathologies: * unregulated growth and differentiation of WBCs in bone marrow → marrow failure → anemia (↓ RBCs), infections (↓ mature WBCs), and hemorrhage (↓ platelets) * usually presents with ↑ circulating WBCs (malignant leukocytes in blood) * rare cases present with normal/↓ WBCs * cell infiltration of liver, spleen, lymph nodes, and skin (leukemia cutis) possible

Leukemia

Lymphoid Neoplasms: * most frequently occurs in children * less common in adults (worse prognosis) * T-cell _____ can present as mediastinal mass (presenting as SVC-like syndrome) * associated with Down Syndrome * peripheral blood and bone marrow have ↑↑↑ lymphoblasts * TdT+ (marker of pre-T and pre-B cells) * CD10+ (marker of pre-B cells) * most responsive to therapy * may spread to CNS and testes * t(12;21) → better prognosis

Acute Lymphoblastic Leukemia/Lymphoma

Lymphoid Neoplasms: * age \> 60 years * most common adult leukemia * CD20+, CD23+, CD5+ B-cell neoplasm * often asymptomatic, progresses slowly * smudge cells in peripheral blood smear * autoimmune hemolytic anemia * Richter Transformation—transformation into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL)

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma **CLL** = **C**rushed **L**ittle **L**ymphocytes (smudge cells)

Lymphoid Neoplasms: * adult males * mature B-cell tumor * cells have filamentous, hair-like projections (fuzzy appearing on LM) * peripheral lymphadenopathy is uncommon * causes marrow fibrosis → dry tap on aspiration * patients usually present with massive splenomegaly and pancytopenia * stains TRAP (tartrate-resistant acid phosphatase) ⊕ * TRAP stain largely replaced with flow cytometry * Treatment: * Cladribine * Pentostatin

Hairy Cell Leukemia

Myeloid Neoplasms: * median onset 65 years * Auer rods * myeloperoxidase ⊕ cytoplasmic inclusions seen mostly in APL (formerly M3) * ↑↑↑ circulating myeloblasts on peripheral smear * Risk Factors: * prior exposure to alkylating chemotherapy * radiation * myeloproliferative disorders * Down Syndrome * APL: * t(15;17) * responds to all-trans retinoic acid (vitamin A) * inducing differentiation of promyelocytes * DIC is a common presentation

Acute Myelogenous Leukemia

Myeloid Neoplasms: * occurs across the age spectrum with peak incidence 45–85 years, median age at diagnosis 64 years * defined by the Philadelphia chromosome (t[9;22], BCR-ABL) and myeloid stem cell proliferation * presents with dysregulated production of mature and maturing granulocytes (eg. neutrophils, metamyelocytes, myelocytes, basophils) and splenomegaly * may accelerate and transform to AML or ALL (“blast crisis”) * very low LAP as a result of low activity in malignant neutrophils (vs. benign neutrophilia [leukemoid reaction], in which LAP is ↑) * responds to bcr-abl tyrosine kinase inhibitors (eg. imatinib, dasatinib)

Chronic Myelogenous Leukemia

Hematologic Pathologies: * the myeloproliferative disorders (polycythemia vera, essential thrombocythemia, myelofibrosis, and CML) are malignant hematopoietic neoplasms with varying impacts on WBCs and myeloid cell lines * associated with V617F JAK2 mutation

Chronic Myeloproliferative Disorders

Chronic Myeloproliferative Disorders: * primary polycythemia * disorder of ↑ RBCs * may present as intense itching after hot shower * rare but classic symptom is erythromelalgia (severe, burning pain and red-blue coloration) due to episodic blood clots in vessels of the extremities * ↓ EPO (vs. 2° polycythemia, which presents with endogenous or artificially ↑ EPO) * Treatment: * phlebotomy * Hydroxyurea * Ruxolitinib (JAK1/2 inhibitor)

Polycythemia Vera

Chronic Myeloproliferative Disorders: * characterized by massive proliferation of megakaryocytes and platelets * symptoms include bleeding and thrombosis * blood smear shows markedly increased number of platelets, which may be large or otherwise abnormally formed * erythromelalgia may occur

Essential Thrombocythemia

Chronic Myeloproliferative Disorders: * obliteration of bone marrow with fibrosis due to ↑ fibroblast activity * often associated with massive splenomegaly and “teardrop” RBCs

Myelofibrosis

Chronic Myeloproliferative Disorders

Polycythemia

Chromosomal Translocations: Burkitt Lymphoma (c-myc activation)

t(8;14) Burk-**8**

Chromosomal Translocations: * CML (BCR-ABL hybrid) * ALL (less common, poor prognostic factor) * 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.

t(9;22) (Philadelphia Chromosome) **Philadelphia C**rea**ML** cheese

Chromosomal Translocations: Mantle Cell Lymphoma (cyclin D1 activation)

t(11;14)

Chromosomal Translocations: Follicular Lymphoma (BCL-2 activation)

t(14;18)

Chromosomal Translocations: * APL (M3 type of AML) * responds to all-trans retinoic acid

t(15;17)

Hematologic Pathologies: * collective group of proliferative disorders of dendritic (Langerhans) cells * presents in a child as lytic bone lesions and skin rash or as recurrent otitis media with a mass involving the mastoid bone * cells are functionally immature and do not effectively stimulate primary T cells via antigen presentatio. * cells express S-100 (mesodermal origin) and CD1a * Birbeck granules (“tennis rackets” or rod shaped on EM) are characteristic

Langerhans Cell Histiocytosis

Hematologic Pathologies: * oncologic emergency triggered by massive tumor cell lysis, most often in lymphomas/leukemias * release of K⁺ → hyperkalemia, release of PO₄^3– → hyperphosphatemia, hypocalcemia due to Ca²⁺ sequestration by PO₄^3– * ↑ nucleic acid breakdown → hyperuricemia → acute kidney injury * prevention and treatment include aggressive hydration, Allopurinol, Rasburicase

Tumor Lysis Syndrome * ↑ K⁺ * ↑ PO₄^3– * ↑ Uric Acid * ↓ Ca²⁺

Hematologic Drugs: * activates antithrombin, which ↓ action of IIa (thrombin) and factor Xa * short half-life * immediate anticoagulation for pulmonary embolism (PE), acute coronary syndrome, MI, deep venous thrombosis (DVT) * used during pregnancy (does not cross placenta) * follow PTT

Heparin

Hematologic Drugs: * causes bleeding, thrombocytopenia (HIT), osteoporosis, and drug-drug interactions * for rapid reversal (antidote), use Protamine Sulfate (positively charged molecule that binds negatively charged \_\_\_\_\_) * low-molecular-weight _____ (eg. enoxaparin, dalteparin) act predominantly on factor Xa * fondaparinux acts only on factor Xa * have better bioavailability and 2–4× longer half life than unfractionated \_\_\_\_\_ * can be administered subcutaneously and without laboratory monitoring * not easily reversible

Heparin

\_\_\_\_\_ is the development of IgG antibodies against heparinbound platelet factor 4 (PF4). Antibody-heparin-PF4 complex activates platelets → thrombosis and thrombocytopenia.

Heparin-Induced Thrombocytopenia (HIT)

Direct Thrombin Inhibitors

* Bivalirudin (related to Hirudin, the anticoagulant used by leeches) * Argatroban * Dabigatran (only oral agent in class)

Hematologic Drugs: * directly inhibits activity of free and clot-associated thrombin * used for venous thromboembolism and atrial fibrillation * can be used in HIT, when heparin is BAD for the patient * does not require lab monitoring * causes bleeding * can reverse Dabigatran with Idarucizumab * consider PCC and/or antifibrinolytics (eg. tranexamic acid) if no reversal agent available

Direct Thrombin Inhibitors

Hematologic Drugs: * interferes with γ-carboxylation of vitamin K-dependent clotting factors II, VII, IX, and X, and proteins C and S * metabolism is affected by polymorphisms in the gene for vitamin K epoxide reductase complex (VKORC1) * in laboratory assay, has effect on extrinsic pathway and ↑ PT * long half-life

Warfarin The **EX**-**P**residen**T** went to **war**(farin).

Hematologic Drugs: * used for chronic anticoagulation (eg. venous thromboembolism prophylaxis, and prevention of stroke in atrial fibrillation) * not used in pregnant women (crosses placenta) * follow PT/INR

Warfarin

Hematologic Drugs: * Causes bleeding, teratogenic effects, skin/tissue necrosis, and drug-drug interactions * initial risk of hypercoagulation: protein C has a shorter half-life than factors II and X * existing protein C depletes before existing factors II and X deplete, and before _____ can reduce factors II and X production → hypercoagulation * skin/tissue necrosis within first few days of large doses believed to be due to small vessel microthrombosis * for reversal, give vitamin K * for rapid reversal, give fresh frozen plasma (FFP) or PCC * Cytochrome P-450 inhibitors increase effect

Warfarin

\_\_\_\_\_ is done when starting warfarin. Heparin’s activation of antithrombin enables anticoagulation during initial, transient hypercoagulable state caused by warfarin. Initial heparin therapy reduces risk of recurrent venous thromboembolism and skin/tissue necrosis.

Heparin “Bridging”

Hematologic Drugs: * parenteral (IV, SC) * acts in the blood * rapid onset (seconds) * activates antithrombin, which ↓ the action of IIa (thrombin) and factor Xa * effect lasts for hours * give Protamine Sulfate for reversal * monitor PTT (intrinsic pathway) * does not cross the placenta

Heparin

Hematologic Drugs: * oral * acts in th liver * slow onset, limited by half-lives of normal clotting factors * impairs synthesis of vitamin K–dependent clotting factors II, VII, IX, and X, and anti-clotting proteins C and S * effect lasts for days * give Vitamin K, FFP or PCC for reversal * monitor PT/INR (extrinsic pathway) * crosses the placenta (teratogenic)

Warfarin

Direct Factor Xa Inhibitors

* Api**Xa**ban * Rivaro**Xa**ban

Hematologic Drugs: * bind to and directly inhibit factor Xa * treatment and prophylaxis for DVT and PE * stroke prophylaxis in patients with atrial fibrillation * oral agents do not usually require coagulation monitoring * causes bleeding * not easily reversible

Direct Factor Xa Inhibitors

Thrombolytics

* Alteplase (tPA) * Reteplase (rPA) * Streptokinase * Tenecteplase (TNK-tPA)

Hematologic Drugs: * directly or indirectly aid conversion of plasminogen to plasmin, which cleaves thrombin and fibrin clots * ↑ PT, ↑ PTT, no change in platelet count * used for early MI, early ischemic stroke, and direct thrombolysis of severe PE * causes bleeding * contraindicated in , patients with active bleeding, history of intracranial bleedingrecent surgery, known bleeding diatheses, or severe hypertension * nonspecific reversal with antifibrinolytics (eg. aminocaproic acid, tranexamic acid), platelet transfusions, and factor corrections (eg. cryoprecipitate, FFP, PCC)

Thrombolytics

ADP Receptor Inhibitors

* Clopidogrel * Prasugrel * Ticagrelor (reversible) * Ticlopidine

Hematologic Drugs: * inhibit platelet aggregation by irreversibly blocking ADP (P2Y12) receptor * prevent expression of glycoproteins IIb/IIIa on platelet surface * used for acute coronary syndrome and coronary stenting * ↓ incidence or recurrence of thrombotic stroke * causes neutropenia (ticlopidine) * TTP may be seen

ADP Receptor Inhibitors

Hematologic Drugs: * phosphodiesterase inhibitors * ↑ cAMP in platelets, resulting in inhibition of platelet aggregation * vasodilators * used for intermittent claudication, coronary vasodilation, and prevention of stroke or TIAs (combined with aspirin) * causes nausea, headache, facial flushing, hypotension, and abdominal pain

* Cilostazol * Dipyridamole

Glycoprotein IIb/IIIa Inhibitors

* Abciximab * Eptifibatide * Tirofiban

Hematologic Drugs: * bind to the glycoprotein receptor IIb/IIIa on activated platelets, preventing aggregation. * Abciximab is made from monoclonal antibody Fab fragments * used fir unstable angina and percutaneous coronary intervention * causes bleeding and thrombocytopenia

Glycoprotein IIb/IIIa Inhibitors

Cancer Drugs—Cell Cycle

Cancer Drugs—Targets

Cancer Drugs: Antimetabolites

* Azathioprine * 6-Mercaptopurine * Cladribine * Cytarabine (Arabinofuranosyl Cytidine) * 5-Fluorouracil * Methotrexate

Antimetabolites are all _____ specific.

S-phase

Cancer Drugs: * antimetabolites * purine (thiol) analogs → ↓ de novo purine synthesis * activated by HGPRT * used for preventing organ rejection, rheumatoid arthritis, IBD and SLE * used to wean patients off steroids in chronic disease and to treat steroid-refractory chronic disease * causes myelosuppression, GI and liver toxicity * metabolized by xanthine oxidase; thus both have ↑ toxicity with Allopurinol or Febuxostat

* Azathioprine—metabolized into 6-MP * 6-Mercaptopurine

Cancer Drugs: * antimetabolite * purine analog → multiple mechanisms (eg. inhibition of DNA polymerase, DNA strand breaks) * used for hairy cell leukemia * causes myelosuppression, nephrotoxicity, and neurotoxicity

Cladribine

Cancer Drugs: * antimetabolite * pyrimidine analog → DNA chain termination * at higher concentrations, inhibits DNA polymerase * used for leukemias (AML) and lymphomas * causes myelosuppression with megaloblastic anemia

Cytarabine (Arabinofuranosyl Cytidine) **CYT**arabine causes pan**CYT**openia.

Cancer Drugs: * antimetabolite * pyrimidine analog bioactivated to 5-FdUMP, which covalently complexes with thymidylate synthase and folic acid * Capecitabine is a prodrug with similar activity * this complex inhibits thymidylate synthase → ↓ dTMP → ↓ DNA synthesis * used for colon cancer, pancreatic cancer, actinic keratosis, and basal cell carcinoma (topical) * effects enhanced with the addition of leucovorin * caues myelosuppression and palmar-plantar erythrodysesthesia (hand-foot syndrome)

5-Fluorouracil

Cancer Drugs: * antimetabolite * folic acid analog that competitively inhibits dihydrofolate reductase → ↓ dTMP → ↓ DNA synthesis * used for leukemias (ALL), lymphomas, choriocarcinoma, and sarcomas * Non-Neoplastic Uses: * ectopic pregnancy * medical abortion (with Misoprostol) * rheumatoid arthritis * psoriasis * IBD * vasculitis * causes myelosuppression, which is reversible with leucovorin “rescue”, hepatotoxicity, mucositis (eg. mouth ulcers), pulmonary fibrosis, folate deficiency, which may be teratogenic (neural tube defects) without supplementation, and nephrotoxicity (rare).

Methotrexate

Cancer Drugs: Antitumor Antibiotics

* Bleomycin * Dactinomycin (Actinomycin D) * Doxorubicin * Daunorubicin

Cancer Drugs: * antitumor antibiotic * induces free radical formation → breaks in DNA strands. * used for testicular cancer and Hodgkin lymphoma * causes pulmonary fibrosis, skin hyperpigmentation and minimal myelosuppression

Bleomycin

Cancer Drugs: * antitumor antibiotic * intercalates into DNA, preventing RNA synthesis * used for Wilms tumor, Ewing sarcoma, and rhabdomyosarcoma * used for childhood tumors * causes myelosuppression

Dactinomycin (Actinomycin D)

Cancer Drugs: * antitumor antibiotics * generate free radicals * intercalate in DNA → breaks in DNA → ↓ replication * interferes with Topoisomerase II enzyme * used for solid tumors, leukemias, and lymphomas * causes cardiotoxicity (dilated cardiomyopathy), myelosuppression, and alopecia * Dexrazoxane (iron chelating agent) is used to prevent cardiotoxicity

* Doxorubicin * Daunorubicin

Cancer Drugs: Alkylating Agents

* Busulfan * Cyclophosphamide * Ifosfamide * Nitrosoureas * Procarbazine

Cancer Drugs: * alkylating agent * cross-links DNA * used to ablate patient’s bone marrow before bone marrow transplantation * causes severe myelosuppression (in almost all cases), pulmonary fibrosis, and hyperpigmentation

Busulfan

Cancer Drugs: * alkylating agents * cross-link DNA at guanine * require bioactivation by liver * nitrogen mustard * used for solid tumors, leukemia, and lymphomas * causes myelosuppression, SIADH, and hemorrhagic cystitis * hemorrhagic cystitis is prevented with mesna (thiol group of mesna binds toxic metabolites) or adequate hydration

* Cyclophosphamide * Ifosfamide

Cancer Drugs: * alkylating agents * require bioactivation * cross blood-brain barrier → CNS * cross-link DNA * used for brain tumors (including glioblastoma multiforme) * causes CNS toxicity (convulsions, dizziness, ataxia)

Nitrosoureas

Cancer Drugs: * alkylating agent * cell cycle phase–nonspecific * mechanism not yet defined * used for Hodgkin lymphoma and brain tumors * causes bone marrow suppression, pulmonary toxicity, and leukemia

Procarbazine

Cancer Drugs: Microtubule Inhibitors

* Paclitaxel (Taxanes) * Vincristine * Vinblastin

Cancer Drugs: * microtubule inhibitors * hyperstabilize polymerized microtubules in M phase so that mitotic spindle cannot break down (anaphase cannot occur) * used for ovarian and breast carcinomas * causes myelosuppression, neuropathy, and hypersensitivity

Paclitaxel (Taxanes) **Tax**es **stabilize** society.

Cancer Drugs: * microtubule inhibitor * vinca alkaloid that binds β-tubulin and inhibit its polymerization into microtubules → prevent mitotic spindle formation (M-phase arrest) * used for solid tumors and leukemias * used for non-Hodgkin lymphomas * causes neurotoxicity (areflexia, peripheral neuritis) and constipation (including paralytic ileus)

Vincristine **Cri**sps the **nerves**.

Vinblastine **Blast**s the **bone marrow**.

Cancer Drugs: * cross-link DNA * used for testicular, bladder, ovary, and lung carcinomas * causes nephrotoxicity, peripheral neuropathy, and ototoxicity * nephrotoxicity is prevented with Amifostine (free radical scavenger) and chloride (saline) diuresis

* Cisplatin * Carboplatin

Cancer Drugs: * inhibit topoisomerase II → ↑ DNA degradation * used for solid tumors (particularly testicular and small cell lung cancer), leukemias, and lymphomas * causes myelosuppression and alopecia

* Etoposide * Teniposide

Cancer Drugs: * inhibit topoisomerase I and prevent DNA unwinding and replication * used for colon cancer, ovarian and small cell lung cancers * causes severe myelosuppression and diarrhea

* Irinotecan * colon cancer * Topotecan * ovarian and small cell lung cancers

Cancer Drugs: * inhibits ribonucleotide reductase → ↓ DNA synthesis (S-phase specific) * used for myeloproliferative disorders (eg. CML, polycythemia vera) and sickle cell (↑ HbF) * cuases severe myelosuppression

Hydroxyurea

Cancer Drugs: * monoclonal antibody against VEGF * inhibits angiogenesis * used for solid tumors (colorectal cancer, renal cell carcinoma) and wet age-related macular degeneration * causes hemorrhage, blood clots, and impaired wound healing

Bevacizumab **B**e**V**acizumab inhibits **B**lood **V**essel formation.

Cancer Drugs: * EGFR tyrosine kinase inhibitor * used for non-small cell lung carcinoma * causes rash

Erlotinib

Cancer Drugs: * monoclonal antibody against EGFR * used for stage IV colorectal cancer (wild-type KRAS), head and neck cancer * causes rash, elevated LFTs, and diarrhea

Cetuximab

Cancer Drugs: * tyrosine kinase inhibitor of BCR-ABL (Philadelphia chromosome fusion gene in CML) and c-kit (common in GI stromal tumors) * used for CML and GI stromal tumors (GIST) * causes fluid retention

Imatinib

Cancer Drugs: * monoclonal antibody against CD20, which is found on most B-cell neoplasms * used for Non-Hodgkin lymphoma, CLL, ITP, and rheumatoid arthritis * ↑ risk of progressive multifocal leukoencephalopathy

Rituximab

Cancer Drugs: * proteasome inhibitors * induce arrest at G2-M phase and apoptosis * used for multiple myeloma and mantle cell lymphoma * causes peripheral neuropathy and herpes zoster reactivation

* Bortezomib * Carfilzomib

Cancer Drugs: * Selective Estrogen Receptor Modulators (SERMs)—receptor antagonists in breast and agonists in bone * block the binding of estrogen to ER ⊕ cells * breast cancer treatment and prevention * prevent osteoporosis * both ↑ risk of thromboembolic events (eg. DVT, PE)

* Tamoxifen * breast CA * partial agonist in endometrium, which ↑ the risk of endometrial cancer * “hot flashes” * Raloxifene * osteoporosis * no ↑ in endometrial carcinoma because it is an estrogen receptor antagonist in endometrial tissue

Cancer Drugs: * monoclonal antibody against HER-2 (c-erbB2), a tyrosine kinase receptor * helps kill cancer cells that overexpress HER-2 through inhibition of HER-2 initiated cellular signaling and antibody-dependent cytotoxicity * used for HER-2 ⊕ breast cancer and gastric cancer * causes cardiotoxicity

Trastuzumab (Herceptin) “**Heart**ceptin” damages the heart.

Cancer Drugs: * small molecule inhibitor of BRAF oncogene ⊕ melanoma * used for V600Emutated BRAF inhibition * used for metastatic melanoma

Vemurafenib **VE**mu**RAF**-enib is for **V**600**E**mutated B**RAF** inhibition.

Cancer Drugs: * recombinant uricase that catalyzes metabolism of uric acid to allantoin * used in prevention and treatment of tumor lysis syndrome

Rasburicase

Common Chemotoxicities

* *C**isplatin/**C**arboplatin → ototoxicity, nephrotoxicity * *V**incristine → peripheral neuropathy * *B**leomycin, **B**usulfan → pulmonary fibrosis * *D**oxorubicin → cardiotoxicity * *T**rastuzumab (Herceptin) → cardiotoxicity * *CY**clophosphamide → hemorrhagic cystitis