FA 2022 Small Size

HIGH-YIELD SYSTEMS
Hematology
and Oncology
“You’re always somebody’s type! (blood type, that is)” Embryology 412
—BloodLink
Anatomy 414
“The best blood will at some time get into a fool or a mosquito.”
—Austin O’Malley Physiology 418
“A life touched by cancer is not a life destroyed by cancer.” Pathology 422
—Drew Boswell, Climbing the Cancer Mountain
Pharmacology 443
“Without hair, a queen is still a queen.”
—Prajakta Mhadnak
"Keep visiting afratafreeh.com fore free stuff like this ebook."

—Saito
When studying hematology, pay close attention to the many cross

connections to immunology. Make sure you master the different types
of anemias. Be comfortable interpreting blood smears. When reviewing
oncologic drugs, focus on mechanisms and adverse effects rather than
details of clinical uses, which may be lower yield.
Please note that solid tumors are covered in their respective organ
system chapters.
411
FAS1_2022_10-HemaOncol.indd 411 11/4/21 12:34 PM

412 SEC TION III HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY—EMBRYOLOGY
HEMATOLOGY AND ONCOLOGY—EMBRYOLOGY
Fetal erythropoiesis Fetal erythropoiesis occurs in: Young liver synthesizes blood.
Yolk sac (3–8 weeks)
Liver (6 weeks–birth)
Spleen (10–28 weeks)
Bone marrow (18 weeks to adult)
Hemoglobin Embryonic globins: ζ and ε.
development Fetal hemoglobin (HbF) = α2γ2. From fetal to adult hemoglobin:
Adult hemoglobin (HbA1) = α2β2. 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.
BIRTH
Site of Yolk Liver Bone marrow

erythropoiesis sac
Spleen
50 α
40
Fetal (HbF) γ Adult (HbA1)
% of total 30
globin synthesis
20 β
ε Embryonic globins
10 ζ
Weeks: 6 12 18 24 30 36 6 12 18 24 30 36 42 >>
EMBRYO FETUS (weeks of development) POSTNATAL (months) ADULT >>

HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY—EMBRYOLOGY SEC TION III 413
Blood groups
ABO classification Rh classification
A B AB O Rh Rh
RBC type
A B AB O
Group antigens on
RBC surface A B A&B Rh (D)
NONE NONE
Antibodies in plasma Anti-B Anti-A Anti-A Anti-B Anti-D
NONE NONE
IgG
(predominantly),
IgM IgM IgM IgG
Clinical relevance
Compatible RBC types A, O B, O AB, A, B, O O Rh⊕ , Rh⊝ Rh⊝
to receive
Compatible RBC types A, AB B, AB AB A, B, AB, O Rh⊕ Rh⊕ , Rh⊝

to donate to
Anti-Kell antibody Complex blood group system with high immunogenicity.

Anti-Kell antibodies (usually IgG) of a Kell-positive pregnant patient may cause hemolytic
disease of the newborn when produced following previous sensitization to the Kell antigen and
transferred through the placenta. Targets fetal RBC precursors ( RBC production) and mature
RBCs ( hemolysis), resulting in severe fetal anemia.
Anti-Kell antibodies may also be associated with hemolytic transfusion reactions.
Hemolytic disease of Also called erythroblastosis fetalis.

the fetus and newborn
Rh hemolytic disease ABO hemolytic disease
INTERACTION Rh ⊝ pregnant patient; Rh ⊕ fetus. Type O pregnant patient; type A or B fetus.
MECHANISM First pregnancy: patient exposed to fetal Preexisting pregnant patient anti-A and/or
blood (often during delivery) formation of anti-B IgG antibodies cross the placenta
maternal anti-D IgG. attack fetal and newborn RBCs
Subsequent pregnancies: anti-D IgG crosses hemolysis.
placenta attacks fetal and newborn RBCs
hemolysis.
PRESENTATION Hydrops fetalis, jaundice shortly after birth, Mild jaundice in the neonate within 24 hours of
kernicterus. birth. Unlike Rh hemolytic disease, can occur
in firstborn babies and is usually less severe.
TREATMENT/PREVENTION Prevent by administration of anti-D IgG to Rh Treatment: phototherapy or exchange
⊝ pregnant patients during third trimester transfusion.
and early postpartum period (if fetus Rh ⊕).
Prevents maternal anti-D IgG production.

414 SEC TION III HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY—ANATOMY
HEMATOLOGY AND ONCOLOGY—ANATOMY
Hematopoiesis
Multipotent stem cell
Myeloid stem cell Lymphoid stem cell
Erythropoiesis Thrombopoiesis Granulocytopoiesis Monocytopoiesis Lymphopoiesis

Erythroblast Megakaryoblast Myeloblast Monoblast Lymphoblast
Bone marrow
Reticulocyte Band
Megakaryocyte
Blood
Erythrocyte Platelets Eosinophil Basophil Neutrophil Monocyte B cell T cell NK cell

Tissues
Macrophage Plasma cell T-helper T-cytotoxic

cell cell
Neutrophils Acute inflammatory response cells. Phagocytic. Neutrophil chemotactic agents: C5a, IL-8,
A
Multilobed nucleus A . Specific granules LTB4, 5-HETE (leukotriene precursor),
contain leukocyte alkaline phosphatase kallikrein, platelet-activating factor,
(LAP), collagenase, lysozyme, and N-formylmethionine (bacterial proteins).
lactoferrin. Azurophilic granules (lysosomes) Hypersegmented neutrophils (nucleus has 6+
contain proteinases, acid phosphatase, lobes) are seen in vitamin B12/folate deficiency.
myeloperoxidase, and β-glucuronidase. Left shift— neutrophil precursors (eg, band
Inflammatory states (eg, bacterial infection) cells, metamyelocytes) in peripheral blood.
cause neutrophilia and changes in neutrophil Reflects states of myeloid proliferation
B morphology, such as left shift, toxic (eg, inflammation, CML).
granulation (dark blue, coarse granules), Döhle Leukoerythroblastic reaction—left shift
bodies (light blue, peripheral inclusions, arrow accompanied by immature RBCs. Suggests
in B ), and cytoplasmic vacuoles. bone marrow infiltration (eg, myelofibrosis,
metastasis).

HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY—ANATOMY SEC TION III 415
Erythrocytes Carry O2 to tissues and CO2 to lungs. Anucleate Erythro = red; cyte = cell.
A and lack organelles; biconcave A , with large Erythrocytosis = polycythemia = Hct.
surface area-to-volume ratio for rapid gas Anisocytosis = varying sizes.
exchange. Life span of ~120 days in healthy Poikilocytosis = varying shapes.
adults; 60–90 days in neonates. Source of
energy is glucose (90% used in glycolysis, 10% Reticulocyte = immature RBC; reflects
used in HMP shunt). Membranes contain erythroid proliferation.
Cl−/HCO3− antiporter, which allow RBCs to Bluish color (polychromasia) on Wright-Giemsa
export HCO3− and transport CO2 from the stain of reticulocytes represents residual
periphery to the lungs for elimination. ribosomal RNA.
Thrombocytes Involved in 1° hemostasis. Anucleate, small Thrombocytopenia or platelet function results

(platelets) cytoplasmic fragments A derived from in petechiae.
A megakaryocytes. Life span of 8–10 days vWF receptor: GpIb.
(pl8lets). When activated by endothelial injury, Fibrinogen receptor: GpIIb/IIIa.
aggregate with other platelets and interact Thrombopoietin stimulates megakaryocyte
with fibrinogen to form platelet plug. Contain proliferation.
dense granules (Ca2+, ADP, Serotonin, Alfa granules contain vWF, fibrinogen,
Histamine; CASH) and α granules (vWF, fibronectin, platelet factor four.
fibrinogen, fibronectin, platelet factor 4).
Approximately 1/3 of platelet pool is stored in
the spleen.
Monocytes Found in blood, differentiate into macrophages Mono = one (nucleus); cyte = cell.
A
in tissues.
Large, kidney-shaped nucleus A . Extensive
“frosted glass” cytoplasm.
Macrophages A type of antigen-presenting cell. Phagocytose Macro = large; phage = eater.

A bacteria, cellular debris, and senescent Macrophage naming varies by specific tissue
RBCs. Long life in tissues. Differentiate from type (eg, Kupffer cells in liver, histiocytes
circulating blood monocytes A . Activated in connective tissue, osteoclasts in bone,
by γ-interferon. Can function as antigen- microglial cells in brain).
presenting cell via MHC II. Also engage in Lipid A from bacterial LPS binds CD14 on
antibody-dependent cellular cytotoxicity. macrophages to initiate septic shock.
Important cellular component of granulomas
(eg, TB, sarcoidosis), where they may fuse to
form giant cells.

416 SEC TION III HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY—ANATOMY
Dendritic cells Highly phagocytic antigen-presenting cells (APCs) A . Function as link between innate and
A
adaptive immune systems (eg, via T-cell stimulation). Express MHC class II and Fc receptors on
surface. Can present exogenous antigens on MHC class I (cross-presentation).
Eosinophils Defend against helminthic infections (major Eosin = pink dye; philic = loving.
A basic protein). Bilobate nucleus. Packed Causes of eosinophilia (PACMAN Eats):
with large eosinophilic granules of uniform Parasites
size A . Highly phagocytic for antigen- Asthma
antibody complexes. Chronic adrenal insufficiency
Produce histaminase, major basic protein (MBP, Myeloproliferative disorders
a helminthotoxin), eosinophil peroxidase, Allergic processes
eosinophil cationic protein, and eosinophil- Neoplasia (eg, Hodgkin lymphoma)
derived neurotoxin. Eosinophilic granulomatosis with polyangiitis
Basophils Mediate allergic reaction. Densely basophilic Basophilic—stains readily with basic stains.
A granules A contain heparin (anticoagulant) Basophilia is uncommon, but can be a sign of
and histamine (vasodilator). Leukotrienes myeloproliferative disorders, particularly CML.
synthesized and released on demand.
Mast cells Mediate local tissue allergic reactions. Contain Involved in type I hypersensitivity reactions.
A basophilic granules A . Originate from same Cromolyn sodium prevents mast cell
precursor as basophils but are not the same degranulation (used for asthma prophylaxis).
cell type. Can bind the Fc portion of IgE to Vancomycin, opioids, and radiocontrast dye can
membrane. Activated by tissue trauma, C3a elicit IgE-independent mast cell degranulation.
and C5a, surface IgE cross-linking by antigen Mastocytosis—rare; proliferation of mast cells in
(IgE receptor aggregation) degranulation skin and/or extracutaneous organs. Associated
release of histamine, heparin, tryptase, and with c-KIT mutations and serum tryptase.
eosinophil chemotactic factors. histamine flushing, pruritus, hypotension,
abdominal pain, diarrhea, peptic ulcer disease.

HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY—ANATOMY SEC TION III 417
Lymphocytes Refer to B cells, T cells, and natural killer (NK) cells. B cells and T cells mediate adaptive
A
immunity. NK cells are part of the innate immune response. Round, densely staining nucleus
with small amount of pale cytoplasm A .
Natural killer cells Important in innate immunity, especially against intracellular pathogens. NK cells are larger than
CD56 B and T cells, with distinctive cytoplasmic lytic granules (containing perforin and granzymes)
CD16 (FcR) that, when released, act on target cells to induce apoptosis. Distinguish between healthy and
Lytic
granules infected cells by identifying cell surface proteins (induced by stress, malignant transformation, or
microbial infections). Induce apoptosis (natural killer) in cells that do not express class I MHC
NK cell cell surface molecules, eg, virally infected cells in which these molecules are downregulated.
B cells Mediate humoral immune response. Originate B = bone marrow.

CD20 CD21 from stem cells in bone marrow and matures in
CD19 marrow. Migrate to peripheral lymphoid tissue
B cell
(follicles of lymph nodes, white pulp of spleen,
unencapsulated lymphoid tissue). When antigen
is encountered, B cells differentiate into plasma
cells (which produce antibodies) and memory
cells. Can function as an APC.
T cells Mediate cellular immune response. Originate T = thymus.

CD8 CD4 from stem cells in the bone marrow, but mature CD4+ helper T cells are the primary target of
CD3 CD3 in the thymus. Differentiate into cytotoxic HIV.
T cells (express CD8, recognize MHC I), Rule of 8: MHC II × CD4 = 8;
Tc Th
helper T cells (express CD4, recognize MHC MHC I × CD8 = 8.
II), and regulatory T cells. CD28 (costimulatory
signal) necessary for T-cell activation. Most
circulating lymphocytes are T cells (80%).
Plasma cells Produce large amounts of antibody specific to Multiple myeloma is a plasma cell dyscrasia.
A
a particular antigen. “Clock-face” chromatin
distribution and eccentric nucleus, abundant
RER, and well-developed Golgi apparatus
(arrows in A ). Found in bone marrow and
normally do not circulate in peripheral blood.

418 SEC TION III HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY—PHYSIOLOGY
HEMATOLOGY AND ONCOLOGY—PHYSIOLOGY
Hemoglobin electrophoresis
Origin During gel electrophoresis, hemoglobin
AA Normal adult migrates from the negatively charged cathode
to the positively charged anode. HbA migrates
AF Normal newborn
the farthest, followed by HbF, HbS, and HbC.
AS Sickle cell trait This is because the missense mutations in HbS
and HbC replace glutamic acid ⊝ with valine
SS Sickle cell disease
(neutral) and lysine ⊕, respectively, making
AC Hb C trait HbC and HbS more positively charged than
CC Hb C disease HbA.
SC Hb SC disease
C S F A
Cathode A: normal hemoglobin chain (HbA, adult) Anode
F: normal hemoglobin chain (HbF, fetal) A Fat Santa Claus can’t (cathode anode) go
S: sickle cell hemoglobin chain (HbS)
C: hemoglobin C chain (HbC) far.
Coombs test Also called antiglobulin test. Detects the presence of antibodies against circulating RBCs.
Direct Coombs test—anti-Ig antibody (Coombs reagent) added to patient’s RBCs. RBCs
agglutinate if RBCs are coated with Ig. Used for AIHA diagnosis.
Indirect Coombs test—normal RBCs added to patient’s serum. If serum has anti-RBC surface Ig,
RBCs agglutinate when Coombs reagent is added. Used for pretransfusion testing.
Patient component Reagent(s) Result Result

(agglutination) (no agglutination)
Direct Coombs
RBCs +/– anti-RBC Ab Anti-human globulin Result Result

(Coombs reagent) Anti-RBC Ab present Anti-RBC Ab absent
Indirect Coombs
Donor blood
Patient serum +/– Anti-human globulin Result Result

anti-donor RBC Ab (Coombs reagent) Anti-donor RBC Ab present Anti-donor RBC Ab absent

HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY—PHYSIOLOGY SEC TION III 419
Platelet plug formation (primary hemostasis)

4A 4B
INJURY EXPOSURE ADHESION ACTIVATION AGGREGATION

Endothelial damage vWF binds to exposed Platelets bind vWF via GpIb ADP binding to P2Y12 Fibrinogen binds GpIIb/IIIa receptors and links platelets
→ transient collagen receptor at the site of injury receptor induces GpIIb/IIIa Balance between
vasoconstriction via vWF is from Weibel-Palade only (specific) → platelets expression at platelet
neural stimulation reflex undergo conformational surface → rapid Pro-aggregation factors: Anti-aggregation factors:
bodies of endothelial
and endothelin (released cells and α-granules of change irreversible platelet TXA2 (released PGI2 and NO (released
from damaged cell) platelets aggregation by platelets) by endothelial cells)
↓ blood flow ↑ blood flow
Platelets release ADP and ↑ platelet aggregation ↓ platelet aggregation
Ca2+ (necessary for
coagulation cascade), TXA2
Temporary plug stops bleeding; unstable, easily dislodged
ADP helps platelets adhere

to endothelium Coagulation cascade
(secondary hemostasis)
Thrombogenesis Formation of insoluble fibrin mesh.

Aspirin irreversibly inhibits cyclooxygenase,
thereby inhibiting TXA2 synthesis.
Clopidogrel, prasugrel, ticagrelor, and
ticlopidine inhibit ADP-induced expression of
GpIIb/IIIa by blocking P2Y12 receptor.
Abciximab, eptifibatide, and tirofiban inhibit
GpIIb/IIIa directly.
Ristocetin activates vWF to bind GpIb. Failure
Clopidogrel, prasugrel,
of aggregation with ristocetin assay occurs in
Platelet
ticagrelor, ticlopidine von Willebrand disease and Bernard-Soulier
Inside vWF syndrome. Desmopressin promotes the release
Aspirin platelets
Fibrinogen of vWF and factor VIII from endothelial cells.
Fibrinogen vWF carries/protects factor VIII; volksWagen
COX
ADP (P2Y12) receptor
Arachidonic TXA2 Factories make gr8 cars.
acid
4B
4A
Deficiency: Glanzmann thrombasthenia
GpIIb/IIIa
Activated
Deficiency: Bernard- Abciximab, Protein C protein C
GpIIb/IIIa Thrombin-
Soulier syndrome eptifibatide, thrombomodulin Vascular endothelial cells Weibel Palade body
insertion
tirofiban complex
Deficiency: von
Willebrand Thromboplastin
Subendothelial GpIb vWF disease (vWF + P-selectin)
tPA, PGI2
collagen

420 SEC TION III HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY—PHYSIOLOGY
Coagulation and kinin PT monitors extrinsic and common pathway, reflecting activity of factors I, II, V, VII, and X.
pathways PTT monitors intrinsic and common pathway, reflecting activity of all factors except VII and XIII.
Collagen, HMWK
basement membrane,
Kallikrein ↑ vasodilation
activated platelets
–#
Contact C1-esterase inhibitor Bradykinin ↑ permeability
activation –
XII XIIa – Kinin cascade ↑ pain
(intrinsic)
pathway XI XIa
REGULATORY ANTICOAGULANT PROTEINS:
IX IXa - proteins C and S
Tissue factor * VIII
* VIIIa with vWF
Tissue factor VII VIIa – ANTICOAGULANTS:
(extrinsic) * * - heparin
pathway X * Xa - LMWH
– Va V - direct thrombin inhibitors (eg, argatroban, bivalirudin,
* dabigatran)
ANTICOAGULANTS:
- LMWH (eg, dalteparin, enoxaparin) II * IIa –
- heparin Prothrombin Thrombin Plasminogen
- direct Xa inhibitors (eg, apixaban) THROMBOLYTICS:
- fondaparinux - alteplase, reteplase,
I Ia tPA streptokinase, tenecteplase
Fibrinogen Fibrin monomers –
ANTIFIBRINOLYTICS:
Aggregation
Plasmin - aminocaproic acid,
tranexamic acid
Hemophilia A: deficiency of factor VIII (XR) Common
Hemophilia B: deficiency of factor IX (XR) pathway Ca2+ XIIIa XIII Fibrinolytic system
Hemophilia C: deficiency of factor XI (AR) Fibrin
stabilizing
Note: Kallikrein activates bradykinin factor
ACE inactivates bradykinin
#
= C1-esterase inhibitor deficiency hereditary angioedema
* = require Ca2+ , phospholipid; Fibrin degradation
= vitamin K-dependent factors products (eg, D-dimer)
= cofactor Fibrin mesh stabilizes
= activates but not part of coagulation cascade platelet plug
LMWH = low-molecular-weight heparin
HMWK = high-molecular-weight kininogen

HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY—PHYSIOLOGY SEC TION III 421
Vitamin K–dependent coagulation

Procoagulation Vitamin K deficiency— synthesis of factors II,
VII, IX, X, protein C, protein S.
Reduced Warfarin inhibits vitamin K epoxide reductase.
vitamin K Inactive II, VII, IX, X, C, S
(active)
-glutamyl carboxylase
Vitamin K administration can potentially
(vitamin K-dependent) reverse inhibitory effect of warfarin on clotting
Warfarin, Epoxide Mature, carboxylated factor synthesis (delayed). FFP or PCC
liver failure reductase II, VII, IX, X, C, S
administration reverses action of warfarin
Oxidized immediately and can be given with vitamin K
vitamin K
(inactive) Clotting Anti- in cases of severe bleeding.
factors coagulants Neonates lack enteric baKteria, which produce
Liver
vitamin K. Early administration of vitamin K
overcomes neonatal deficiency/coagulopathy.
Factor VII (seven)—shortest half-life.
Fibrinogen Fibrin Factor II (two)—longest (too long) half-life.
Anticoagulation Antithrombin inhibits thrombin (factor IIa) and
factors VIIa, IXa, Xa, XIa, XIIa.
Heparin enhances the activity of antithrombin.
Principal targets of antithrombin: thrombin and
factor Xa.
Thrombin
Factor V Leiden mutation produces a factor V
Heparinlike molecule bin Pr
o
(enhances ATIII activity) rom ay pa tein resistant to inhibition by activated protein C.
tith w thw C
tPA is used clinically as a thrombolytic.
An path ay Thrombin-
Antithrombin III thrombomodulin
complex
(endothelial cells)
Inhibits thrombin
(and VIIa, IXa, Xa, XIa, XIIa) Protein C Activated protein C
Requires
protein S
Cleaves and
inactivates Va, VIIIa

422 SEC TION III HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY—PATHOLOGY
HEMATOLOGY AND ONCOLOGY—PATHOLOGY
RBC morphology
TYPE EXAMPLE ASSOCIATED PATHOLOGY NOTES
Acanthocytes Liver disease, abetalipoproteinemia, Projections of varying size at
(“spur cells”) vitamin E deficiency irregular intervals (acanthocytes
are asymmetric).
Echinocytes Liver disease, ESRD, pyruvate Smaller and more uniform

(“burr cells”) kinase deficiency projections than acanthocytes
(echinocytes are even).
Dacrocytes Bone marrow infiltration (eg, RBC “sheds a tear” because it’s
(“teardrop cells”) myelofibrosis) mechanically squeezed out of its
home in the bone marrow
Schistocytes MAHAs (eg, DIC, TTP/HUS, Fragmented RBCs

(“helmet” cells) HELLP syndrome), mechanical
hemolysis (eg, heart valve
prosthesis)
Degmacytes (“bite G6PD deficiency Due to removal of Heinz bodies

cells”) by splenic macrophages (they
“deg” them out of/bite them off
of RBCs)
Elliptocytes Hereditary elliptocytosis Caused by mutation in genes

encoding RBC membrane
proteins (eg, spectrin)

HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY—PATHOLOGY SEC TION III 423
RBC morphology (continued)

Spherocytes Hereditary spherocytosis, Small, spherical cells without
autoimmune hemolytic anemia central pallor
surface area-to-volume ratio
Macro-ovalocytes Megaloblastic anemia (also

hypersegmented PMNs)
Target cells HbC disease, Asplenia, “HALT,” said the hunter to his
Liver disease, Thalassemia target
surface area-to-volume ratio
Sickle cells Sickle cell anemia Sickling occurs with low O2

conditions (eg, high altitude,
acidosis)

RBC inclusions
Bone marrow
Iron granules Sideroblastic anemias (eg, lead Perinuclear mitochondria with
poisoning, myelodysplastic excess iron (forming ring in
syndromes, chronic alcohol ringed sideroblasts)
overuse) Require Prussian blue stain to be
visualized
Peripheral smear
Howell-Jolly bodies Functional hyposplenia (eg, sickle Basophilic nuclear remnants (do
cell disease), asplenia not contain iron)
Usually removed by splenic
macrophages
Basophilic stippling Sideroblastic anemias, thalassemias Basophilic ribosomal precipitates

(do not contain iron)
Pappenheimer bodies Sideroblastic anemia Basophilic granules (contain iron)
Heinz bodies G6PD deficiency Denatured and precipitated

hemoglobin (contain iron)
Phagocytic removal of Heinz
bodies bite cells
Requires supravital stain (eg,
crystal violet) to be visualized

Anemias
Anemias
Microcytic Normocytic Macrocytic

(MCV < 80 fL) (MCV 80–100 fL) (MCV > 100 fL)
Hemoglobin affected (TAIL) Nonhemolytic Hemolytic Megaloblastic Nonmegaloblastic

Defective globin chain: (low reticulocyte index) (high reticulocyte index)
•Thalassemias DNA affected
•Iron deficiency (early)
Defective heme synthesis: Defective DNA synthesis
•Anemia of chronic disease •Diamond-Blackfan anemia
•Anemia of chronic disease •Folate deficiency
•Aplastic anemia •Liver disease
•Iron deficiency (late) •Vitamin B12 deficiency
•Chronic kidney disease •Chronic alcohol overuse
•Lead poisoning •Orotic aciduria
Defective DNA repair
•Fanconi anemia
Intrinsic Extrinsic
Membrane defects •Autoimmune

•Hereditary spherocytosis •Microangiopathic
•Paroxysmal nocturnal •Macroangiopathic
hemoglobinuria •Infections
Enzyme deficiencies
•G6PD deficiency
•Pyruvate kinase deficiency
Hemoglobinopathies
•Sickle cell anemia
•HbC disease
Reticulocyte Also called corrected reticulocyte count. Used to correct falsely elevated reticulocyte count
production index in anemia. Measures appropriate bone marrow response to anemic conditions (effective
erythropoiesis). High RPI (> 3) indicates compensatory RBC production; low RPI (< 2) indicates
inadequate response to correct anemia. Calculated as:
RPI = % reticulocytes × ( normal Hct)

actual Hct
/ maturation time

Microcytic,
hypochromic anemias MCV < 80 fL.
Iron deficiency 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, RI. Microcytosis and
hypochromasia ( central pallor) A .
Symptoms: fatigue, conjunctival pallor B , pica (persistent craving and compulsive eating of
nonfood substances), spoon nails (koilonychia).
May manifest as glossitis, cheilosis, Plummer-Vinson syndrome (triad of iron deficiency anemia,
esophageal webs, and dysphagia).
α-thalassemia α-globin gene deletions on chromosome 16 α-globin synthesis. May have cis deletion
(deletions occur on same chromosome) or trans deletion (deletions occur on separate
chromosomes). Normal is αα/αα. Often RBC count, in contrast to iron deficiency anemia.
# OF α-GLOBIN GENES DELETED DISEASE CLINICAL OUTCOME
1 (α α/α –) α-thalassemia minima No anemia (silent carrier)
2 (α –/α –; trans) or α-thalassemia minor Mild microcytic, hypochromic anemia;
(α α/– –; cis) cis deletion may worsen outcome for the
carrier’s offspring
3 (– –/– α) Hemoglobin H disease Moderate to severe microcytic
(HbH); excess β-globin hypochromic anemia
forms β4
4 (– –/– –) Hemoglobin Barts disease; Hydrops fetalis; incompatible with life
no α-globin, excess
γ-globin forms γ4
β-thalassemia Point mutation in splice sites or Kozak consensus sequence (promoter) on chromosome 11
β-globin synthesis (β+) or absent β-globin synthesis (β0). prevalence in people of Mediterranean
descent.
# OF β-GLOBIN GENES MUTATED DISEASE CLINICAL OUTCOME
1 (β/β+ or β/β0) β-thalassemia minor Mild microcytic anemia. HbA2.
2 (β+/β+ or β+/β0) β-thalassemia intermedia Variable anemia, ranging from mild/

asymptomatic to severe/transfusion-
dependent.
2 (β0/β0) β-thalassemia major Severe microcytic anemia with target
(Cooley anemia) cells and anisopoikilocytosis
requiring blood transfusions ( risk
of 2º hemochromatosis), marrow
expansion (“crew cut” on skull x-ray)
skeletal deformities, extramedullary
hematopoiesis HSM. risk of
parvovirus B19-induced aplastic crisis.
HbF and HbA2, becomes symptomatic
after 6 months when HbF declines (HbF
is protective). Chronic hemolysis
pigmented gallstones.
1 (β+/HbS or β0/HbS) Sickle cell β-thalassemia Mild to moderate sickle cell disease
depending on whether there is (β+/HbS)
or absent (β0/HbS) β-globin synthesis.

Microcytic, hypochromic anemias (continued)

Lead poisoning Lead inhibits ferrochelatase and ALA dehydratase heme synthesis and RBC protoporphyrin.
Also inhibits rRNA degradation RBCs retain aggregates of rRNA (basophilic stippling).
Symptoms of LEAD poisoning:
Lead Lines on gingivae (Burton lines) and on metaphyses of long bones D on x-ray.
Encephalopathy and Erythrocyte basophilic stippling.
Abdominal colic and sideroblastic Anemia.
Drops—wrist and foot drop.
Treatment: chelation with succimer, EDTA, dimercaprol.
Exposure risk in old houses (built before 1978) with chipped paint (children) and workplace
(adults).
Sideroblastic anemia Causes: genetic (eg, X-linked defect in ALA synthase gene), acquired (myelodysplastic syndromes),
and reversible (alcohol is most common; also lead poisoning, vitamin B6 deficiency, copper
deficiency, drugs [eg, isoniazid, linezolid]).
Lab findings: iron, normal/ TIBC, ferritin. Ringed sideroblasts (with iron-laden, Prussian
blue–stained mitochondria) seen in bone marrow E . Peripheral blood smear: basophilic stippling
of RBCs. Some acquired variants may be normocytic or macrocytic.
Treatment: pyridoxine (B6, cofactor for ALA synthase).
A B C D E
Interpretation of iron studies

Iron Chronic Pregnancy/
deficiency disease Hemochromatosis OCP use
Serum iron —
Transferrin or TIBC a
Ferritin —
% transferrin saturation —/
(serum iron/TIBC)
= 1° disturbance.
Transferrin—transports iron in blood.
TIBC—indirectly measures transferrin.
Ferritin—1° iron storage protein of body.
a
Evolutionary reasoning—pathogens use circulating iron to thrive. The body has adapted a system in which iron is stored
within the cells of the body and prevents pathogens from acquiring circulating iron.

Macrocytic anemias MCV > 100 fL.

DESCRIPTION FINDINGS
Megaloblastic anemia Impaired DNA synthesis maturation of RBC macrocytosis, hypersegmented neutrophils
A nucleus of precursor cells in bone marrow (arrow in A ), glossitis.
delayed relative to maturation of cytoplasm.
Causes: vitamin B12 deficiency, folate deficiency,
medications (eg, hydroxyurea, phenytoin,
methotrexate, sulfa drugs).
Folate deficiency Causes: malnutrition (eg, chronic alcohol homocysteine, normal methylmalonic acid.
overuse), malabsorption, drugs (eg, No neurologic symptoms (vs B12 deficiency).
methotrexate, trimethoprim, phenytoin),
requirement (eg, hemolytic anemia,
pregnancy).
Vitamin B12 Causes: pernicious anemia, malabsorption homocysteine, methylmalonic acid.
(cobalamin) (eg, Crohn disease), pancreatic insufficiency, Neurologic symptoms: reversible dementia,
deficiency gastrectomy, insufficient intake (eg, veganism), subacute combined degeneration (due to
Diphyllobothrium latum (fish tapeworm). involvement of B12 in fatty acid pathways and
myelin synthesis): spinocerebellar tract, lateral
corticospinal tract, dorsal column dysfunction.
Folate supplementation in vitamin B12
deficiency can correct the anemia, but worsens
neurologic symptoms.
Historically diagnosed with the Schilling test,
a 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 (vs folate deficiency, which takes weeks to
months).
Orotic aciduria Inability to convert orotic acid to UMP Orotic acid in urine.
(de novo pyrimidine synthesis pathway) Treatment: uridine monophosphate or uridine
because of defect in UMP synthase. triacetate to bypass mutated enzyme.
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).
Nonmegaloblastic Macrocytic anemia in which DNA synthesis is RBC macrocytosis without hypersegmented
anemia normal. neutrophils.
Causes: chronic alcohol overuse, liver disease.
Diamond-Blackfan A congenital form of pure red cell aplasia % HbF (but total Hb).
anemia (vs Fanconi anemia, which causes Short stature, craniofacial abnormalities, and
pancytopenia). Rapid-onset anemia within 1st upper extremity malformations (triphalangeal
year of life due to intrinsic defect in erythroid thumbs) in up to 50% of cases.
progenitor cells.

Normocytic, Normocytic, normochromic anemias are classified as nonhemolytic or hemolytic. The hemolytic
normochromic anemias are further classified according to the cause of the hemolysis (intrinsic vs extrinsic to the
anemias RBC) and by the location of hemolysis (intravascular vs extravascular). Hemolysis can lead to in
LDH, reticulocytes, unconjugated bilirubin, pigmented gallstones, and urobilinogen in urine.
Intravascular Findings: haptoglobin, schistocytes on blood smear. Characteristic hemoglobinuria,
hemolysis hemosiderinuria, and urobilinogen in urine. Notable causes are mechanical hemolysis (eg,
prosthetic valve), paroxysmal nocturnal hemoglobinuria, microangiopathic hemolytic anemias.
Extravascular Mechanism: macrophages in spleen clear RBCs. Findings: splenomegaly, spherocytes in peripheral
hemolysis smear (most commonly due to hereditary spherocytosis and autoimmune hemolytic anemia), no
hemoglobinuria/hemosiderinuria. Can present with urobilinogen in urine.
Nonhemolytic, normocytic anemias

Anemia of chronic Inflammation (eg, IL-6) hepcidin iron, TIBC, ferritin.
disease (released by liver, binds ferroportin on Normocytic, but can become microcytic.
intestinal mucosal cells and macrophages, Treatment: address underlying cause of
thus inhibiting iron transport) release of inflammation, judicious use of blood
iron from macrophages and iron absorption transfusion, consider erythropoiesis-
from gut. Associated with conditions such stimulating agents such as EPO (eg, in chronic
as chronic infections, neoplastic disorders, kidney disease).
chronic kidney disease, and autoimmune
diseases (eg, SLE, rheumatoid arthritis).
Aplastic anemia Failure or destruction of hematopoietic stem reticulocyte count, EPO.
A
cells. Causes (reducing volume from inside Pancytopenia characterized by anemia,
diaphysis): leukopenia, and thrombocytopenia (vs aplastic
Radiation crisis, which causes anemia only). Normal cell
Viral agents (eg, EBV, HIV, hepatitis viruses) morphology, but hypocellular bone marrow
Fanconi anemia (autosomal recessive DNA with fatty infiltration A .
repair defect bone marrow failure); Symptoms: fatigue, malaise, pallor, purpura,
normocytosis or macrocytosis on CBC mucosal bleeding, petechiae, infection.
Idiopathic (immune mediated, 1° stem cell Treatment: withdrawal of offending
defect); may follow acute hepatitis agent, immunosuppressive regimens (eg,
Drugs (eg, benzene, chloramphenicol, antithymocyte globulin, cyclosporine), bone
alkylating agents, antimetabolites) marrow allograft, RBC/platelet transfusion,
bone marrow stimulation (eg, GM-CSF).

Intrinsic hemolytic anemias

Hereditary Primarily autosomal dominant. Due to defect Splenomegaly, pigmented gallstones, aplastic
spherocytosis in proteins interacting with RBC membrane crisis (parvovirus B19 infection).
skeleton and plasma membrane (eg, ankyrin, Labs: mean fluorescence of RBCs in eosin
band 3, protein 4.2, spectrin). 5-maleimide (EMA) binding test, fragility
Small, round RBCs with no central pallor. in osmotic fragility test (RBC hemolysis with
surface area/dehydration MCHC exposure to hypotonic solution). Normal to
premature removal by spleen (extravascular MCV with abundance of RBCs.
hemolysis). Treatment: splenectomy.
Paroxysmal nocturnal Hematopoietic stem cell mutation Triad: Coombs ⊝ hemolytic anemia (mainly
hemoglobinuria complement-mediated intravascular intravascular), pancytopenia, venous
hemolysis, especially at night. Acquired PIGA thrombosis (eg, Budd-Chiari syndrome).
mutation impaired GPI anchor synthesis Pink/red urine in morning. Associated with
for decay-accelerating factor (DAF/CD55) and aplastic anemia, acute leukemias.
membrane inhibitor of reactive lysis (MIRL/ Labs: CD55/59 ⊝ RBCs on flow cytometry.
CD59), which protect RBC membrane from Treatment: eculizumab (targets terminal
complement. complement protein C5).
G6PD deficiency X-linked recessive. G6PD defect Back pain, hemoglobinuria a few days after
NADPH reduced glutathione oxidant stress.
RBC susceptibility to oxidative stress Labs: G6PD activity (may be falsely normal
(eg, sulfa drugs, antimalarials, fava beans) during acute hemolysis), blood smear shows
hemolysis. RBCs with Heinz bodies and bite cells.
Causes extravascular and intravascular hemolysis. “Stress makes me eat bites of fava beans with
Heinz ketchup.”
Pyruvate kinase Autosomal recessive. Pyruvate kinase defect Hemolytic anemia in a newborn.
deficiency ATP rigid RBCs extravascular Labs: blood smear shows burr cells.
hemolysis. Increases levels of 2,3-BPG
hemoglobin affinity for O2.
Sickle cell anemia Point mutation in β-globin gene single Complications:
A amino acid substitution (glutamic acid Aplastic crisis (transient arrest of
valine). Mutant HbA is termed HbS. Causes erythropoiesis due to parvovirus B19).
extravascular and intravascular hemolysis. Autosplenectomy (Howell-Jolly bodies)
Pathogenesis: low O2, high altitude, or acidosis risk of infection by encapsulated
precipitates sickling (deoxygenated HbS organisms (eg, S pneumoniae).
polymerizes) anemia, vaso-occlusive disease. Splenic infarct/sequestration crisis.
Newborns are initially asymptomatic because of Salmonella osteomyelitis.
HbF and HbS. Painful vaso-occlusive crises: dactylitis
Heterozygotes (sickle cell trait) have resistance (painful swelling of hands/feet), priapism,
to malaria. acute chest syndrome (respiratory distress,
Sickle cells are crescent-shaped RBCs A . new pulmonary infiltrates on CXR, common
“Crew cut” on skull x-ray due to marrow cause of death), avascular necrosis, stroke.
expansion from erythropoiesis (also seen in Sickling in renal medulla ( Po2) renal
thalassemias). papillary necrosis hematuria.
Hb electrophoresis: HbA, HbF, HbS.
Treatment: hydroxyurea ( HbF), hydration.
HbC disease Glutamic acid–to-lycine (lysine) mutation in HbSC (1 of each mutant gene) milder than HbSS.
β-globin. Causes extravascular hemolysis. Blood smear in homozygotes: hemoglobin
crystals inside RBCs, target cells.

Extrinsic hemolytic anemias

Autoimmune A normocytic anemia that is usually idiopathic Spherocytes and agglutinated RBCs A on
hemolytic anemia and Coombs ⊕. Two types: peripheral blood smear.
A Warm AIHA–chronic anemia in which Warm AIHA treatment: steroids, rituximab,
primarily IgG causes extravascular splenectomy (if refractory).
hemolysis. Seen in SLE and CLL and with Cold AIHA treatment: cold avoidance,
certain drugs (eg, β-lactams, α-methyldopa). rituximab.
“Warm weather is Good.”
Cold AIHA–acute anemia in which
primarily IgM + complement cause RBC
agglutination and extravascular hemolysis
upon exposure to cold painful, blue
fingers and toes. Seen in CLL, Mycoplasma
pneumoniae infections, infectious
mononucleosis.
Microangiopathic RBCs are damaged when passing through Schistocytes (eg, “helmet cells”) are seen on
hemolytic anemia obstructed or narrowed vessels. Causes peripheral blood smear due to mechanical
intravascular hemolysis. destruction (schisto = to split) of RBCs.
Seen in DIC, TTP/HUS, SLE, HELLP
syndrome, hypertensive emergency.
Macroangiopathic Prosthetic heart valves and aortic stenosis may Schistocytes on peripheral blood smear.
hemolytic anemia also cause hemolytic anemia 2° to mechanical
destruction of RBCs.
Hemolytic anemia due destruction of RBCs (eg, malaria, Babesia).
to infection
Leukopenias
CELL TYPE CELL COUNT CAUSES
Neutropenia Absolute neutrophil count < 1500 cells/mm3 Sepsis/postinfection, drugs (including
Severe infections typical when < 500 cells/mm3 chemotherapy), aplastic anemia, SLE,
radiation, congenital
Lymphopenia Absolute lymphocyte count < 1500 cells/mm3 HIV, DiGeorge syndrome, SCID, SLE,
(< 3000 cells/mm³ in children) glucocorticoidsa, radiation, sepsis,
postoperative
Eosinopenia Absolute eosinophil count < 30 cells/mm3 Cushing syndrome, glucocorticoidsa
a
Glucocorticoids cause neutrophilia, despite causing eosinopenia and lymphopenia. Glucocorticoids activation of neutrophil
adhesion molecules, impairing migration out of the vasculature to sites of inflammation. In contrast, glucocorticoids
sequester eosinophils in lymph nodes and cause apoptosis of lymphocytes.

Heme synthesis, The porphyrias are hereditary or acquired conditions of defective heme synthesis that lead to the
porphyrias, and lead accumulation of heme precursors. Lead inhibits specific enzymes needed in heme synthesis,
poisoning leading to a similar condition.
CONDITION AFFECTED ENZYME ACCUMULATED SUBSTRATE PRESENTING SYMPTOMS
Lead poisoning Ferrochelatase and Protoporphyrin, ALA Microcytic anemia (basophilic stippling in
A ALA dehydratase (blood) peripheral smear A , ringed sideroblasts in
bone marrow), GI and kidney disease.
Children—exposure to lead paint mental
deterioration.
Adults—environmental exposure (eg, batteries,
ammunition) headache, memory loss,
demyelination (peripheral neuropathy).
Acute intermittent Porphobilinogen Porphobilinogen, ALA Symptoms (5 P’s):
porphyria deaminase (autosomal Painful abdomen
dominant mutation) Port wine–colored Pee
Polyneuropathy
Psychological disturbances
Precipitated by factors that ALA synthase
(eg, drugs [CYP450 inducers], alcohol,
starvation)
Treatment: hemin and glucose.
Porphyria cutanea Uroporphyrinogen Uroporphyrin (tea- Blistering cutaneous photosensitivity and
tarda decarboxylase colored urine) hyperpigmentation B .
B
Most common porphyria. Exacerbated with
alcohol consumption.
Causes: familial, hepatitis C.
Treatment: phlebotomy, sun avoidance,
antimalarials (eg, hydroxychloroquine).
MITOCHONDRIA Glucose, hemin CYTOPLASM

Sideroblastic anemia (X-linked) Lead poisoning
Aminolevulinic
Succinyl CoA + glycine Porphobilinogen
B₆ acid
ALA synthase ALA dehydratase
Porphobilinogen
(rate-limiting step) deaminase
Acute
intermittent
Hydroxymethylbilane porphyria
Mitochondrial
membrane
Uroporphyrinogen III
Heme Uroporphyrinogen
decarboxylase
Ferrochelatase Porphyria cutanea tarda
Lead
poisoning Fe2+
Protoporphyrin Coproporphyrinogen III

Iron poisoning
Acute Chronic
FINDINGS High mortality rate associated with accidental Seen in patients with 1° (hereditary) or 2° (eg,
ingestion by children (adult iron tablets may chronic blood transfusions for thalassemia or
look like candy). sickle cell disease) hemochromatosis.
MECHANISM Cell death due to formation of free radicals and
peroxidation of membrane lipids.
SYMPTOMS/SIGNS Abdominal pain, vomiting, GI bleeding. Arthropathy, cirrhosis, cardiomyopathy, diabetes
Radiopaque pill seen on x-ray. May progress to mellitus and skin pigmentation (“bronze
anion gap metabolic acidosis and multiorgan diabetes”), hypogonadism.
failure. Leads to scarring with GI obstruction.
TREATMENT Chelation (eg, deferoxamine, deferasirox), Phlebotomy (patients without anemia) or
gastric lavage. chelation.
Coagulation disorders PT—tests function of common and extrinsic pathway (factors I, II, V, VII, and X). Defect PT
(Play Tennis outside [extrinsic pathway]).
INR (international normalized ratio) = patient PT/control PT. 1 = normal, > 1 = prolonged. Most
common test used to follow patients on warfarin, which prolongs INR.
PTT—tests function of common and intrinsic pathway (all factors except VII and XIII). Defect
PTT (Play Table Tennis inside).
Coagulation disorders can be due to clotting factor deficiencies or acquired factor inhibitors (most
commonly against factor VIII). 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.
DISORDER PT PTT MECHANISM AND COMMENTS
Hemophilia A, B, or C — Intrinsic pathway coagulation defect ( PTT).
A A: deficiency of factor VIII; X-linked recessive. Pronounce “hemophilia
eight.”
B: deficiency of factor IX; X-linked recessive.
C: deficiency of factor XI; autosomal recessive.
Hemorrhage in hemophilia—hemarthroses (bleeding into joints, eg, knee A ),
easy bruising, bleeding after trauma or surgery (eg, dental procedures).
Treatment: desmopressin, factor VIII concentrate, emicizumab (A); factor IX
concentrate (B); factor XI concentrate (C).
Vitamin K deficiency General coagulation defect. Bleeding time normal.
activity of factors II, VII, IX, X, protein C, protein S.

Platelet disorders All platelet disorders have bleeding time (BT), mucous membrane bleeding, and
microhemorrhages (eg, petechiae, epistaxis). Platelet count (PC) is usually low, but may be
normal in qualitative disorders.
DISORDER PC BT NOTES
Bernard-Soulier –/ Autosomal recessive defect in adhesion. GpIb platelet-to-vWF adhesion.
syndrome Labs: abnormal ristocetin test, Big platelets.
Glanzmann – Autosomal recessive defect in aggregation. GpIIb/IIIa ( integrin αIIbβ3)
thrombasthenia platelet-to-platelet aggregation and defective platelet plug formation.
Labs: blood smear shows no platelet clumping.
Immune Destruction of platelets in spleen. Anti-GpIIb/IIIa antibodies splenic
thrombocytopenia macrophages phagocytose platelets. May be idiopathic or 2° to autoimmune
disorders (eg, SLE), viral illness (eg, HIV, HCV), malignancy (eg, CLL), or
drug reactions.
Labs: megakaryocytes on bone marrow biopsy, platelet count.
Treatment: glucocorticoids, IVIG, rituximab, TPO receptor agonists (eg,
eltrombopag, romiplostim), or splenectomy for refractory ITP.
Uremic platelet – In patients with renal failure, uremic toxins accumulate and interfere with
dysfunction platelet adhesion.
Thrombotic Disorders overlap significantly in symptomatology. May resemble DIC, but do not exhibit lab
microangiopathies findings of a consumptive coagulopathy (eg, PT, PTT, fibrinogen), as etiology does not
involve widespread clotting factor activation.
Thrombotic thrombocytopenic purpura Hemolytic-uremic syndrome
EPIDEMIOLOGY Typically females Typically children
PATHOPHYSIOLOGY Inhibition or deficiency of ADAMTS13 (a Predominately caused by Shiga toxin–producing
vWF metalloprotease) degradation of Escherichia coli (STEC) infection (serotype
vWF multimers large vWF multimers O157:H7), which causes profound endothelial
platelet adhesion and aggregation dysfunction.
(microthrombi formation)
PRESENTATION Triad of thrombocytopenia ( platelets), microangiopathic hemolytic anemia ( Hb, schistocytes,
LDH), acute kidney injury ( Cr)
DIFFERENTIATING SYMPTOMS Triad + fever + neurologic symptoms Triad + bloody diarrhea
LABS Normal PT and PTT helps distinguish TTP and HUS (coagulation pathway is not activated) from
DIC (coagulation pathway is activated)
TREATMENT Plasma exchange, glucocorticoids, rituximab Supportive care

Mixed platelet and coagulation disorders

DISORDER PC BT PT PTT NOTES
von Willebrand — — —/ Intrinsic pathway coagulation defect: vWF
disease PTT (vWF carries/protects factor VIII).
Defect in platelet plug formation: vWF
defect in platelet-to-vWF adhesion.
Most are autosomal dominant. Mild but most
common inherited bleeding disorder. No
platelet aggregation with ristocetin cofactor
assay. Treatment: desmopressin, which
releases vWF stored in endothelium.
Disseminated Widespread clotting factor activation
intravascular thromboembolic state with excessive
coagulation clotting factor consumption
thromboses, hemorrhages (eg, blood
oozing from puncture sites). May be acute
(life-threatening) or chronic (if clotting
factor production can compensate for
consumption).
Causes: heat Stroke, Snake bites, Sepsis
(gram ⊝), Trauma, Obstetric complications,
acute Pancreatitis, malignancy, nephrotic
syndrome, transfusion (SSSTOP making
new thrombi).
Labs: schistocytes, fibrin degradation
products (d-dimers), fibrinogen, factors V
and VIII.
Hereditary Autosomal dominant disorders resulting in hypercoagulable state ( tendency to develop

thrombophilias thrombosis).
DISEASE DESCRIPTION
Antithrombin Has no direct effect on the PT, PTT, or thrombin time but diminishes the increase in PTT
deficiency following standard heparin dosing.
Can also be acquired: renal failure/nephrotic syndrome antithrombin loss in urine
inhibition of factors IIa and Xa.
Factor V Leiden Production of mutant factor V (guanine adenine DNA point mutation Arg506Gln mutation
near the cleavage site) that is resistant to degradation by activated protein C. Complications
include DVT, cerebral vein thrombosis, recurrent pregnancy loss.
Protein C or S ability to inactivate factors Va and VIIIa. risk of warfarin-induced skin necrosis. Together,
deficiency protein C Cancels, and protein S Stops, coagulation.
Prothrombin G20210A Point mutation in 3′ untranslated region production of prothrombin plasma levels and
mutation venous clots.

Blood transfusion therapy

COMPONENT DOSAGE EFFECT CLINICAL USE
Packed RBCs Hb and O2 binding (carrying) capacity Acute blood loss, severe anemia
Platelets platelet count ( ∼ 5000/mm3/unit) Stop significant bleeding (thrombocytopenia,
qualitative platelet defects)
Fresh frozen plasma/ coagulation factor levels; FFP contains all Cirrhosis, immediate anticoagulation reversal
prothrombin coagulation factors and plasma proteins; PCC
complex concentrate generally contains factors II, VII, IX, and X, as
well as protein C and S
Cryoprecipitate Contains fibrinogen, factor VIII, factor XIII, Coagulation factor deficiencies involving
vWF, and fibronectin fibrinogen and factor VIII
Albumin intravascular volume and oncotic pressure Post-paracentesis, therapeutic plasmapheresis
Blood transfusion risks include infection transmission (low), transfusion reactions, iron overload (may lead to 2°
hemochromatosis), hypocalcemia (citrate is a Ca2+ chelator), and hyperkalemia (RBCs may lyse in old blood units).
Leukemia vs lymphoma
Leukemia Lymphoid or myeloid neoplasm with widespread involvement of bone marrow. Tumor cells are
usually found in peripheral blood.
Lymphoma Discrete tumor mass arising from lymph nodes. Variable clinical presentation (eg, arising in
atypical sites, leukemic presentation).
Hodgkin vs Hodgkin Non-Hodgkin

non-Hodgkin Both may have constitutional (“B”) signs/symptoms: low-grade fever, night sweats, weight loss.
lymphoma
Localized, single group of nodes with Multiple lymph nodes involved; extranodal
contiguous spread (stage is strongest predictor involvement common; noncontiguous spread.
of prognosis). Better prognosis. Worse prognosis.
Characterized by Reed-Sternberg cells. Majority involve B cells; rarely of T-cell lineage.
Bimodal distribution: young adults, > 55 years. Can occur in children and adults.
Associated with EBV. May be associated with autoimmune diseases
and viral infections (eg, HIV, EBV, HTLV).
Hodgkin lymphoma Contains Reed-Sternberg cells: distinctive tumor giant cells; bilobed nucleus with the 2 halves as
A
mirror images (“owl eyes” A ). RS cells are CD15+ and CD30+ B-cell origin. 2 owl eyes × 15 = 30.
SUBTYPE NOTES
Nodular sclerosis Most common
Mixed cellularity Eosinophilia; seen in immunocompromised
patients
Lymphocyte rich Best prognosis (the rich have better bank accounts)
Lymphocyte depleted Worst prognosis (the poor have worse bank
accounts); seen in immunocompromised patients

Non-Hodgkin lymphoma
TYPE OCCURS IN GENETICS COMMENTS
Neoplasms of mature B cells
Burkitt lymphoma Adolescents or young t(8;14)—translocation “Starry sky” appearance (StarBurst), sheets of
adults of c-myc (8) and lymphocytes with interspersed “tingible body”
heavy-chain Ig (14) macrophages (arrows in A ). Associated with
EBV.
Jaw lesion B in endemic form in Africa; pelvis
or abdomen in sporadic form.
Diffuse large B-cell Usually older adults, Mutations in BCL-2, Most common type of non-Hodgkin lymphoma
lymphoma but 20% in children BCL-6 in adults.
Follicular lymphoma Adults t(14;18)—translocation Indolent course with painless “waxing and
of heavy-chain Ig (14) waning” lymphadenopathy. Bcl-2 normally
and BCL-2 (18) inhibits apoptosis.
Mantle cell lymphoma Adult males >> adult t(11;14)—translocation Very aggressive, patients typically present with
females of cyclin D1 (11) and late-stage disease.
heavy-chain Ig (14),
CD5+
Marginal zone Adults t(11;18) Associated with chronic inflammation (eg,
lymphoma Sjögren syndrome, chronic gastritis [MALT
lymphoma; may regress with H pylori
eradication]).
Primary central Adults EBV related; Considered an AIDS-defining illness. Variable
nervous system associated with HIV/ presentation: confusion, memory loss, seizures.
lymphoma AIDS CNS mass (often single, ring-enhancing lesion
on MRI) in immunocompromised patients C ,
needs to be distinguished from toxoplasmosis
via CSF analysis or other lab tests.
Neoplasms of mature T cells
Adult T-cell lymphoma Adults Caused by HTLV Adults present with cutaneous lesions; common
(associated with IV in Japan (T-cell in Tokyo), West Africa, and the
drug use) Caribbean.
Lytic bone lesions, hypercalcemia.
Mycosis fungoides/ Adults Mycosis fungoides: skin patches and plaques D
Sézary syndrome (cutaneous T-cell lymphoma), characterized by
atypical CD4+ cells with “cerebriform” nuclei
and intraepidermal neoplastic cell aggregates
(Pautrier microabscess). May progress to Sézary
syndrome (T-cell leukemia).
A B C D

Plasma cell disorders Characterized by monoclonal immunoglobulin (paraprotein) overproduction due to plasma cell
disorder.
M spike Labs: serum protein electrophoresis (SPEP) or free light chain (FLC) assay for initial tests (M
spike on SPEP represents overproduction of a monoclonal Ig fragment). For urinalysis, use 24-hr
urine protein electrophoresis (UPEP) to detect light chain, as routine urine dipstick detects only
albumin.
Albumin α1 α2 β Confirm with bone marrow biopsy.
Multiple myeloma Overproduction of IgG (55% of cases) > IgA.
Clinical features: CRAB
HyperCalcemia ( secretion of cytokines [eg, IL-1, TNF-a, RANK-L] by malignant plasma cells
osteoclast activity)
Renal involvement
Anemia
Bone lytic lesions (“punched out” on X-ray A ) back pain.
Peripheral blood smear shows rouleaux formation B (RBCs stacked like poker chips).
Urinalysis shows Ig light chains (Bence Jones proteinuria) with ⊖ urine dipstick.
Bone marrow analysis shows > 10% monoclonal plasma cells with clock-face chromatin C and
intracytoplasmic inclusions containing IgG.
Complications: infection risk, 1° amyloidosis (AL).
Waldenstrom Overproduction of IgM (macroglobulinemia because IgM is the largest Ig).
macroglobulinemia Clinical features:
Peripheral neuropathy
No CRAB findings
Hyperviscosity syndrome:
Headache
Blurry vision
Raynaud phenomenon
Retinal hemorrhages
Bone marrow analysis shows > 10% small lymphocytes with intranuclear pseudoinclusions
containing IgM (lymphoplasmacytic lymphoma).
Complication: thrombosis.
Monoclonal Overproduction of any Ig type.
gammopathy of Usually asymptomatic. No CRAB findings.
undetermined Bone marrow analysis shows < 10% monoclonal plasma cells.
significance Complication: 1–2% risk per year of transitioning to multiple myeloma.
A B C

Myelodysplastic Stem cell disorders involving ineffective Pseudo-Pelger-Huët anomaly—neutrophils

syndromes hematopoiesis defects in cell maturation of with bilobed (“duet”) nuclei A . Associated
A
nonlymphoid lineages. Bone marrow blasts with myelodysplastic syndromes or drugs
< 20% (vs > 20% in AML). Caused by de (eg, immunosuppressants).
novo mutations or environmental exposure
(eg, radiation, benzene, chemotherapy). Risk
of transformation to AML. More common in
older adults.

Leukemias 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), although some cases present with
normal/ WBCs.
Leukemic cell infiltration of liver, spleen, lymph nodes, and skin (leukemia cutis) possible.
TYPE NOTES
Lymphoid neoplasms
Acute lymphoblastic Most frequently occurs in children; less common in adults (worse prognosis). T-cell ALL can
leukemia/lymphoma present as mediastinal mass (presenting as SVC-like syndrome). Associated with Down syndrome.
Peripheral blood and bone marrow have lymphoblasts A .
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; t(9;22) (Philadelphia chromosome) worse prognosis.
Chronic lymphocytic Age > 60 years. Most common adult leukemia. CD20+, CD23+, CD5+ B-cell neoplasm. Often
leukemia/small asymptomatic, progresses slowly; smudge cells B in peripheral blood smear; autoimmune
lymphocytic hemolytic anemia. CLL = Crushed Little Lymphocytes (smudge cells).
lymphoma Richter transformation—CLL/SLL transformation into an aggressive lymphoma, most commonly
diffuse large B-cell lymphoma (DLBCL).
Hairy cell leukemia Adult males. Mature B-cell tumor. Cells have filamentous, hairlike projections (fuzzy appearing on
LM C ). 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) ⊕ (TRAPped in a hairy situation). TRAP stain
largely replaced with flow cytometry. Associated with BRAF mutations.
Treatment: purine analogs (cladribine, pentostatin).
Myeloid neoplasms
Acute myelogenous Median onset 65 years. Auer rods D ; myeloperoxidase ⊕ cytoplasmic inclusions seen mostly in
leukemia APL (formerly M3 AML); circulating myeloblasts on peripheral smear. May present with
leukostasis (capillary occlusion by malignant, nondistensible cells organ damage).
Risk factors: prior exposure to alkylating chemotherapy, radiation, benzene, myeloproliferative
disorders, Down syndrome (typically acute megakaryoblastic leukemia [formerly M7 AML]).
APL: t(15;17), responds to all-trans retinoic acid (vitamin A) and arsenic trioxide, which induce
differentiation of promyelocytes; DIC is a common presentation.
Chronic myelogenous Peak incidence: 45–85 years; median age: 64 years. Defined by the Philadelphia chromosome
leukemia (t[9;22], BCR-ABL) and myeloid stem cell proliferation. Presents with dysregulated production of
mature and maturing granulocytes (eg, neutrophils, metamyelocytes, myelocytes, basophils E )
and splenomegaly. May accelerate and transform to AML or ALL (“blast crisis”).
Responds to BCR-ABL tyrosine kinase inhibitors (eg, imatinib).
A B C D E

Myeloproliferative Malignant hematopoietic neoplasms with varying impacts on WBCs and myeloid cell lines.
neoplasms
Polycythemia vera Primary polycythemia. Disorder of RBCs, usually due to acquired JAK2 mutation. May present
as intense itching after shower (aquagenic pruritus). Rare but classic symptom is erythromelalgia
(severe, burning pain and red-blue coloration) due to episodic blood clots in vessels of the
extremities A . Associated with hyperviscosity and thrombosis (eg, PE, DVT, Budd-Chiari
syndrome).
EPO (vs 2° polycythemia, which presents with endogenous or artificially EPO).
Treatment: phlebotomy, hydroxyurea, ruxolitinib (JAK1/2 inhibitor).
Essential Characterized by massive proliferation of megakaryocytes and platelets. Symptoms include
thrombocythemia bleeding and thrombosis. Blood smear shows markedly increased number of platelets, which may
be large or otherwise abnormally formed B . Erythromelalgia may occur.
Myelofibrosis Atypical megakaryocyte hyperplasia TGF-β secretion fibroblast activity obliteration of
bone marrow with fibrosis C . Associated with massive splenomegaly and “teardrop” RBCs D .
“Bone marrow cries because it’s fibrosed and is a dry tap.”
RBCs WBCs PLATELETS PHILADELPHIA CHROMOSOME JAK2 MUTATIONS
Polycythemia vera ⊝ ⊕
Essential − − ⊝ ⊕ (30–50%)
thrombocythemia
Myelofibrosis Variable Variable ⊝ ⊕ (30–50%)
CML ⊕ ⊝
A B C D
Leukemoid reaction vs chronic myelogenous leukemia

Leukemoid reaction Chronic myelogenous leukemia
DEFINITION Reactive neutrophilia > 50,000 cells/mm 3
Myeloproliferative neoplasm ⊕ for BCR-ABL
NEUTROPHIL MORPHOLOGY Toxic granulation, Döhle bodies, cytoplasmic Pseudo-Pelger-Huët anomaly
vacuoles
LAP SCORE (LAP enzyme in malignant neutrophils)
EOSINOPHILS AND BASOPHILS Normal

Polycythemia
PLASMA VOLUME RBC MASS O2 SATURATION EPO LEVELS ASSOCIATIONS
Relative – – – Dehydration, burns.
Appropriate absolute – Lung disease, congenital heart disease, high
altitude, obstructive sleep apnea.
Inappropriate absolute – – Exogenous EPO (athlete misuse, also called “blood
doping”), androgen supplementation.
Inappropriate EPO secretion: malignancy (eg, RCC,
HCC).
Polycythemia vera – EPO in PCV due to negative feedback suppressing
renal EPO production.
= 1º disturbance
Chromosomal translocations
TRANSLOCATION ASSOCIATED DISORDER NOTES
t(8;14) Burkitt (Burk-8) lymphoma (c-myc activation) The Ig heavy chain genes on chromosome 14
t(11;14) Mantle cell lymphoma (cyclin D1 activation) are constitutively expressed. When other
genes (eg, c-myc and BCL-2) are translocated
t(11;18) Marginal zone lymphoma
next to this heavy chain gene region, they are
t(14;18) Follicular lymphoma (BCL-2 activation) overexpressed.
t(15;17) APL (formerly M3 type of AML)
t(9;22) (Philadelphia CML (BCR-ABL hybrid), ALL (less common);
chromosome) Philadelphia CreaML cheese
Langerhans cell Collective group of proliferative disorders of A B

histiocytosis Langerhans cells (antigen-presenting cells Birbeck granules
normally found in the skin). Presents in a
child as lytic bone lesions A 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 presentation. Cells
express S-100 and CD1a. Birbeck granules
(“tennis rackets” or rod shaped on EM) are
characteristic B .

HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY—PHARMACOLOGY SEC TION III 443
Tumor lysis syndrome

Muscle Oncologic emergency triggered by massive
weakness tumor cell lysis, seen most often with
K+ lymphomas/leukemias. Usually caused
Arrhythmias, by treatment initiation, but can occur
ECG changes spontaneously with fast-growing cancers.
Ca2+ Release of K+ hyperkalemia, release of PO43–
Seizures, hyperphosphatemia, hypocalcemia due to
tetany Ca2+ sequestration by PO43–. nucleic acid
Tumor cell Calcium
lysis PO₄³
_
phosphate
breakdown hyperuricemia acute kidney
crystals Acute kidney injury. Prevention and treatment include
injury aggressive hydration, allopurinol, rasburicase.
Uric acid Uric acid
crystals
HEMATOLOGY AND ONCOLOGY—PHARMACOLOGY
Heparin
MECHANISM Activates antithrombin, which action primarily of factors IIa (thrombin) and Xa. Short half-life.
CLINICAL USE Immediate anticoagulation for pulmonary embolism (PE), acute coronary syndrome, MI, deep
venous thrombosis (DVT). Used during pregnancy (does not cross placenta). Monitor PTT.
ADVERSE EFFECTS Bleeding (reverse with protamine sulfate), heparin-induced thrombocytopenia (HIT), osteoporosis
(with long-term use), drug-drug interactions, type 4 renal tubular acidosis.
HIT type 1—mild (platelets > 100,000/mm3), transient, nonimmunologic drop in platelet count
that typically occurs within the first 2 days of heparin administration. Not clinically significant.
HIT type 2—development of IgG antibodies against heparin-bound platelet factor 4 (PF4) that
typically occurs 5–10 days after heparin administration. Antibody-heparin-PF4 complex binds
and activates platelets removal by splenic macrophages and thrombosis platelet count.
Highest risk with unfractionated heparin. Treatment: discontinue heparin, start alternative
anticoagulant (eg, argatroban). Fondaparinux safe to use (does not interact with PF4).
NOTES Low-molecular-weight heparins (eg, enoxaparin, dalteparin) act mainly on factor Xa. Fondaparinux
acts only on factor Xa. Both are not easily reversible. Unfractionated heparin used in patients with
renal insufficiency (low-molecular-weight heparins should be used with caution because they
undergo renal clearance).

444 SEC TION III HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY—PHARMACOLOGY
Warfarin
MECHANISM Inhibits vitamin K epoxide reductase by competing with vitamin K inhibition of vitamin K–
dependent γ-carboxylation of clotting factors II, VII, IX, and X and proteins C and S. Metabolism
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.
“The ex-PresidenT went to war(farin).”
CLINICAL USE Chronic anticoagulation (eg, venous thromboembolism prophylaxis and prevention of stroke
in atrial fibrillation). Not used in pregnant patients (because warfarin, unlike heparin, crosses
placenta). Monitor PT/INR.
ADVERSE EFFECTS Bleeding, teratogenic effects, skin/tissue necrosis A , drug-drug interactions (metabolized by
A
cytochrome P-450 [CYP2C9]).
Initial risk of hypercoagulation: protein C has shorter half-life than factors II and X. Existing
protein C depletes before existing factors II and X deplete, and before warfarin 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.
Heparin “bridging”: heparin frequently used 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.
For reversal of warfarin, give vitamin K. For rapid reversal, give FFP or PCC.
Heparin vs warfarin
Heparin Warfarin
ROUTE OF ADMINISTRATION Parenteral (IV, SC) Oral
SITE OF ACTION Blood Liver
ONSET OF ACTION Rapid (seconds) Slow, limited by half-lives of normal clotting
factors
DURATION OF ACTION Hours Days
MONITORING PTT (intrinsic pathway) PT/INR (extrinsic pathway)
CROSSES PLACENTA No Yes (teratogenic)
Direct coagulation factor inhibitors

DRUG MECHANISM CLINICAL USE ADVERSE EFFECTS
Bivalirudin, Directly inhibit thrombin Venous thromboembolism, Bleeding (reverse dabigatran
argatroban, (factor IIa) atrial fibrillation. Can be used with idarucizumab)
dabigatran in HIT, when heparin is BAD Dabigatran is the only oral
for the patient agent in class
Do not require lab monitoring
Apixaban, edoxaban, Directly inhibit factor Xa Treatment and prophylaxis Bleeding (reverse with
rivaroxaban for DVT and PE; stroke andexanet alfa)
prophylaxis in patients with Oral agents that do not usually
atrial fibrillation require lab monitoring

Anticoagulation reversal
ANTICOAGULANT REVERSAL AGENT NOTES
Heparin Protamine sulfate ⊕ charged peptide that binds ⊝ charged
heparin
Warfarin Vitamin K (slow) +/– FFP or PCC (rapid)
Dabigatran Idarucizumab Monoclonal antibody Fab fragments
Direct factor Xa Andexanet alfa Recombinant modified factor Xa (inactive)
inhibitors
Antiplatelets All work by platelet aggregation.

Aspirin Irreversibly blocks COX Acute coronary syndrome; Gastric ulcers, tinnitus, allergic
TXA2 release coronary stenting. incidence reactions, renal injury
or recurrence of thrombotic
stroke
Clopidogrel, Block ADP (P2Y12) receptor Same as aspirin; dual Neutropenia (ticlopidine); TTP
prasugrel, ticagrelor, ADP-induced expression antiplatelet therapy may be seen
ticlopidine of GpIIb/IIIa
Abciximab, Block GpIIb/IIIa (fibrinogen Unstable angina, percutaneous Bleeding, thrombocytopenia
eptifibatide, tirofiban receptor) on activated coronary intervention
platelets. Abciximab is made
from monoclonal antibody
Fab fragments
Cilostazol, Block phosphodiesterase Intermittent claudication, Nausea, headache, facial
dipyridamole cAMP hydrolysis stroke prevention, cardiac flushing, hypotension,
cAMP in platelets stress testing, prevention of abdominal pain
coronary stent restenosis
Thrombolytics Alteplase (tPA), reteplase (rPA), streptokinase, tenecteplase (TNK-tPA).

MECHANISM Directly or indirectly aid conversion of plasminogen to plasmin, which cleaves thrombin and fibrin
clots. PT, PTT, no change in platelet count.
CLINICAL USE Early MI, early ischemic stroke, direct thrombolysis of severe PE.
ADVERSE EFFECTS Bleeding. Contraindicated in patients with active bleeding, history of intracranial bleeding,
recent 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).

Cancer therapy—cell cycle

Bleomycin Microtubule inhibitors
Taxanes
– Vinca alkaloids
– –
G2 Mit M
os
Double check is
repair
–
is
nes
oki
Cy t
Topoisomerase inhibitors
Etoposide
INT
Teniposide RP
E
Irinotecan HASE Duplicate
–
Topotecan DNA cellular content
synthesis Cell cycle–independent drugs
Antimetabolites – G1 Platinum compounds
Cladribine* GO Alkylating agents:
Cytarabine S Resting Anthracyclines
5-fluorouracil Busulfan
Hydroxyurea Dactinomycin
Methotrexate Rb, p53 modulate Nitrogen mustards
*Cell cycle Pentostatin G1 restriction point Nitrosoureas
nonspecific Thiopurines Procarbazine
Cancer therapy—targets
Nucleotide synthesis DNA RNA Protein Cellular division
MTX, 5-FU: Vinca alkaloids:

Alkylating agents, platinum compounds:
↓ thymidine synthesis inhibit microtubule formation
cross-link DNA
Thiopurines: Taxanes:
Bleomycin:
↓ de novo purine synthesis inhibit microtubule disassembly
DNA strand breakage
Hydroxyurea: Anthracyclines, dactinomycin:

inhibits ribonucleotide DNA intercalators
reductase
Etoposide/teniposide:
inhibits topoisomerase II
Irinotecan/topotecan:
inhibits topoisomerase I

Antibody-drug conjugates
Formed by linking monoclonal antibodies
with cytotoxic chemotherapeutic drugs.
Antibody selectivity against tumor antigens
Lysosomal
degradation
allows targeted drug delivery to tumor cells
while sparing healthy cells efficacy and
Receptor-mediated
Antibody endocytosis toxicity.
Conjugate
Drug Example: ado-trastuzumab emtansine (T-DM1)
for HER2 ⊕ breast cancer.
Cytotoxicity Drug release

Tumor antigen
Antitumor antibiotics All are cell cycle nonspecific, except bleomycin which is G2/M phase specific.
Bleomycin Induces free radical formation Testicular cancer, Hodgkin Pulmonary fibrosis, skin
breaks in DNA strands lymphoma hyperpigmentation
Dactinomycin Intercalates into DNA, Wilms tumor, Ewing sarcoma, Myelosuppression
(actinomycin D) preventing RNA synthesis rhabdomyosarcoma
Anthracyclines Generate free radicals Solid tumors, leukemias, Dilated cardiomyopathy
Doxorubicin, Intercalate in DNA breaks in lymphomas (often irreversible; prevent
daunorubicin DNA replication with dexrazoxane),
Inhibit topoisomerase II myelosuppression

Antimetabolites All are S-phase specific except cladribine, which is cell cycle nonspecific.
Thiopurines Purine (thiol) analogs Rheumatoid arthritis, IBD, Myelosuppression; GI, liver
Azathioprine, de novo purine synthesis SLE, ALL; steroid-refractory toxicity
6-mercaptopurine AZA is converted to 6-MP, disease 6-MP is inactivated by
which is then activated by Prevention of organ rejection xanthine oxidase ( toxicity
HGPRT Weaning from glucocorticoids with allopurinol or febuxostat)
Cladribine, Purine analogs multiple Hairy cell leukemia Myelosuppression
pentostatin mechanisms (eg, inhibition of
ADA, DNA strand breaks)
Cytarabine Pyrimidine analog DNA Leukemias (AML), lymphomas Myelosuppression
(arabinofuranosyl chain termination
cytidine) Inhibits DNA polymerase
5-Fluorouracil Pyrimidine analog bioactivated Colon cancer, pancreatic Myelosuppression, palmar-
to 5-FdUMP thymidylate cancer, actinic keratosis, basal plantar erythrodysesthesia
synthase inhibition cell carcinoma (topical) (hand-foot syndrome)
dTMP DNA Effects enhanced with the
synthesis addition of leucovorin
Capecitabine is a prodrug
Hydroxyurea Inhibits ribonucleotide Myeloproliferative disorders Severe myelosuppression,
reductase DNA synthesis (eg, CML, polycythemia megaloblastic anemia
vera), sickle cell disease
( HbF)
Methotrexate Folic acid analog that Cancers: leukemias Myelosuppression (reversible
competitively inhibits (ALL), lymphomas, with leucovorin “rescue”),
dihydrofolate reductase choriocarcinoma, sarcomas hepatotoxicity, mucositis (eg,
dTMP DNA Nonneoplastic: ectopic mouth ulcers), pulmonary
synthesis pregnancy, medical fibrosis, folate deficiency
abortion (with misoprostol), (teratogenic), nephrotoxicity
rheumatoid arthritis, psoriasis,
IBD, vasculitis

Alkylating agents All are cell cycle nonspecific.

Busulfan Cross-links DNA Used to ablate patient’s bone Severe myelosuppression (in
marrow before bone marrow almost all cases), pulmonary
transplantation fibrosis, hyperpigmentation
Nitrogen mustards Cross-link DNA Solid tumors, leukemia, Myelosuppression, SIADH,
Cyclophosphamide, Require bioactivation by liver lymphomas, rheumatic Fanconi syndrome
ifosfamide disease (eg, SLE, (ifosfamide), hemorrhagic
granulomatosis with cystitis and bladder cancer
polyangiitis) (prevent with mesna)
Nitrosoureas Cross-link DNA Brain tumors (including CNS toxicity (convulsions,
Carmustine, lomustine Require bioactivation by liver glioblastoma multiforme) dizziness, ataxia)
Cross blood-brain barrier Put nitro in your Mustang and
CNS entry travel the globe
Procarbazine Mechanism unknown Hodgkin lymphoma, brain Myelosuppression, pulmonary
Weak MAO inhibitor tumors toxicity, leukemia, disulfiram-
like reaction
Temozolomide DNA methylation Glioblastoma multiforme Myelosuppression
Platinum compounds Cisplatin, carboplatin, oxaliplatin.

MECHANISM Cross-link DNA. Cell cycle nonspecific.
CLINICAL USE Solid tumors (eg, testicular, bladder, ovarian, GI, lung), lymphomas.
ADVERSE EFFECTS Nephrotoxicity (eg, Fanconi syndrome; prevent with amifostine), peripheral neuropathy, ototoxicity.
Microtubule inhibitors All are M-phase specific.

Taxanes Hyperstabilize polymerized Various tumors (eg, ovarian Myelosuppression, neuropathy,
Docetaxel, paclitaxel microtubules prevent and breast carcinomas) hypersensitivity
mitotic spindle breakdown Taxes stabilize society
Vinca alkaloids Bind β-tubulin and inhibit Solid tumors, leukemias, Vincristine (crisps the nerves):
Vincristine, vinblastine its polymerization into Hodgkin and non-Hodgkin neurotoxicity (axonal
microtubules prevent lymphomas neuropathy), constipation
mitotic spindle formation (including ileus)
Vinblastine (blasts the
marrow): myelosuppression

Topoisomerase All cause DNA degradation resulting in cell cycle arrest in S and G2 phases.
inhibitors
Irinotecan, topotecan Inhibit topoisomerase I Colon, ovarian, small cell lung Severe myelosuppression,
“-tecone” cancer diarrhea
Etoposide, teniposide Inhibit topoisomerase II Testicular, small cell lung Myelosuppression, alopecia
“-bothside” cancer, leukemia, lymphoma
Tamoxifen
MECHANISM Selective estrogen receptor modulator with complex mode of action: antagonist in breast tissue,
partial agonist in endometrium and bone. Blocks the binding of estrogen to ER in ER ⊕ cells.
CLINICAL USE Prevention and treatment of breast cancer, prevention of gynecomastia in patients undergoing
prostate cancer therapy.
ADVERSE EFFECTS Hot flashes, risk of thromboembolic events (eg, DVT, PE) and endometrial cancer.
Anticancer monoclonal Work against extracellular targets to neutralize them or to promote immune system recognition
antibodies (eg, ADCC by NK cells). Eliminated by macrophages (not cleared by kidneys or liver).
AGENT TARGET CLINICAL USE ADVERSE EFFECTS
Alemtuzumab CD52 Chronic lymphocytic leukemia risk of infections and
(CLL), multiple sclerosis. autoimmunity (eg, ITP)
Bevacizumab VEGF (inhibits blood vessel Colorectal cancer (CRC), Hemorrhage, blood clots,
formation) renal cell carcinoma (RCC), impaired wound healing
non–small cell lung cancer
(NSCLC), angioproliferative
retinopathy
Cetuximab, EGFR Metastatic CRC (wild-type Rash, elevated LFTs, diarrhea
panitumumab RAS), head and neck cancer
Rituximab CD20 Non-Hodgkin lymphoma, Infusion reaction due to
CLL, rheumatoid arthritis, cytokine release following
ITP, TTP, AIHA, multiple interaction of rituximab with
sclerosis its target on B cells
Trastuzumab HER2 (“trust HER”) Breast cancer, gastric cancer Dilated cardiomyopathy (often
reversible)
Pembrolizumab, PD-1
nivolumab,
cemiplimab risk of autoimmunity (eg,
Various tumors (eg, NSCLC,
dermatitis, enterocolitis,
Atezolizumab, PD-L1 RCC, melanoma, urothelial
hepatitis, pneumonitis,
durvalumab, carcinoma)
endocrinopathies)
avelumab
Ipilimumab CTLA-4

Anticancer small molecule inhibitors

AGENT TARGET CLINICAL USE ADVERSE EFFECTS
Alectinib, crizotinib ALK Non–small cell lung cancer Edema, rash, diarrhea
Erlotinib, gefitinib, EGFR Non–small cell lung cancer Rash, diarrhea
afatinib
Imatinib, dasatinib, BCR-ABL (also other tyrosine CML, ALL, GISTs Myelosuppression, LFTs,
nilotinib kinases [eg, c-KIT]) edema, myalgias
Ruxolitinib JAK1/2 Polycythemia vera Bruises, LFTs
Bortezomib, ixazomib, Proteasome (induce Multiple myeloma, mantle cell Peripheral neuropathy, herpes
carfilzomib arrest at G2-M phase via lymphoma zoster reactivation ( T-cell
accumulation of abnormal activation cell-mediated
proteins apoptosis) immunity)
Vemurafenib, BRAF Melanoma Rash, fatigue, nausea, diarrhea
encorafenib, Often co-administered
dabrafenib with MEK inhibitors (eg,
trametinib)
Palbociclib Cyclin-dependent kinase 4/6 Breast cancer Myelosuppression, pneumonitis
(induces arrest at G1-S phase
apoptosis)
Olaparib Poly(ADP-ribose) polymerase Breast, ovarian, pancreatic, and Myelosuppression, edema,
( DNA repair) prostate cancers diarrhea
Chemotoxicity amelioration
DRUG MECHANISM CLINICAL USE
Amifostine Free radical scavenger Nephrotoxicity from platinum compounds
Dexrazoxane Iron chelator Cardiotoxicity from anthracyclines
Leucovorin (folinic Tetrahydrofolate precursor Myelosuppression from methotrexate (leucovorin
acid) “rescue”); also enhances the effects of 5-FU
Mesna Sulfhydryl compound that binds acrolein (toxic Hemorrhagic cystitis from cyclophosphamide/
metabolite of cyclophosphamide/ifosfamide) ifosfamide
Rasburicase Recombinant uricase that catalyzes metabolism Tumor lysis syndrome
of uric acid to allantoin
Ondansetron, 5-HT3 receptor antagonists
granisetron Acute nausea and vomiting (usually within
Prochlorperazine, D2 receptor antagonists 1-2 hr after chemotherapy)
metoclopramide
Aprepitant, NK1 receptor antagonists Delayed nausea and vomiting (>24 hr after
fosaprepitant chemotherapy)
Filgrastim, Recombinant G(M)-CSF Neutropenia
sargramostim
Epoetin alfa Recombinant erythropoietin Anemia

Key chemotoxicities
Cisplatin, Carboplatin ototoxicity
↓
Vincristine peripheral neuropathy
↓
Bleomycin, Busulfan pulmonary fibrosis
↓
Doxorubicin, Daunorubicin cardiotoxicity
↓
Trastuzumab cardiotoxicity
↓
Cisplatin, Carboplatin nephrotoxicity
↓
CYclophosphamide hemorrhagic cystitis
↓
Nonspecific common toxicities of nearly
all cytotoxic chemotherapies include
myelosuppression (neutropenia, anemia,
thrombocytopenia), GI toxicity (nausea,
vomiting, mucositis), alopecia.

FA 2022 Small Size

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

FA 2022 Small Size

Uploaded by

Copyright:

Available Formats

HIGH-YIELD SYSTEMS

"Keep visiting afratafreeh.com fore free stuff like this ebook."

When studying hematology, pay close attention to the many cross

FAS1_2022_10-HemaOncol.indd 411 11/4/21 12:34 PM

HEMATOLOGY AND ONCOLOGY—EMBRYOLOGY

Site of Yolk Liver Bone marrow

FAS1_2022_10-HemaOncol.indd 412 11/4/21 12:34 PM

ABO classification Rh classification

Antibodies in plasma Anti-B Anti-A Anti-A Anti-B Anti-D

Compatible RBC types A, AB B, AB AB A, B, AB, O Rh⊕ Rh⊕ , Rh⊝

Anti-Kell antibody Complex blood group system with high immunogenicity.

Hemolytic disease of Also called erythroblastosis fetalis.

FAS1_2022_10-HemaOncol.indd 413 11/4/21 12:34 PM

HEMATOLOGY AND ONCOLOGY—ANATOMY

Multipotent stem cell

Myeloid stem cell Lymphoid stem cell

Erythropoiesis Thrombopoiesis Granulocytopoiesis Monocytopoiesis Lymphopoiesis

Erythrocyte Platelets Eosinophil Basophil Neutrophil Monocyte B cell T cell NK cell

Macrophage Plasma cell T-helper T-cytotoxic

FAS1_2022_10-HemaOncol.indd 414 11/4/21 12:34 PM

Thrombocytes Involved in 1° hemostasis. Anucleate, small Thrombocytopenia or platelet function results

Macrophages A type of antigen-presenting cell. Phagocytose Macro = large; phage = eater.

FAS1_2022_10-HemaOncol.indd 415 11/4/21 12:34 PM

FAS1_2022_10-HemaOncol.indd 416 11/4/21 12:34 PM

B cells Mediate humoral immune response. Originate B = bone marrow.

T cells Mediate cellular immune response. Originate T = thymus.

FAS1_2022_10-HemaOncol.indd 417 11/4/21 12:34 PM

HEMATOLOGY AND ONCOLOGY—PHYSIOLOGY

Patient component Reagent(s) Result Result

RBCs +/– anti-RBC Ab Anti-human globulin Result Result

Patient serum +/– Anti-human globulin Result Result

FAS1_2022_10-HemaOncol.indd 418 11/4/21 12:34 PM

Platelet plug formation (primary hemostasis)

INJURY EXPOSURE ADHESION ACTIVATION AGGREGATION

ADP helps platelets adhere

Thrombogenesis Formation of insoluble fibrin mesh.

FAS1_2022_10-HemaOncol.indd 419 11/4/21 12:34 PM

FAS1_2022_10-HemaOncol.indd 420 11/4/21 12:34 PM

Vitamin K–dependent coagulation

FAS1_2022_10-HemaOncol.indd 421 11/4/21 12:34 PM

HEMATOLOGY AND ONCOLOGY—PATHOLOGY

Echinocytes Liver disease, ESRD, pyruvate Smaller and more uniform

Schistocytes MAHAs (eg, DIC, TTP/HUS, Fragmented RBCs

Degmacytes (“bite G6PD deficiency Due to removal of Heinz bodies

Elliptocytes Hereditary elliptocytosis Caused by mutation in genes

FAS1_2022_10-HemaOncol.indd 422 11/4/21 12:34 PM

RBC morphology (continued)

Macro-ovalocytes Megaloblastic anemia (also

Sickle cells Sickle cell anemia Sickling occurs with low O2

FAS1_2022_10-HemaOncol.indd 423 11/4/21 12:34 PM

Basophilic stippling Sideroblastic anemias, thalassemias Basophilic ribosomal precipitates

Pappenheimer bodies Sideroblastic anemia Basophilic granules (contain iron)

Heinz bodies G6PD deficiency Denatured and precipitated

FAS1_2022_10-HemaOncol.indd 424 11/4/21 12:34 PM

Microcytic Normocytic Macrocytic

Hemoglobin affected (TAIL) Nonhemolytic Hemolytic Megaloblastic Nonmegaloblastic

Membrane defects •Autoimmune

RPI = % reticulocytes × ( normal Hct)

FAS1_2022_10-HemaOncol.indd 425 11/4/21 12:34 PM

2 (β+/β+ or β+/β0) β-thalassemia intermedia Variable anemia, ranging from mild/

FAS1_2022_10-HemaOncol.indd 426 11/4/21 12:34 PM

Microcytic, hypochromic anemias (continued)

Interpretation of iron studies

FAS1_2022_10-HemaOncol.indd 427 11/4/21 12:34 PM