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

jaundice shortly after birth kernicterus hydrops fetalis

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.

Type O mothers Type A or B fetus

phototherapy exchange transfusion

Pathologic RBC Forms: HbC disease asplenia liver disease thalassemia

Target Cells “HALT,” said the hunter to his target. HbC disease Asplenia Liver disease Thalassemia

Hematology and Oncology - First Aid Flashcards by Grazielle Verzosa

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:

Parasites
Asthma
Churg-Strauss Syndrome
Chronic Adrenal Insufficiency
Myeloproliferative Disorders
Allergic Processes
Neoplasia (eg. Hodgkin Lymphoma)

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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

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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

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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

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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

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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 = Bone marrow

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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 = Thymus

Rule of 8:

MHC II × CD4 = 8
MHC I × CD8 = 8

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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

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Fetal Erythropoiesis

Young Liver Synthesizes Blood.

Yolk sac (3–8 weeks)
Liver (6 weeks–birth)
Spleen (10–28 weeks)
Bone marrow (18 weeks to adult)

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Hemoglobin Development

Embryonic Globins: ζ and ε

fetal → adult hemoglobin:
Alpha Always; Gamma Goes, Becomes Beta

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.

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Blood Groups

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Hemolytic disease of the newborn is also known as _____.

Erythroblastosis Fetalis

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Rh HDN:

Interaction

Rh ⊝ mothers
Rh ⊕ fetus

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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

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Rh HDN:

Presentation

jaundice shortly after birth
kernicterus
hydrops fetalis

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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.

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ABO HDN:

Interaction

Type O mothers
Type A or B fetus

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ABO HDN:

Mechanism

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

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ABO HDN:

Presentation

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

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ABO HDN:

Treatment

phototherapy
exchange transfusion

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Hemoglobin Electrophoresis

On a gel, hemoglobin migrates from the negatively charged cathode to the positively charged anode.
HbA migrates the farthest, followed by HbF, HbS, and HbC.
This is because the missense mutations in HbS and HbC replace glutamic acid ⊝ with valine (neutral) and lysine ⊕, respectively, impacting the net protein charge.

A Fat Santa Claus

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Coagulation and Kinin Pathways

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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

volksWagen Factories make gr8 cars.

vWF carries/protects factor VIII

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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.

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Platelet Plug Formation

(Primary Hemostasis)

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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.

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Pathologic RBC Forms:

liver disease
abetalipoproteinemia (states of cholesterol dysregulation)
spiny appearance

Acanthocytes

(“Spur Cells”)

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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

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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”)

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Pathologic RBC Forms:

G6PD deficiency

Degmacytes

(“Bite Cells”)

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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”)

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Pathologic RBC Forms:

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

Elliptocytes

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Pathologic RBC Forms:

megaloblastic anemia (also hypersegmented PMNs)

Macro-Ovalocytes

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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

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Pathologic RBC Forms:

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

Schistocytes

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Pathologic RBC Forms:

sickle cell anemia
sickling occurs with dehydration, deoxygenation, and at high altitud

Sickle Cells

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Pathologic RBC Forms:

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

Spherocytes

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Pathologic RBC Forms:

HbC disease
asplenia
liver disease
thalassemia

Target Cells

“HALT,” said the hunter to his target.

HbC disease
Asplenia
Liver disease
Thalassemia

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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)

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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.

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Anemias

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Microcytic, Hypochromic Anemias

MCV < 80 fL

Defective Heme Synthesis:
- iron deficiency (late)
- lead poisoning
- sideroblastic anemia
- anemia of chronic disease
Defective Globin Chain:
- thalassemias

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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

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

Plummer-Vinson Syndrome

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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

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α-Thalassemia:

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

α-Thalassemia Minima

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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

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α-Thalassemia:

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

Hemoglobin H Disease (HbH)

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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)

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Anemias:

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

β-Thalassemia

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β-Thalassemia:

heterozygote
β chain is underproduced
usually asymptomatic
diagnosis confirmed by ↑ HbA2 (> 3.5%) on electrophoresi

β-Thalassemia Minor

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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

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β-Thalassemia:

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

HbS/β-Thalassemia Heterozygote

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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

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Symptoms of Lead Poisoning

LEAD:

Lead Lines on gingivae (Burton lines) and on metaphyses of long bones on x-ray
Encephalopathy and Erythrocyte basophilic stippling
Abdominal colic and sideroblastic Anemia
Drops—wrist and foot drop, Dimercaprol and EDTA are 1st line of treatment

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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

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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

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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

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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

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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

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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

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Anemias:

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

Nonmegaloblastic Anemia

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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

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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

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Normocytic, Nonhemolytic Anemias

MCV 80–100 fL, reticulocyte count ≤ 2%:

iron deficiency (early)
anemia of chronic disease
aplastic anemia
chronic kidney disease

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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

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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

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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

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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

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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

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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

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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 bites 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–lyCine, hemoglobin Crystals

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 Great, cold weather is MMMiserable.

Warm—IgG
Cold
- IgM and Complement
- Mycoplasma pneumoniae
- Infectious Mononucleosis

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):

Painful abdomen
Port wine–colored urine
Polyneuropathy
Psychological disturbances
Precipitated 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:

Fever
microangiopathic hemolytic Anemia
Thrombocytopenia
Renal failure
Neurologic 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 Making New Thrombi.

Sepsis (gram ⊝)
Trauma
Obstetric complications
acute Pancreatitis
Malignancy
Nephrotic syndrome
Transfusion

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 Cancels, and protein S Stops, 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 CD15+ and CD30+ 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:

HyperCalcemia
Renal involvement
Anemia
Bone lytic lesions/Back pain

Monoclonal 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.

HyperCalcemia
Renal involvement
Anemia
Bone lytic lesions/Back 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.

HyperCalcemia
Renal involvement
Anemia
Bone lytic lesions/Back 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 = Crushed Little Lymphocytes (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 CreaML 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-PresidenT 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

ApiXaban
RivaroXaban

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)

CYTarabine causes panCYTopenia.

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)

Taxes 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

Crisps the nerves.

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 Hodgkin lymphomas
causes bone marrow suppression

Vinblastine

Blasts 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

BeVacizumab inhibits Blood Vessel 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)

“Heartceptin” damages the heart.

Cancer Drugs:

small molecule inhibitor of BRAF oncogene ⊕ melanoma
used for V600Emutated BRAF inhibition
used for metastatic melanoma

Vemurafenib

VEmuRAF-enib is for V600Emutated BRAF 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

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

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Hematology and Oncology - First Aid Flashcards

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