Hematology Flashcards by Melanie Bray

Most common cancer of childhood
Immature B cells or T cells
Occurs before age 15 but most are age 1-3 yr
Cells: TdT+

Acute Lymphoblastic Leukemia

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poor outcome in adult ALL

t(9;22) Philadelphia

Good outcome in child: t(12;21)

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contains Major Basic Protein
Phagocytic for antigen-antibody complexes
Produces histaminase -> limits reaction following mast cell degranulation

Eosinophils

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monocyte in the tissue

macrophage

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mediates allergic reaction due to granule contents

heparin, histamine & leukotrienes

Basophil

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mediates local allergic reaction
Binds Fc portion of IgE
Degranulates releasing histamine, heparin & eosinophilic chemotactic factors

Mast cell

Tx: cromolyn sodium

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dendritic cell in skin

Langerhans cell

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Functions as link between innate and adaptive immune systems.
Expresses Fc and MHC II
Highly phagocytic

dendritic cell

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Where does B cell mature?

bone marrow

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costimulatory signal required for T cell activation

CD28

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chromatin distribution described as “clock-face”

plasma cell

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Which antibodies cross the placenta?

IgG

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Age: > 60 yr
CD20+, CD5+ B-cell neoplasm
smudge cells in peripheral smear
typically asymptomatic at diagnosis but may present with fatigue, anorexia, weight loss

Small lymphocytic lymphoma/chronic lymphocytic leukemia (CLL)

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complication of CLL

hypogammaglobulinemia -> infection is most common cause of death

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Late adulthood painless lymphadenopathy
t(14;18)
BCL2 gene product overexpression -> inhibition of apoptosis
tumor arises in germinal centers
incurable with waxing & waning course

Follicular lymphoma

*note when any leukemia involves the lymph NODE it is referred to as LYMPHOMA

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proliferation of large B cells that grow diffusely in sheets
high-grade
late adulthood
dysregulation of BCL6 (required for normal germinal center formation) -> p53 silenced -> no apoptosis

Diffuse Large B-cell Lymphoma

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tumor of mature B cells
extranodal mass in child or young adult
African form: mandible
Sporadic form: abdomen (ileocecum &amp; peritoneum)
Translocation of c-MYC: t(8;14)
associated with EBV
starry sky

Burkitt lymphoma

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Age: 65-70 yr
destructive plasma cell tumors involving axial skeleton
Most commonly involves: vertebral column, ribs, skull, pelvis, femur, clavicle and scapula
Lytic, punched out vertebral & skull lesions on xray-> fracture risk
free Ig light chain excretion in urine (Bence Jones proteinuria)
Hypercalcemia: confusion, weakness, lethargy, constipation, polyuria (renal dysfunction)

Multiple Myeloma
cause of death: infection
2nd most common cause of death: renal insufficiency
CRAB: hyperCalcemia, Renal insuff, Anemia, Bone lesions/Back pain

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hyperviscosity syndrome caused by excess secretion of IgM

no lytic bone lesions

Waldenstrom macroglobulinemia

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asymptomatic plasma cell dyscrasia

precursor to multiple myeloma (1-2%)

MGUS => monoclonal gammopathy of undetermined significance

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proliferation of small B cells in males age 50s-60s
t(11:14)
cyclin D1 overexpression -> promotes G1/S transition -> proliferation
expansion of mantle zone
symptoms related to spleen and gut in 50%

Mantle Cell Lymphoma

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Arise in tissues involved in chronic inflammatory disorders of infectious or autoimmune etiology (Hashimoto, Sjogren, H pylori gastritis)
Memory B cell origin
More common in southern Europe than US
Ex: MALToma

Marginal Zone Lymphoma

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B cell neoplasm of middle-aged white males
TRAP
“dry tap” due to marrow fibrosis

Hairy Cell Leukemia
cells have hairy cytoplasmic processes
Tx: cladribine

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T cell tumors that home to the skin
Early stages have eczema-like lesions
Cells can spread to the blood and cause Sezary syndrome -> lymphocytes with cerebriform nuclei

Mycosis Fungoides

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-Endemic to southern Japan, West Africa and Caribbean basin -associated with HTLV-1 -> encodes Tax which activates NF-kappaB -Skin lesions (rash), generalized lymphadenopathy, hepatosplenomegaly, peripheral blood lymphocytosis and hypercalcemia Rapidly fatal (months-1 yr)

Adult T cell Leukemia/Lymphoma

○ Large multimeric glycoprotein that stabilizes factor VIII and protects it from degradation ○ Synthesized by endothelial cells and megakaryocytes ○ Concentrated in the endothelium of blood vessels and released in response to stress hormones of endothelial damage

• Von Willebrand factor

extrinsic coagulation pathway vs. intrinsic coagulation pathway

* Extrinisic pathway is initiated by trauma & tissue factor exposure * Intrinsic pathway is activated when factor XI is converted the factor XIa by thrombin

serine protease that degrades fibrin

plasminogen -> plasmin

vitamin K antagonist

warfarin

oxidation of Hb sulfhydryl groups Denatured Hb precipitates Seen with G6PD deficiency

Heinz bodies

Seen with functional asplenia -> normally removed | basophilic nuclear remnants

Howell-Jolly bodies

triad of iron deficiency anemia, esophageal webs and atrophic glossitis

Plummer-Vinson syndrome

homozygote with absent beta chain marrow expansion causing "crew cut" on skull xray chipmunk facies extramedullary hematopoiesis increased risk of parvo B19 aplastic crisis

beta-thalassemia major

deficiency of ADAMTS13 (which can be inherited or acquired) | decreased degradation of vWF multimers

Thrombotic Thrombocytopenic Purpura

Bleeding due to defective platelet aggregation (platelet plug) in response to ADP, collagen, epinephrine or thrombin because of deficiency or dysfunction of GpIIb-IIIa, AR

Glanzmann Thrombasthenia

defect in platelet plug formation due to deficiency of GpIb | AR

Bernard-Soulier syndrome

antibodies to GpIIb/IIIa with splenic macrophage consumption of platelet/antibody complex Bone marrow bx: increased megakaryocytes

Immune thrombocytopenia (ITP)

Hypercoagulability in whites with increased risk of cerebral vein thrombosis, especially with oral contraceptive use

Factor V Leiden | resists degradation by activated protein C

inactivates factor V

protein C PROC mutations causes deficiency protein S enhances protein C cleavage of factor V

X-linked intrinsic coagulation pathway defect hemarthroses, easy bruising, increased PTT classically affected male and carrier females

Hemophilia A: deficiency factor VIII Hemophilia B: deficiency factor IX cure: liver transplant

see normal bleeding time but decreased synthesis of factors 2, 7, 9, 10, protein C & S

vitamin K deficiency

which chromosome for ABO blood groups?

chromosome 9

when is Rhogam given?

28-32 weeks

inhibits ferrochelatase and ALA dehydratase therefore decreases heme synthesis inhibits rRNA degradation -> basophilic stippling seen symptoms: Burton lines on xray, encephalopathy, abdominal colic, sideroblastic anemia, wrist & foot drop

lead poisoning ALA dehydratase contains zinc and is therefore sensitive to inhibition by lead Tx: EDTA and dimercaprol; succimer in children

glutamic acid -> valine change in codon for beta globin AR hemolytic condition painful swelling in hands and feet splenic infarct at low O2 tensions

sickle cell anemia HbS is less soluble so RBC less deformable when moving through capillaries heterozygote advantage for malaria

X-linked enzyme deficiency common in Mediterranean hemolysis in response to bacterial & viral infections Deficiency of reducing equivalents (NADPH) in RBC drug-induced hemolysis

glucose 6 phosphate dehydrogenase deficiency anemia with eating fava beans Presents: back pain, hemoglobinuria a few days after oxidative stress RBCs with Heinz bodies and bite cells on peripheral smear

first-line therapy for CML

imatinib | MOA: inhibitor of BCR-ABL tyrosine kinase

allosteric activator at low concentration, but is a competitive inhibitor for oxygen binding at higher concentration

carbon monoxide

has 1 polypeptide chain and 1 O2 binding site binds O2 better at low O2 concentrations heart and skeletal muscle

myoglobin

4 pyrrole rings linked by alpha-methylene bridges

heme

competitive inhibitors of O2 binding

CO and NO | both bind to the O2 binding site on heme

formed in RBCs from 1,3-bisphosphoglycerate & binds to Hb in the central cavity formed by the 4 subunits and increases the energy required for conformational changes which facilitate O2 binding

2,3-BPG levels of this increase at high altitudes in order to increase O2 delivery to the tissues adjustment to high altitude occurs over approx lifespan of RBC

bind to Hb and cause a conformational change which releases O2

protons

What lab value predicts sickle cell crisis?

MCHC

decreases cell volume by increasing potassium and water efflux reduced chance of malaria development because of decreased lifespan of RBC (40 days for homozygote) & inhibition of cell lysis for parasitized RBCs

HbC Crystals form in O2-rich blood, so formation is more likely in the larger vessels and less likely to cause vascular occlusion. Crystallization only occurs with ligand bound

hypersegmented neutrophils

folate and B12 deficiencies

B12 deficiency causes

dietary, malabosorption, pernicious anemia, Diphyllobothrium latum (fish tapeworm), proton pump inhibitors

hemoproteins

``` hemoglobin myoglobin CYPs catalase myeloperoxidase NO synthase ```

cellular storage for iron

ferritin

iron transport in the plasma

transferrin

gene mutations which decrease hepcidin synthesis chronic iron toxicity increased iron absorption iron deposition within the joints and tissues of the heart, liver and pancreas, causing organ damage and failure slate-blue skin appearance

hemochromatosis

rate-limiting enzyme in porphyrin synthesis in the liver

ALA synthase

needed for hephaestin and ceruloplasmin activity (mobilization of iron)

copper

defect in hydroxymethylbilane gene accumulation of ALA and PMB precursors causes abdominal pain, neurologic dysfunction but NOT photosensitivity Painful abdomen Port wine urine Polyneuropathy Psychological disturbances Precipitated by drugs, alcohol & starvation

Acute Intermittent Porphyria AD Tx: glucose and heme -> inhibit ALA synthase

X-linked defect resulting in reduced catalytic activity of ALAS2 during the block in heme synthesis, iron delivery to the mitochondria continues so have accumulation of non-heme iron as ferrochelatase

sideroblastic anemia

Glycoprotein produced by the kidney in proportion to intracellular oxygen concentration

erythropoietin

○ Transfer of methyl group from N5-methyl-FH4 to homocysteine to form methionine ○ Rearrangement of methylmalonyl-CoA to form succinyl-CoA

functions of B12 if have deficiency see: decrease in methionine and SAM ↑homocysteine in blood and methylmalonic acid in urine Folate deficiency: ↑homocysteine but no methylmalonic acid in urine

deficiency of intrinsic factor

pernicious anemia

defect in UMP synthase causing inability to convert orotic acid to UMP (in the de novo pyrimidine synthesis pathway) AR megaloblastic anemia in children that cannot be cured with folate or B12

orotic aciduria

oxidized free Hb

methemoglobin

How do you test for folate deficiency?

If suspect folic acid deficiency, give large histidine load and patient will excrete FIGLU in urine see bright red tongue too!

proteins secreted by the salivary gland and gastric mucosa (parietal cells) & bind B12

haptocorrins

RBC proteins

• Spectrin, ankyrin, anion exchange protein (band 3), band 4.1, band 4.2 and actin all participate in the cytoskeleton, giving the RBC its biconcave shape Function of band 3: exchange of chloride and bicarbonate ions

falsely elevated in anemia due to decrease in RBCs

reticulocyte count a properly functioning marrow increases the RC to >3% RC >3% suggests peripheral destruction

RBC destruction by macrophages of spleen, liver & lymph nodes (RES)

extravascular hemolysis see: anemia with splenomegaly, jaundice, increased risk of gallstones spherocytes in peripheral smear

hemolysis of RBCs within blood vessels

intravascular hemolysis see: hemoglobinemia, hemoglobinuria, hemosiderinuria (iron), decreased serum haptoglobin schistocytes and increased reticulocytes on peripheral smear

AD: Mutations which deplete band 3, RhAG, band 4.2, ankyrin or spectrin small round RBCs with no central pallor increased RDW premature removal of RBCs by the spleen

Hereditary spherocytosis | tx: splenectomy

major energy source for RBC

glycolysis and pentose pathway shunt

highly condensed X chromosome

Barr body

Why does malaria grow poorly in G6PD deficiency?

ROS generation (glutathione depletion)

phenotypically "O" blood type but also have anti-H antibody

Bombay blood type

sugars that determine blood type

A: galactosamine B: galactose

> 20% blasts in the bone marrow

leukemia will also see decreases in normal blood cells (RBCs -> anemia; neutropenia; thrombocytopenia) Blasts in the blood are larger than normal RBCs and have large nucleus, little cytoplasm, punched-out nucleolus

markers for myeloblasts vs lymphoblasts

Myeloblasts (AML): MPO -> look for Auer Rod** | Lymphoblasts (ALL): tDt

accumulation of myeloblasts in AML has what major risk

DIC AML is a disruption to the Retinoic Acid Receptor (RAR) Treat with ATRA -> causes myeloblasts to mature to neutrophils

subtype of myeloblastic leukemia in which presentation is swelling of the gums (blasts invade gums) cells lack MPO

acute monocytic leukemia

causes of myeloblastic syndrome

prior exposure to alkylating agent or radiotherapy

neoplastic proliferation of naive B cells in older patient coexistence of CD5 and CD20 is characteristic (CD5 is normally on T cells) smudge cells

CLL

Why is there an increased risk of hyperuricemia & gout in myeloproliferative disorders?

high cell turnover

worst complication of CML

``` acute leukemia (can convert to ALL or AML) CML has a characteristic increase in basophils** t(9;22) generating BCR-ABL fusion protein with increased tyrosine kinase activity ```

proliferation of mature myeloid cells esp RBCs Granulocytes & platelets also elevated associated with JAK2 kinase mutation** Symps: blurry vision, headache, flushed face (plethora), ITCHING after bathing (histamine release from extra mast cells), increased risk of venous thrombosis

Polycythemia Vera (PV) Tx: phlebotomy (1st) hydroxyurea (2nd)

causes of reactive polycythemia

hypoxia from lung disease | EPO production by renal cell carcinoma

neoplastic proliferation of megakaryocytes assoc with JAK2 kinase mutation progresses to marrow fibrosis Slide: tear-drop RBCs, nucleated RBCs, immature granulocytes Increased risk of infection, thrombosis, bleeding

Myelofibrosis complications: splenomegaly from extramedullary hematopoiesis