Hematology Flashcards
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
poor outcome in adult ALL
t(9;22) Philadelphia
Good outcome in child: t(12;21)
contains Major Basic Protein
Phagocytic for antigen-antibody complexes
Produces histaminase -> limits reaction following mast cell degranulation
Eosinophils
monocyte in the tissue
macrophage
mediates allergic reaction due to granule contents
heparin, histamine & leukotrienes
Basophil
mediates local allergic reaction
Binds Fc portion of IgE
Degranulates releasing histamine, heparin & eosinophilic chemotactic factors
Mast cell
Tx: cromolyn sodium
dendritic cell in skin
Langerhans cell
Functions as link between innate and adaptive immune systems.
Expresses Fc and MHC II
Highly phagocytic
dendritic cell
Where does B cell mature?
bone marrow
costimulatory signal required for T cell activation
CD28
chromatin distribution described as “clock-face”
plasma cell
Which antibodies cross the placenta?
IgG
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)
complication of CLL
hypogammaglobulinemia -> infection is most common cause of death
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
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
tumor of mature B cells extranodal mass in child or young adult African form: mandible Sporadic form: abdomen (ileocecum & peritoneum) Translocation of c-MYC: t(8;14) associated with EBV starry sky
Burkitt lymphoma
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
hyperviscosity syndrome caused by excess secretion of IgM
no lytic bone lesions
Waldenstrom macroglobulinemia
asymptomatic plasma cell dyscrasia
precursor to multiple myeloma (1-2%)
MGUS => monoclonal gammopathy of undetermined significance
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
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
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
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
-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
