Flashcards in Hematology Deck (373):
What are the sites of fetal hematopoiesis?
0-2 mos: yolk sac
2-7 mos: liver and spleen
5-9 mos: bone marrow
How do sites of hematopoiesis differ between infants and adults?
Infants: marrow in all bones
Adult: more limited: *vertebrae and pelvis*, ribs, sternum, skull, sacrum, proximal ends of femur
In bone marrow, how many cells are stem cells?
1 in 20x10^6 (20 million)
Beyond this: sign of potential leukemia
What are molecular markers for hematopoietic stem cells (HSCs)?
HSC: CD34+ and CD38-
Once committed to differentiation, become CD38+, but lack lineage specific markers.
What transcription factors regulate the survival of HSCs in bone marrow?
What transcription factors commit cells to the myeloid lineage in early hematopoiesis?
What transcription factors commit cells to erythropoietic and megakaryopoietic lineages?
Where are Erythropoietin and Thrombopoietin produced?
EPO: 90% in kidney
3 roles of growth factors in hematopoiesis
1. control of cell cycle
2. gene activation
3. inhibition of apoptosis
What is BCL-2?
Production stimulated by growth factor
Inhibits release of cytochrome C from mitochondria
3 families of adhesion molecules
Immunoglobin superfamily: antigen dependent surface receptors (TCR, etc) and antigen independent surface adhesion molecules
Selectins: leukocyte and platelet adhesion to endothelium
Integrins: cell adhesion to ECM
What is CFU-GEMM?
first step of erythropoiesis: commitment of pluripotent stem cells to non-lymphoid lineage
CFU-GEMM: Colony Forming Unit - Granulocyte, Erythrocyte, Megakaryocyte, Macrophage
What is BFU-E?
Erythrocyte Burst Forming Unit - first committed erythroid progenitor
divides -> CFU-E
Is there RNA in the cytoplasm of an RBC?
What is erythropoietin? Where is it produced?
Glycosylated polypeptide (165 AA)
90% produced by peritubular interstitial cells of kidney
10% in liver and elsewhere
What factors in the kidney stimulate erythropoietin production?
HIF-2a and B
What type of anemia results following kidney damage (failure, removal, etc.)
Because of reduced production rather than Hb or structure problem.
What is normal adult hemoglobin and what are its subunits?
consists of 2a and 2B
What forms of Hb are normally found in adult blood?
HbA (a2B2): dominant
HbF (a2Y2): fetal
Where are the components of hemoglobin synthesized?
All in RBC precursor cells
protoporphyrin: in mitochondria
Fe2+: transported by Transferrin -> mito -> + protoporphyrin -> haem
What is the P50 of hemoglobin under normal conditions? How does it change?
P50: partial pressure of O2 at which Hb is 50% sat.
normal blood: 26.6
increased affinity: falls
decreased affinity (ex. 2,3-DPG): rises
4 factors that move Hb O2 dissociation curve to the right
Move to right (low O2 affinity)
factors that move Hb O2 dissociation curve to the left
Move to left (high affinity)
What is methemoglobinemia? Causes?
Circulating Hb w/ Fe3+ rather than 2+ (patients often cyanotic)
Hereditary HbM: AA substitution affecting heme pocket
Hereditary deficiency of methemoglobin reductase
Toxic: drug or toxin induced oxidation of Fe2+ in Hb.
How do RBCs produce energy?
ATP and NADH: Embden-Meyerhof pathway (glycolytic)
NADPH: Hexose Monophosphate Shunt (PPP)
Important proteins in RBC membrane structure.
Band 3 (Cl- / HCO3- exchanger): binds ankyrin which binds protein 4.2 which together bind alpha spectrin
Glycophorin binds protein 4.1 and actin which bind spectrin
What is the relationship between anemia and 2,3-DPG?
2,3-DPG usually rises in setting of anemia -> rightward shift of Hb / O2 dissociation curve: Hb gives O2 to tissues more readily.
With what Hb concentration do symptoms of anemia usually become apparent?
What are the criteria for microcytic, hypochromic anemia, and what are the causes?
Iron deficiency, thalassemia, anemia of chronic disease (some), lead poisoning, sideroblastic anemia
What constitutes normocytic, normochromic anemia and what are the types / causes?
MCV: 80-95 fL
may be hemolytic or non-hemolytic
Acute blood loss, chronic disease, renal disease, mixed deficiencies, bone marrow failure (post-chemo)
What constitutes macrocytic anemia and what are the causes?
MCV >95 fL
Megaloblastic: B12 or folate deficiency
Non-megaloblastic: ETOH, liver disease, myelodysplasia, aplastic anemia
What is a normal reticulocyte count (% and absolute) and how does it change with anemia?
Normal: 0.5-2.5%, absolute: 50-150x10^9 /L
should rise w/ anemia due to increase EPO
If anemia is suspected, what should the first step be toward making a diagnosis?
look at a blood film to count / characterize
What stain is used to visualize RNA and Heinz bodies in a blood smear?
Methylene Blue (supra-vital staining)
What are Pappenheimer bodies?
Iron containing RBC/reticulocyte inclusions - siderotic granules
What is a Howell-Jolly body?
DNA remnant seen in reticulocytes
What are Heinz bodies?
Reticulocyte/RBC inclusions of oxidized, denatured Hb
What is ineffective hemopoiesis?
Death of erythroblasts before production of mature cells
Normally, 10-15% of developing erythroblasts die in marrow.
What is seen in anemia w/ ineffective hemopoiesis?
If marked: elevated unconjugated bilirubin and lactate dehydrogenase
Low reticulocyte count relative to degree of anemia and number of erythroblasts in marrow.
How is total erythropoiesis assessed?
myeloid : erythroid ratio (normally 2.5 : 1 to 12 : 1, smaller with increased erythropoiesis)
What are microscopic features of Iron deficiency anemia?
Central pallor in RBCs (>1/3 diameter)
Small RBCs (smaller than lymphocyte)
4 causes of iron deficiency anemia
1. dietary lack
2. impaired absorption
3. increased requirement
4. chronic blood loss (most importantly)
What is the gold standard test for iron deficiency anemia?
Prussian Blue staining of Bone Marrow
Reveals a lack of granular iron stores
Where in the GI tract is iron absorbed?
Duodenum (mostly proximal)
3 ways iron is absorbed in duodenum
1) complexed with mucin
2) complexed with ascorbate
3) complexed with heme (globin enzymatically removed)
How is iron transported from intestinal enterocytes into plasma?
Fe2+ is transported across basolateral membrane by ferroportin, oxidized to Fe3+ by hephaestin and released into plasma where it binds Transferrin
What is hephaestin?
ferricoxicase enzyme in basolateral enterocyte membrane. Oxidizes iron to Fe3+
How is iron transported into enterocytes?
Fe3+ -> Fe2+ in lumen by dcytb on brush border (ferric reductase)
Transported across by DMT-1
What is dcytb?
Ferric reductase found on apical brush border of duodenal enterocytes.
Fe3+ -> Fe2+ for transport into cell by DMT-1
What is DMT-1?
transporter on apical brush border of enterocytes. Transports Fe2+ into cell
How is iron transported in the blood?
Solubilized by Transferrin, which carries 80% to bone marrow and most of the rest to liver and kidney
Where is Transferrin produced?
What is ferritin?
Iron storage protein found in many cell types
Hepatic parenchymal cells, macrophages
What is ferrochelatase?
found in mitochondria. inserts iron into protoporphyrin
How much of absorbed iron is incorporated into Hb?
rest in storage
What are and how do IRE and IRPs work?
IRE: iron responsive element - found in iron metabolism mRNA
IRP: iron responsive protein - IRE affinity modulated by iron levels
In high iron levels: IRP binds iron and has low affinity for IRE
Iron deficiency: IRP affinity for IRE is enhanced:
IRP binding in 3' region ->up-regulation of transferrin receptor
IRP binding in 5' region -> down-regulation of ferritin and ALA
What is the function of hepcidin?
Central regulator of iron metabolism
High levels of hepatic iron uptake -> Hepcidin production
Hepcidin binds ferroportin -> internalization and degradation -> DECREASED IRON ABSORPTION
What is TfR2?
Hepatic trasnferrin receptor - hepatocellular iron uptake.
What is the effect of inflammation on iron metabolsim?
Inflammation -> cytokine production, esp IL-6 -> increased hepcidin -> decreased iron absorption; increased hemophagocytosis, decreased erythropoietin production -> inhibited erythroid proliferation
What is ceruloplasmin?
ferricoxidase enzyme in plasma, oxidezes iron (Fe2+ -> Fe3+)
How much iron is in 1g of Hb?
How much iron is absorbed / lost daily?
1-2 mg absorbed
1-2 mg lost (desquamation, sweat, no pathway)
How much iron is lost in a pregnancy?
500 mg total
How much iron is lost in a menstrual period?
Physical signs of iron deficiency
What is TIBC?
Total Iron Binding Capacity
What happens to TIBC in Iron Deficiency Anemia?
Increased due to increased hepatic production of Transferrin
What lab tests are ordered in iron deficiency anemia and what are the usual findings?
Serum Transferrin: elevated
Serum Iron: low
Serum Ferritin: low
What is the preferred oral iron suppliment?
Ferrous Sulfate 324 mg (65mg iron) 3x daily
Is dietary intervention appropriate for iron deficiency anemia?
No - 3oz steak contains 3mg iron
adults need 150-200 mg = 10lbs steak
What are benefits of IV iron therapy?
Correction of nonhematologic effects of iron deficiency
What is the #1 reason for failure to respond to oral iron supplimentation?
Failure to take pill
What is hereditary hemochromatosis and what kind of anemia does it produce?
#1 single gene inherited disease in US
Not anemic - iron overload
Iron deposits in organs -> dysfunction
What is the most common mutation found in heredetary hemochromatosis?
C282Y in HFE gene (6p21.3)
Mutation results in low levels of hepcidin -> elevated levels of ferroportin and increased iron absorption
How is iron toxic (as in hemochromatosis)?
Direct tissue toxicity
1. lipid peroxidation via iron-catalyzed free radical rxns
2. stimulation of collagen formation by stimulation of hepatic stellate cells
3. interaction of reactive oxygen species and of iron itself w/ DNA
How many blood transfusions does it take for signs of iron overload to become apparent?
200mg iron / unit blood
How is iron overload (hemochromatosis) treated?
phlebotomy goals: ferritin <50
Conditions associated w/ anemia of chronic disease
Chronic infections (osteomyelitis)
Inflammatory Bowel Disease
What is the primary mechanism underlying anemia of chronic disease?
IL-6 produces an increase in hepcidin -> decreased iron absorption, decreased iron release from macrophages
Erythropoietin depression (production in kidney and decreased sensitivity in bone marrow)
Features of anemia of chronic disease
Low serum iron
Low serum transferrin
Low transferrin saturation
Normal to High serum ferritin
What defines a finding of hypersegmented PMNs?
>5% PMNs w/ 5 nuclear lobes or more
What causes megaloblastic anemia?
Vitamin B12 or folate deficiency or metabolic impairment-> impairment of DNA synthesis (impaired thymidine and purine synth)
What are some causes of non-megaloblastic macrocytic anemia?
Liver disease, hemolysis, splenectomy, Myelodysplastic syndromes, hypothyroid, hemorrhage, etoh, pregnancy
What abnormal RBCs are seen in non-megaloblastic anemia assoc. w/ liver disease?
target cells, stomatocytes
What is a schistocyte?
Fragmented RBC - seen in hemolysis that may be associated with macrocytosis
Are patients who have undergone splenectomy typically anemic?
No, though they may display macrocytosis with Howell-Jolley bodies
What are Pelger-Huet cells?
bilobed PMNs seen in myelodysplastic syndrome
What is the association between hypothyroidism and macrocytosis?
May be due to nutrient malabsorption or menorrhagia
What is a normal serum B12 level
What are 2 important biochemical roles of vitamin B12?
serves as a cofactor
1: Methylcobalamin: cofactor for methinonine synthase (methyltransferase): Homocysteine + mTHF -> methionine + THF
2: Adenosylcobalamin: cofactor for methylmalonyl CoA mutase: Methylmalonyl CoA -> Succinyl CoA
B12 deficiency results in the elevated levels of what substances?
Precursors in reactions in which B12 is a cofactor:
homocysteine and methylmalonyl CoA
How is B12 absorbed?
in food -> stomach where R-protein binds -> duodenum -> pancreatic enzymes degrade R-protein -> IF binds -> enterocyte -> IF degradation -> transcobalamin II binding and absorption to blood
What antibodies are associated with pernicious anemia?
Intrinsic Factor Autoantibodies (IFA): 100% specific for atrophic body gastritis
Gastric Parietal Cell Autoantibodies (PCA): non-specific for atrophic body gastritis
What are gastric parietal cell autoantibodies associated with?
What does a positive IFA titer indicate?
IFA: Intrinsic Factor Autoantibody
Indicates atrophic damage in gastric body mucosa (contributes to pernicious anemia)
Where is folic acid absorbed?
What is the daily intake requirement for B12 and folate?
B12: 7-30 mcg
Folate: 50-100 mcg
What are body stores of B12 and Folate?
B12: 2-3 mg (enough for 2-4 years)
Folate: 10-12 mg (enough for 4 months)
How is folic acid lost from the body?
bile and urine
What is methotrexate's role in folate deficiency?
inhibits folic acid -> THF rxn
decreased purine and pyrimidine production
What is compensated hemolysis?
Marrow produces more RBCs in face of hemolysis -> higher circulating reticulocyte numbers.
What is the effect of intravascular hemolysis? Cause?
severe and rapid process -> free Hb in circulation, renal toxicity
ex: mismatched blood transfusion
What happens in extravascular hemolysis? Cause?
Insidious process. RBCs in liver or spleen. Hb bound by serum proteins
ex: hereditary spherocytosis
Intracorpuscular vs extracorpuscular hemolytic anemia, inherited or acquired?
Intracorpuscular: inherited (except PNH)
Clinical findings in hemolysis
Jaundice (elevated bilirubin)
Dark Urine (hemoglobin or urobilin)
Gallstones (elevated bilirubin)
Aplastic crises (exp Parvovirus B19 -> suppression of erythropoiesis)
What is the cause of Hereditary Spherocytosis?
RBC cytoskeletal defects: Band 3, ankyrin, and band 4.2 defects and spectrin deficiency (vertical interaction defect)
Autosomal dominant, poorly penetrant
How is hereditary spherocytosis diagnosed?
Osmotic fragility testing (hypotonic intolerance)
EMA fluorescence test (band 3 deficiency)
Clinical features of hereditary spherocytosis
often presents as neonatal jaundice
aplastic crisis (parvovirus implicated)
may need transfusion
How is splenectomy helpful in hereditary spherocytosis and when is it warranted?
eliminates stressful microcirculatory environment, increases RBC lifespan.
warranted if Hb 9 gm% (gram solute / 100g solution)
What defect occurs in hereditary elliptocytosis?
Horizontal defect: spectrin and band 4.1 defect -> reduced RBC lifespan, but milder than spherocytosis
What is Southeast Asian Ovalocytosis?
Band 3 defect -> severe hemolysis
What is Paroxysmal Nocturnal Hemoglobinuria?
Acquired intrinsic RBC disorder
Mutation of PIG-A in stem cell progenitor in marrow -> lack of glycosyl phosphatidyl inositol (GPI) anchor results in loss of CD55 and CD59 -> no inhibition of compliment activation -> MAC induced lysis
What is a common progression of PNH?
Leukemia - premalignant condition
What is the appearance of bone marrow in PNH?
Hypoplastic with low Fe stores
defective clone -> harm to normal marrow elements -> symptomatic state
What is Budd-Chiari?
Occlusion of IVC or Hepatic vein -> congestive liver disease
May be present in PNH due to platelet abnormality / hypercoagulability
What vessels are often affected in PNH?
Large veins: mesenteric, portal, hepatic
How is G6PD deficiency inherited?
What substances can trigger hemolysis in pts with G6PD deficiency?
What population has the highest frequency of G6PD deficiency?
Blacks - 10% affected
Highest incidence in malarial areas
B-subtype affects caucasians - chronic hemolysis
2 types of autoimmune hemolytic anemia
Warm-reactive: idiopathic, involves IgG
Cold-reactive: associated with infection (mycoplasma, CMV, mono, lymphoma), involves IgM
What is Evan's Syndrome?
May occur with autoimmune hemolytic anemia
Ab coat platelets -> thrombocytopenia
How is AIHA diagnosed?
Coomb's tests (direct or indirect)
At what temperature are cold-reactive AIHA antibodies most active?
2-4 degrees C
How is AIHA treated?
Transfusion for low Hb
Protect kidney: alkalinize urine, maintain hydration
plasmaphoresis (remove Ab from plasma, controversial)
Splenectomy (last resort)
What are causes of fragmentation hemolysis?
Microangiopathy: as in DIC - fibrin strands produce shear stress
March hemoglobinuria: repeated trauma - runners, karate, soldiers
Heat denaturation: pre-trasfusion cell warmers
What subunit interface of Hb is particularly important for O2 binding?
Mutations alter O2 affinity
What percent of delivered O2 are tissues able to extract?
What is the P50 of Hb?
O2 tension at which Hb is 50% saturated
Normal ~26 torr
What chromosomes are Hb genes located on?
What are the forms of hemoglobins in normal adults?
HbA (a2B2) 96%
HbF (a2Y2) 1%
AbA2 (a2d2) 3%
What are the alpha thalassemias?
1 gene deletion: silent carrier
2 gene deletion (cis or trans, cis high risk to offspring): mild anemia
3 gene deletion: HbH disease: hypochromic microcytic anemia w/ splenomegaly (extramedullary hematopoiesis). Moderate anemia.
4 gene deletion: hydrops fetalis, intrauterine death
What Hb tetramers are seen in alpha thalassemia?
Insoluble tetramers formed due to inadequate alpha production
Bart's Hb: gamma Hb tetramers. only present in first few weeks of live
HbH: Beta tetramers in adults.
Both move faster than reg. Hb on electrophoresis.
What chelation agent is used for B-thalassemia major?
What does management of B-thalassemia major consist of?
Folic acid supplimentation
Bone Marrow Transplant
What is Hb like in SC disorder?
2 abnormal B alleles:
HbS and HbC present
Patient produces no HbA
What is Sickle-B-Thalassemia?
Patient with HbS allele and either fully (SB0thal) or partially (SB+thal) suppressed 2nd B allele
Both have elevated HbA2
Both are microcytic
What is the inheritance pattern of sickling hemoglobins?
Heterozygous individuals have discernable, but very mild clinical findings.
What is sickle cell Trait?
Heterozygousity for HbS
Rarely symptomatic: heat + dehydration + exercise, high altitude
Always: HbA > HbS
What bones are frequently involved in osteonecrosis in adults with SS disease?
Vertebrae and femur heads
What is acute chest syndrome in SS disease?
Pulmonary infarct or pneumonia caused by vascular occlusion
What is the result of co-inheritance of a-thalassemia with SS disease?
Reduces severity of symptoms
What tests are used for diagnosis of Sickle Cell?
Solubility test: Cells lysed by saponin, deoxygenated by N-diathionite. HbS falls out of solution
What drug is given to Sickle Cell patients to stimulate HbF?
Hydroxyurea - iron chelator, anti-cancer - increases HbF
What occurs in combined HbE / B-thalassemia phenotype?
Transfusion dependent thalassemic phenotype
2 broad groups of WBCs
Immunocytes (lymphocytes, plasma cells)
Total number of leukocytes in peripheral blood
4-11x10^9 / L
2 classes of granules in PMN and when in development do they appear?
Secondary: Myelocyte: dominant in mature cells
What are the stages of PMN development and where are those stages found?
Marrow: Myeloblast -> Promyelocyte -> Myelocyte -> Metamyelocyte -> Band -> Neutrophil
Blood: Neutrophil only
Developmental process of monocyte / macrophage
Myeloblast -> Promonocyte -> monocyte (circulating) -> macrophage (tissue)
At what stage of development can Basophil, Eosinophil and PMN be differentiated?
Do metamyelocytes divide?
NO. First stage that is non-dividing.
What is the typical ratio of myeloid: erythroid cells in bone marrow?
2:1 - 12:1
What is the lifespan of a granulocyte once released from the marrow?
6-10 hours circulating (2 pools of equal size, circulating and marginating. Marginating not counted in CBC)
4-5 days in tissue
What growth factors stimulate the myeloid line of cells?
IL-1, IL-3, IL-5 (eosinophil), IL-6, IL-11, GM-CSF, M-CSF, G-CSF
What is the difference between G-CSF and pegylated G-CSF? When are they used?
G-CSF: must be given daily
pegylated G-CSF (PEG): long acting, given 1x every 7-14 days
Used post chemo, AML, + EPO to improve marrow function, Peripheral blood stem cell harvesting ***
In peripheral blood stem cell harvesting what substance is given to increase the number of circulating stem cells?
After leaving the bone marrow what is the lifespan of a monocyte?
20-40 hours in circulation
months - years once in tissue as macrophage
What is a histiocyte?
macrophage in destination tissue
What receptors facilitate opsonization enhanced phagocytosis and what cells are involved?
Receptors: Fc and C3b on macrophages and neutrophils
2 classes of chemokines and cells responsive
CXC (alpha): neutrophils
CC: macrophage, basophil, eosinophil, NK
What disorders can lead to dysfunction of phagocyte chemotaxis?
Lazy leukocyte syndrome (congenital)
Myeloid leukemia, Myelodysplastic syndrome, Myeloproliferative syndrome
What can cause defect in phagocyte phagocytosis?
defective opsonization (hypogammaglobinemia)
What can produce defective phagocyte killing?
Chronic Granulomatous disease (X-linked or AR - respiratory burst impaired)
Chediak-Higashi: phagosome-lysosome fusion defect
bilobed or unsegmented neutrophils
neutrophils have basophilic RNA inclusions
Associated with giant platelet thrombocytopenia
What is the appearance of PMNs in Chediak-Higashi syndrome?
Giant odd granules in phagocytic cells
Circulating neutrophils >7.5x10^9/L
What is Leukemoid Reaction?
reactive, excessive leukocytosis characterized by immature cells in circulation
Associated w/ severe / chronic infections, hemolysis, metastatic cancer.
What is Leukoerythroblastic Reaction?
Erythrocyte and Granulocyte precursors in blood
metastatic infiltration of the marrow, benign or neoplastic blood disorders
What constitutes neutropenia?
Neutrophil count <1.5*10^9 /L
below 0.2 is very serious
Blacks and middle eastern - typically low (benign ethnic neutropenia)
Neutrophil Elastase defect -> life-threatening infections in first year
-> marrow fibrosis and AML
G-CSF may help
Neutrophil elastase defect (usually)
cyclical (3-4 week cycles) fall in neutrophils and usually corresponding rise in monocytes
Clinical features of neutropenia
Infections of mouth and throat -> ulceration and bleeding
Septicemia (s.epidermidis, gram - in gut)
What are treatments for autoimmune neutropenia?
Rituximab (Anti-CD20 (Bcell marker))
Eosinophilic leukocytosis and Hypereosinophilic syndrome
Eosinophilic leukocytosis (eosinophilia): >0.4*10^9
Hypereosionophilic sydrome: >1.5*10^9 for over 6 mos w/ assoc. tissue damage
-heart valves, skin, lungs. treat w/ 'roids or cytotoxic drugs
What is basophil leukocytosis?
Basophils >0.1*10^9 /L
Usually myeloproliferative disorder such as chronic myeloid leukemia or polycythemia vera
3 causes of reactive basophil increases
Smallpox or chickenpox
What is chronic eosinophilic leukemia?1
Eosinophils >1.5*10^9 with tissue dammage
Clonal cytogenetic or molecular abnormality is present.
Where are dendritic cells found?
Skin, lymph nodes, spleen, thymus
What are Birbeck granules characteristic of?
What is Langerhan's Histiocytosis?
Clonal proliferation of CD1a + cells
Letterer-Siwe: before 2yoa. cutaneous eruptions, hepatosplenomegaly
Eosinophilic Granuloma: calvarium, ribs, femur. sometimes skin, lungs, stomach. Involvement of pituitary stalk -> DI
Hand-Schuller-Christian: calvarial defects, diabetes i., exophtalmos
AR, more frequenly acquired post infection (EBV, herpes, fung, bact, tumor. pt. may be immunocompromised)
Histiocytes in bone marrow destroy red cells, white cells and platelets
Fever, pancytopenia, multiorgan dysfunction, CNS involvement
Sinus Histiocytosis w/ massive lymphadenopathy
Painless, chronic cervical lymphadenopathy - normal histology
Fever and weight loss
Usually subsides over mos/ years
Glucocerebrosidase deficiency -> glucocerebroside laden macrophages
Hepatosplenomegaly, bone deformity and fractures
Activated macs (Gaucher cells)-> IL1, IL6, TNF -> tissue damage
Cherry-red spot, hepatosplenomegaly, CNS involvement - retardation
Sphingomyelin and cholesterol accumulation in tissues
Typical presentation of myeloproliferative neoplasm
increased peripheral neutrophils, RBCs, and/or platelets
What disease can myeloproliferative neoplasm progress to?
What is CML?
Chronic Myelogenous Leukemia (MPN disease)
t(9;22) -> fusion of BCR (C22) + ABL (C9) -> constitutively active TK -> proliferation of granulocytes and megakaryocytes
What is a myeloproliferative neoplasm?
Overpopulation of one or more of myeloid lineage
3 stages of CML
Chronic: leukocytosis w/ ~2% blasts, marrow fibrosis possible, no significant dysplasia
Accelerated: increased blasts 20% in blood or marrow
***70% are myeloid (AML), 20-30% lymphoid (ALL)***
What is Philadelphia Chromosome?
t(9;22) as seen in CML
Results in BCL + ABL fusion -> constitutively active TK
What is polycythemia vera?
Increased RBC production independent of normal regulatory mechanisms
Red cell mass >25% above mean normal (18.5 g/dL men, 16.5 g/dL women)
low rate of progression to AML
most deaths due to thrombosis or hemorrhage
What mutation is present in polycythemia vera?
Most prevalent is JAK2 gain of function (>95% of cases, but non-specific)
What is the progression of polycythemia vera?
Polycythemic: increased red cell mass
Spent: marrow failure / fibrosis -> cytopenia and anemia
May present w/ HTN or thrombosis of mesenteric, portal, splenic veins
What is primary myelofibrosis?
Early hypercellular marrow progresses to marrow fibrosis
Features: leukoerythroblastosis, tear shaped RBCs, extramedulary hematopoiesis
Progression to acute leukemia in 30%
What is the most common mutation seen in Primary Myelofibrosis?
JAK2 mutation in 50%
What is essential thrombocytopenia?
MPN involving megakaryocytic lineage
Sustained platelet count of >450*10^9 /L
Diagnosis of exclusion: rule out other MPN, MDS and causes of reactive thrombosis
Rare (<5%) progression to AML or MDS
What is the most frequent mutation seen in essential thrombocytopenia?
JAK2 - but non-specific. only 40-50% of cases
What marker is found on Mast cells involved in cutaneous mastocytosis?
What is a myelodysplastic syndrome?
secondary to cytopenia - clonal disorder of marrow stem cells
Hypercellular marrow, but failure to produce mature cells
What are non-clonal causes of myelodysplasia type changes?
Heavy metal poisoning
Drugs / chemo
What is seen in Refractory Anemia with Excess Blasts?
Type 1: <5% blasts in blood, 5-9% blasts in marrow. No Auer Rods.
25% progression to AML
Type 2: 5-19% blasts in blood, 10-19% in marrow. +/- Auer Rods
33% progression to AML
What are auer rods?
Seen in dysplastic myeloid blast cells (not always present, but markers of myeloid line in dysplastic conditions)
What is Myelodysplastic Syndrome del(5q)
Single deletion -> megakaryocytic dysplasia, leukopenia, often refractory macrocytic anemia,
Usually middle-older females
What is chronic myelomonocytic leukemia?
Peripheral monocytosis (>10%, >1x10^9 /L)
no philadelphia chrom
3mos with other causes ruled out.
What is Juvenile Myelomonocytic Leukemia?
Monocytic leukemia in kids 1,000/microL
Death by organ failure 2ndary to leukemic infiltration
Bone Marrow Transpant needed
What are DAF and MIRL?
Missing on RBC cell surface in PNH
What is Fanconi's anemia?
AR -> congenital aplastic anemia w/ skeletal abnormality, renal abnormality, growth tard
Due to chromosomal fragility
Treatment: support / BMT
2 classifications of acute leukemia
ALL: Acute Lymphatic Leukemia: >20% lymphoid blasts in blood or bone marrow
AML: Acute Myeloid Leukemia: >20% myeloid blasts in blood or bone marrow
What do the following stains indicate?
Non-specific Esterase (NSE)
MPO: specefic for myeloid differentiation
Sudan Black: Pos. in myeloid cells
NSE: Pos. for monocyte lineage
What is immunophenotyping?
Detection of surface markers by flow cytometery
What are cell surface markers for:
Immature (stem) cells
Myeloid: CD 13, 33, 177
Monocyte: CD 11c, 14
Immature: CD 34
Genetic anormalities associated with Acute Myelogenous Leukemia
Point mutations: NPM1 and FLT3
What is the result of t(8;21)(q22; q22)?
Fusion of AML1 (21) and ETO (8) -> chimeric protein that blocks core binding factor needed for transcription, blocking maturation
When detected, even if <20% blasts present, diagnosis is AML
What is inv(16) associated with?
AML w/ favorable prognosis
-> protein that interferes w/ core binding complex (sim to t(8;21))
Marked by myeloblasts, immature monocytes, and increased eosinophils
What is Acute Promyelocytic Leukemia?
AML usually associated with t(15;17)(q22;q12)
Many auer rods / cel
Surface markers: CD13 and 33 pos, CD 34 neg
Frequently associated w/ DIC
What oncogenes are involved in Acute Promyelocytic Anemia?
PML/RARA fusion -> retinoic acid insufficiency
Supplimentation is curative
What AML is especially associated with gingival hypertrophy?
Associated with DNA topoisomerase II inhibitors (leukemia treatment)
Often in infants
Monocytic (CD11c and CD14 pos)
What anti-cancer drugs are most often associated with AML?
Alkylating agents (cyclophosphamide)
Topoisomerase II inhibitors (Etoposide)
7 types of AML not otherwise specified (M types)
M0: AML w/ minimal differentiation
M1: AML w/o maturation
M2: AML w/ maturation
M3: Promyelocytic Leukemia
Characteristics of acute megakaryobastic leukemia (FAB M7)
Extrememely rare. Down's predisposed, esp. before age 5)
Large cells w/ pseudopods
Extensive marrow fibrosis -> "dry tap"
Characteristics of Acute Monoblastic Leukemia (FAB M5)
High number of circulating monoblasts (CD 11c, 14; NSE pos)
2 presentations of Acute Lymphoblastic Leukemia/Lymphoma
Leukemia: Involves blood / bone marrow
Lymphoma: Involves lymph nodes and other tissues
Mostly children / young adults
May be T or B cell
How are the Cells of T lymphoblastic Leukemia/Lymphoma identifiec?
PAS positive nuclear ring
CD3 surface maker
MPO, Sudan Black neg
How are cells of B Lymphoblastic Leukemia/Lymphoma identified?
PAS dot like nuclear ring
CD10, 19, TdT
3 common mutations of B Lymphoblastic Leukemia Lymphoma
Philadelphia chromosome: t(9;22) poor prog
MLL gene: t(v;11q23) poor prog
TEL-AML1: t(12;21) good prog
What factors in the coagulation cascade are affected by Warfarin?
Vitamin K dependent: II, VII, IX, X
Why is Warfarin usually initially administered with UFH or LMWH?
Due to early depletion of proteins C and S -> prothrombotic state
C and S are depleted before coagulation factors
How is Warfarin therapy monitored?
PT and INR
INR = PT(patient) / PT( lab standard)
Other than Warfarin, what conditions can elevate PT and INR?
Prolonged Antibiotic treatment
What is target INR for most warfarin patients? What is the outcome of higher or lower values? What is normal INR for a healthy person?
2-3 on Warfarin. Normal person: <1.3
Higher: over anti-coagulation
Lower: under anticoagulation
How long does it take for Warfarin to reach therapeutic levels?
t1/2 = 36 - 42 hrs
Steady state: 4-5 * t1/2
Warfarin major drug interactions
Inducers (decrease anticoag effect): Rifampin
Inhibitor (increase anticoag effect): Amiodarone, Quinalones, TMP-SMX, Metronidazole
What is the INR "cut-off" for patients undergoing surgery? How long should patients be off Warfarin before surgery?
Cut off: 1.6 - below this patients should be ok for Sx.
Stop 5 days prior to procedure (2x factor II half-life)
What is Dabigatran?
Direct Thrombin inhibitor
No INR monitoring needed
No antidote - FFP is not useful!
Use in patients who are not controlled or non-compliant w/ warfarin
What is the timeframe for Dabigatran discontinuation before surgery?
Dependent on renal clearance:
CrCl >50mL/ min: 1-2 days prior
CrCl <50mL/min: 3-5 days
Can Dabigatran be used in patients undergoing valve replacement surgery?
No! Apparent increased likelihood of thrombotic event!
What are Rivaroxaban and Apixaban?
Direct Xa inhibitors
More GI bleeds than warfarin
Less GI intolerance than dabigatran
binds AT III, exposes catalytic site, binds thrombin and factor X -> inactivation
-> 1000x increased activity of AT III
protamine: binds and neutralizes heparin
indirect factor X inhibitor
does not bind Thrombin
Indications for Heparin / LMWH
Initial treatment of DVT and PE
Post surgery prophylaxis (abdominal or orthopedic sx)
What is heparin induced thrombocytopenia?
Ab formed against Heparin + Platelet Factor 4 -> prothrombotic state (Ab activates platelets)
Onset >7-10 days after initiation of heparin therapy
Once developed, no more heparin ever.
Can Fondaparinux be used in HIT patients?
Yes! Not officially approved, but safe.
What is first line treatment for heparin induced thrombocytopenia?
Parenteral Direct Thrombin Inhibitor
**no antidote, but short half-life (0.5 - 1.5 hrs), so ok
Primary use for Factor VII administration
Hemophilia A and B
May be used off-label for severe bleeding
Difficult to monitor
Arterial thromboembolism more common than venous
How is the effectiveness of antiplatelet therapy monitored?
Bleeding Time: cut and time to stop bleeding. 1-9 min is normal. (rarely done)
Aggregometery: >50% aggregation is unacceptable - target <50%
Aspirin dosing and side effects
75-325 mg / day (no value in larger dose)
Dyspepsia, GI bleed
Tinnitus in overexposure
How long before surgery should aspirin be witheld?
Aspirin is irreversible COX inhibitor
Platelet t1/2 is 7-10 days - need time to replenish
increases cAMP production and inhibits PDE -> decreased degradation
Inhibits adenosine uptake
Inhibits platelet activity
Used in stroke treatment w/ aspirin
Immediate release formulation rarely used (poor absorption, short t1/2)
Clopidogrel mechanism and indication
Irreversible inhibition of PG2Y12 receptor - blocking Adenosine mediated platelet activation
indications: ACS, MI, stroke, peripheral arterial disease
What genetic polymporphisms affect clopidogrel activity?
CYP2C19 is required for prodrug activation
*2 and *3 -> complete loss of enzymatic activity -> ineffectiveness of drug
*17 -> higher rate of activity -> patients may experience exaggerated effect (elevated bleeding risk)
Side effects of ticagrelor and mechanism
Reversible P2Y12 receptor
may cause dyspnea and ventricular pauses
Due to increased ATP release from RBCs -> elevated levels of Adenosine
**Avoid in pts w/ asthma/COPD, sick sinus syndrome, AV block, bradycardia related syncope
What effect does aspirin have on ticagrelor?
ASA doses over 100mg reduce effectiveness of ticagrelor
3 iron chelators
deferoxamine, deferiprone, defirasirox
How long does it take for iron chelation therapy to take effect? What is the goal of therapy?
Onset in 3-6 mos
Goal: < 500mcg/L circulating ferritin
What drug targets the product of t(9;22)?
Philadelphia chromosome -> Bcr-Abl fusion protein - constitutively active TK
Imatinib, Dasatinib, Nilotinib - TK inhibitors
What is azacytidine
Hypomethylating agent -> tumor cell apoptosis
**Only drug to show survival benefit in MDS**
Overall effect of rituximab
Long lasting effect. Vaccines given after admin are not effective. Takes months to replenish Bcells
1 in what number of bone marrow cells is a true hematopoietic stem cell?
1 in 10,000
How is stem cell harvesting from peripheral blood done?
G-CSF is administered -> efflux of marrow stem cells into circulation
Harvest stem cells on day 4-5 post administration
What is the mechanism of cure in autologous stem cell transplantation?
Transplant is essentially a support device facilitating the high dose of chemo.
3 diseases treated by autologous stem cell transplantation
Non-Hodgkin's and Hodgkins Lymphoma
What is the mechanism of cure in allogenic stem cell transplantation?
Complex: high dose therapy
complete replacement of patient's stem cell compartment
Graft vs. Tumor action
What are drawbacks of allogenic stem cell transplantation
difficulty finding donor
Toxicity: 20-30% mortality, 30-40% cure rate
What diseases are treated by allogenic stem cell transplantation?
Hematologic malignancy: ALL, AML, NHL, MDS
Stem cell disorders, hemoglobinopathies
What HLA antigens must be matched for transplantation?
A, B, C, DR
encode glycoproteins - transmembrane receptors that present antigen to immune cells
A,B,C: MHC I
DR: MHC II
After stem cell transplant, how long does it take for the cells to assume function?
Timeframe until function requires intensive hospital care - need for platelet and blood transfusions
What organs are initially targeted in GVHD?
Skin, Liver, GI
What infections are stem cell transplant recipients susceptible to?
Normal flora - damaged mucosal barrier
HSV, CMV, EBV - reactivation - if hx, prophylactic antivirals given
RSV - acquired
fungal - candida, aspergillus
Rate of GVHD on stem cell transplants
50% in allogenic
70% in unrelated
What is c-MPL?
receptor for thrombopoietin
2 platelet granules and their contents
alpha granules: 50-70/platelet. Adhesion, growth, coagulation factors: fibrinogen, fibronectin, VWF, PDGF, PF4, factor V, factor XI, HMWK, PAI-1
delta (electron dense): 2-7/platelet. ADP, ATP, serotonin, Ca2+
What platelet receptors bind VWF?
GPIIbIIIa: VWF, fibronectin, thrombospondin, fibrinogen
GP1b/v/ix: insoluble VWF
What cells produce VWF and where is it stored?
Endothelial cells and megakaryocyte
stored in Weibel-Palade bodies (W-P bodies)
How do cAMP and Ca++ impact platelet adhesion and activation?
low cAMP and high Ca++ -> activation and adhesion
substances that stimulate and inhibit platelet activation and adhesion
stimulate: ADP, TXA2
inhibit: ASA, Prostaglandin, Prostacyclin
What is glanzmann's thrombasthenia?
Deficiency of GpIIaIIIb -> platelet aggregation defect
What is Bernard-Solier syndrome?
Deficiency of GP1b -> platelet aggregation defect
3 defects in platelet aggregation
GPIIaIIIb: glanzmans thrombasthenia
P1b: Bernard Solier
VWF: VW disease
Platelet counts indicating thrombocytopenia and thrombocytosis
What is the importance of MNSsU glycoproteins?
Sialic acids impart negative charge to RBCs which draws Na+ -> zeta potential which repels other cells.
What differentiates ABO antigens?
H antigen: O blood group: terminal sugar is single fucose
B antigen: terminal sugar is fuc + galactose
A antigen: terminal sugar is fuc + N-acetylgalactosamein (galnac)
What kind of antibodies are formed against the major blood groups?
anti A and B: IgM
What is coomb's reagent?
Anti Human Immunoglobin
5 blood groupings that may result in transfusion reactoins
All may -> HTR and HDFN
How are red blood cell units stored? What is HCT?
Store at 4 +-2 deg C for 35 days
What are the major Rh antigens?
D, C, c, E, e
>50 Rh antigens, these are most clinically relevant
What are the cellular functions of Rh antigens?
cation transport and membrane integrity
What is Rh null?
complete lack of Rh antigens -> abnormal membrane and decreased RBC lifespan (hemolytic anemia)
What is the most common cause of HDFN?
ABO antibodies, though Rh is more severe
What is anti-A,B and in whom is it found?
IgG that reacts to both A and B blood groups
Type O people have anti-A,B
What is the survival rate for hydrops fetalis?
What is the cause of edema seen in hydrops fetalis?
Anemia -> tissue anoxia -> increased CO -> HF
Tissue Anoxia -> endothelial permeability -> decreased osmotic pressure -> edema
What enzyme underlies infant jaundice?
begins working ~ 3 days after birth
At what level of bilirubin does kernicterus develop?
Indirect bilirubin (unconjugated) 20mg/dL or higher
What is weak D procedure?
If test for D Ag is negative, Weak D procedure with antiglobulin serum. If +2 to +4 agglutination, consider Rh positive
What should be done in the case of a pregnant woman with a positve Ab screening?
Any IgG Ab must be titered at 2-4 week intervals after 20 wks gestation
What is the L:S ratio?
Lecithin : Sphingomyelin
Indicates degree of fetal lung maturity
>2:1 indicates mature enough to function after birth
1.5-2:1 40% will develop RDS
<1.5:1 70% will develop RDS
Can a mother already producing anti-D receive RhIg?
What is the best practice for administration of RhIg?
300mcg of anti-D w/in 72 hours of delivery
300mcg neutralizes 15mL packed RBC or 30 mL whole blood
What cord blood studies are required after birth?
ABO typing: If mom is type O and baby is A or B - worry about HDN
Rh typing: if baby is Rh+ and mom is Rh-, RhIg candidate
Direct Antiglobulin Testing: If positive, eluate to ID Ab coating baby's RBCs
What is definitive therapy for HDN? What is accomplished?
-removes Ab coated RBCs
-removes maternal Ab
-removal of bilirubin
-replacement of RBCs (treats anemia)
What antibody can be formed in mycoplasma pneumonia infection?
What antibody can be formed during infectious mononucleosis?
What is the McLeod Phenotype?
Lacks Kx Ag
Assoc. w/ chronic granulomatous disease with acanthrocytes
What is Fy(a-b-) phenotype?
Lacks Duffy Ag
Malaria (P. vivax) resistance
68% in african americans, more in africa
Fyb present in other tissues, absent in RBC
What are "nuisance antibodies"?
Lewis, M, N
cause discrepancies in reverse typing
no clinical significance
What is cryoprecipitate?
Blood product: concentrated fibrinogen, "antihemophiliac factor"
How are platelets stored and how long can they be kept?
Stored at room temp with agitation
Keep for 5 days
Weight and Hb cutoffs for blood donation. Age and timing.
56 days between donations
What diseases are screened for in blood donations?
Hep B and C
HIV 1 and 2
What is TRALI?
Transfusion Related Lung Injury - ARDS like
Usually blood donation from multiparous female
Anti-granulocyte of anti-HLA
Chills, fever, dyspnea 4-8 hrs. post transfusion
What incompatibility is most prevalent in Acute Transfusion Reaction?
What is TACO?
Transfusion Associated Circulatory Overload
Fluids administered faster than patient can accomodate volume
What transfusion reaction is responsible for most fatalities?
Describe the composition of the B-cell receptor
2 heavy chains, 2 light chains, CD79 heterodimer (a + b) (signal transducer)
4 pan-B cell markers
CD19, CD20, PAX5, CD79
Order of Immunoglobin gene rearrangement
Heavy chain then kappa followed by lambda if kappa is deleted
Describe the composition of Tcell Receptor
a and B antigen binding chains
gamma, delta, epsilon, zeta signal transduction chains
CD8 (interacts with a3 domain of MHC-1 of APC)
Earliest Tcell marker
CD7 - present through life of cell
Where is CD3 found in Tcells
At onset of negative selection, before transitioning from cortex to medulla transitions to surface
What are NK cells?
CD8+ Tcells that lack TCR
Large Granular Lymphocytes (LGL)
Kill cells w/ low HLA-I
What cancer is caused by transformation of NK cells?
Large Granular Lymphocyte Leukemia
What are major functions of lymph?
Maintain fluid balance (interstitial fluid and protein -> blood)
Absorb lipid from intestine and transport -> blood
Defend against infectious agents
Reduction of at least one cell line in blood w/ normal bone marrow function
--large spleen sequesters more cells w/ growth
vaccination in asplenic individual
Pneumococcal 2wks prior to splenectomy
H.flu and meningococcal
2 classifications of lymphocyte disorders
Reactive / benign
-lymphadenopathy / lymphocytosis
-lymphocyte deficiency or dysfunction
Malignant / neoplastic
define lymphadenopathy and generalized lymphadenopathy
lymphadenopathy: >1cm or >2cm inguinal
Generalized: 3+ non-contiguous areas of lymphadenopathy
What is a normal lymphocyte count for adults and infants?
birth - 6 mo: 5500-7300/mcL
Total count is normal, but % is increased
4 causes of relative lymphocytosis
Exanthem (mumps/ german measels)
Convalescence phase of acute infection
Neutropenia (low neutrophil -> relative increase in lymphocytes)
What causes infectious mononucleosis?
complications of infectious mono
hemolytic anemia: IgM cold auto-antibody, i blood group
What is the treatment for lymphopenia?
Monthly IV immunoglobulins
What is curative for chronic lymphoid leukemia
nothing - incurable
What is the most common adult leukemia in the Western Hemisphere?
Chronic Lymphocytic Leukemia
rare in Middle East
Describe staging and treatment for chronic lymphocytic leukemia
0: absolute lymphocytosis >15 x 10^9/L : observe
I: + enlarged lymph nodes : treat select cases
II: + ellarged liver and/or spleen : treat select cases
III: + anemia (marrow failure): Treat
IV: +thrombocytopenia: Treat
What cytologic markers contribute to a poor prognosis in chronic lymphocytic leukemia?
high is bad in both cases
Best treatment strategy for Chronic Lymphocytic Leukemia
Rituximab + chemotherapy
What drugs are used to treat chronic lymphocytic leukemia?
Chlorambucil (alkylating agent, nitrogen mustard)
Fludarabine (purine analog)
Campath H1 (anti-CD52)
What is Richter's Syndrome?
Transformation of chronic lymphocytic leukemia to diffuse large cel (Bcell) lymphoma
-sudden (w/in 6mos) increase in size of a lymph node out of proportion to others in pt.
What is Evan's Syndrome?
Complication of chronic lymphocytic leukemia
Autoimmune Hemolytic Anemia + Autoimmune Thrombocytopenia
Features of prolymphocytic leukemia
Massive splenomegaly w/o lymphadenopathy
Lymphocytosis (high and rising)
Lymphocytes w/ prominent nucleoli
Bcell > Tcell 3:1
Features of Hairy Cell Leukemia
Older men affected
Splenomegaly w/o lymphadenopathy
Dry BM tap
CD19, 20 Bcell markers) Plus CD11c, 25, 103
What is treatment of choice for hairy cell leukemia (HCL)?
90% complete remission
Features of Large Granular Lymphocytic Leukemia (LGLL)
Splenomegaly, arthralgia, positive RA serology
Neutropenia + infections
Tcell or NK cells
Treatment often not needed, but: MTX, cyclophosphamide, 'roids, G-CSF (for neutropenia)
Features of Adult Tcell Lymphoma
HTLV-1 virus (esp. Japan and Carribbean)
Poor prognosis - aggressive chemo needed
hypercalcemia, skin lesions, hepatosplenomegaly, lymphadenopathy
What is the characteristic cell of Hodgkin's Lymphoma?
Reed-Sternberg cell (seen in cHL, not NLPHL)
CD15 and 13 positive
Large bi-nuclear "owls eye" appearance
Features of Hodgkin's Lymphoma
large rubbery lymphadenopathy
normocytic, normochromic anemia
ESR and CRP elevation
What are "B" symptoms
fever, night sweats, weight loss
worse prognosis (Hodgkins)
What is treatment for Hodgkin's Lymphoma
Early stages (I and II): 2-4 cycles AVBD chemo (adriamycin, bleomycin, vinblastine, dacarbazine) followed by radiation therapy
Late stages: AVBD alone
Features of Non-Hodgkin's Lymphoma
lymphadenopathy: painless, firm
B symptoms (fever, night sweats, weight loss)
Organ specific presentation: SOB, early satiety, marrow failure, CNS involvement (headache, focal deficits), rash
What genetic abnormalities are most common in follicular lymphoma?
What is treatment for follicular lymphoma?
Mean survival is 6-9 years
Grades of follicular lymphoma
I: small, cleaved cells predominate
II: mix of small and larger cells
III: large cells predominate
What is small lymphocytic lymphoma?
Counterpart to chronic lymphocytic leukemia w/ lymph node presentation rather than blood/ bone marrow.
What is the differential diagnosis for a pt. w/ massive splenomegaly and no lymphadenopathy?
Hairy Cell Leukemia
Marginal Zone Lymphoma
What is the characteristic karyotype of marginal zone lymphoma?
t(11;14)(q13;32) -> overexpression of cyclin D1 / BCL1
What is the most common Non-Hodgkins Lymphoma?
Diffuse Large Cell Lymphoma (aggressive tumor)
Is Diffuse Large Cell Lymphoma curable?
treat with R-CHOP (Rituximab, cyclophosphamide, hydroxydoxorubicin, oncovin, prednisone)
What is Burkitt's Lymphoma?
Very aggressive lymphoma
2 forms: endemic: EBV +, Africa, children's jaws
sporadic: 20% EBV+, nodal or extranodal
starry-sky histology, vacuolated cells
What genetic abnormality is associated with Burkitt's Lymphoma?
t(8;14) and myc overexpressoin
What is mycosis fungoides?
Chronic cutaneous Tcell lymphoma
Looks like psoriasis
progresses to deeper organs
What are Sezary cells?
Seen in Sezary syndrome - Tcells (CD4+) with cerebreform nuclei
subform of Mycosis Fungoides
What is multiple myeloma?
Plasma Cell malignancy that homes to bone marrow
Production of monoclonal protein
>10% plasma cells in BM (<4% normal)
In symptomatic: CRAB (hyperCalcemia, Renal impairment, Anemia, Bone disease)
What is MGUS?
Monoclonal Gammopathy of Uncertain Significance
Similar to multiple myeloma but no CRAB and <10% plasma cells in marrow
What markers are expressed on cells in multiple myeloma?
CD38 and 138
What is Rouleaux Formation?
Stacking of RBCs due to excess Ig (as in multiple myeloma) -> disturbance of surface charge
What is the pathogenesis of bone disease in multiple myeloma?
IL6 -> plasma cell growth factor
MIP1a -> activation of osteoclasts
Other tumor factors suppress osteoblast activity
6 clinical features of multiple myeloma
hyperviscosity syndrome (2%)