Rubin's 26. Flashcards
What is the origin of hematopoietic stem cells?
mesoderm
Where does blood cell formation take place in the fetus?
begins in yolk sac - moves to liver around month 3, go to bone marrow in 4th month
CFU-GEMM
Colony forming unit - multipotential cells: granulocyte, erythroid, macrophage, and megakaryocyte elements
CFU-L
colony forming unti lymphoid precursor cells
CFU-GM
granulocytic and monocytic cells
SCF
stem cell factor -support survival and proliferation of pluripotent stem cells, CFU-GEMM and various progenitor cells
Flt3 ligand (Flt3L)
support survival and proliferation of pluripotent stem cells, CFU-GEMM and various progenitor cells
Which cytokines support survival and proliferation of pluripotent stem cells, CFU-GEMM and various progenitor cells?
SCF and Flt3L
IL-3
important for proliferation of CFU-GEMM and multiple CFUs
GM-CSF
granulocyte-macrophage colony-stimulating factor: important for proliferation of CFU-GEMM and multiple CFUs
Which cytokines important for proliferation of CFU-GEMM and multiple CFUs?
IL-3 and GM-CSF
Erythropoietin
activates erythroid progenitor cells
Thrombopoietin (TPO)
facilitates production and maturation of megakaryocytic
How is a deficiency in one or more blood cell population treated?
growth factors: GM-CSF, G-CSF and EPO
What do progenitor cells mature into?
precursor cells called blasts
How do pro erythroblasts appear?
intensely basphilic cytoplasm with large round nucleus - maturation = progressive decrease of nucleus, increased nuclear chromatin density, progressive hemoglobinization of cytoplasm (changing it to red)
What defines erythroid lineage?
expression of glycophorin
How od myeloblasts appear?
round to oval nuclei with delicate chromatin, visible nucleoli, and blue-gray cytoplasm
How do promyelocytes appear?
similiar nuclei to myeloblasts (round to oval nuclei with delicate chromatin, visible nucleoli) but cytoplasm contains granules
How do mature neutrophils appear?
from promyelocytes: progressive nuclear chromatin condensation, increasing nuclear lobulation, appearance of secondary granules
How do megakaryocytic appear?
big multi lobed cells by endomitotic division
What is a common source of bone marrow for analysis in adults?
posterior iliac crest (rarely the sternum)
What is the fat-to-cell ratio in normal adult bone marrow?
50 to 50
What is the myeloid to erythroid ratio in normal adult bone marrow?
3:1 ish
Left shift
changes in the normal number and distribution of mature cells compared to immature cells
How can iron metabolism and storage be tested?
staining bone marrow aspirate with prussian blue: shows iron granules within cytoplasm of macrophages and nucleated red blood cell precursors
Where do RBCs get their color?
hemoglobin
What allows RBCs to deform their shape?
interconnected spectrin dimers and other stabilizing proteins (ankyrin, actin, band 4.1)
What is a cause of premature destruction of circulating RBCs?
changes in membrane-cytoskeletal unit that leads to increased cell rigidity
What is each hemoglobin molecule comprised of?
4 heme groups, 4 globin chains, which can transport 4 molecules of oxygen
What is the heme part of hemoglobin comprised of?
porphyrin ring (protoporphryin IX) and one ferrous iron ion
hemoglobin A
two alpha and two beta globin chains (normal)
Which types of hemoglobin are normally found in the blood in addition to hemoglobin A?
hemoglobin F (2 alpha and 2 gamma) and hemoglobin A2 (2 alpha and 2 delta)
Deoxygenated hemoglobin has a ______ oxygen affinity and requires _______ oxygen tension for heme-oxygen binding to occur
low; increased
Acidosis shifts the slop of the oxygen dissociation curve to the _______, which ________ tissue oxygen delivery.
right; increases
What is the average life span of blood erythrocyte?
120 dayss
What does the CBC measure?
hemoglobin, RBC count, and mean corpuscular volume
hematorcrit
MCV X RBC
RDW
variability in RBC size = RBC distribution width
poikilocytes
abnormally shaped RBCs
What are the four groups of anemia?
- acute blood loss; 2. decreased production by stem cell or progenitor cells; 3. ineffective hematopoiesis; 4. increased RBC destruction
What are the causes of microcytic anemias?
iron deficiency, thalassemias, sideroblastic
What are the causes of macrocytic anemias?
nutritional deficiency, alcohol, liver disease, hypothyroidism, reticulocytosis, primary bone marrow disease
What are the causes of normocytic anemia?
anemia of chronic disease/inflammation, anemia of renal disease, acute blood loss
What are the clinical features of anemia?
increased cardiac output; increased RR; shunting of blood flow to vital organs; decreased hgb-oxygen affinity; increased marrow erythrocyte production
What is the pathology of acute blood loss anemia?
initial - anemia not appreciated/noticed. within 24-48 hours, fluid is mobilized from extravascular to intravascular space to restore blood volume - red cell replacement not as rapid - will be gradually corrected
Iron deficiency
interfers with normal heme
hemosiderin
large aggregates of iron with a disorganized structure (as apposed to ferritin that is highly organized)
anisocytosis
variation in RBC size
What are lab findings on iron deficient anemia?
serum iron and ferritin low; total iron-binding capacity increased; transferrin saturation is lowered
What are the clinical features of advanced iron deficient anemia?
pica, smooth glistening tongue (atrophic glossitis), inflammation at corners of the mouth (angular stomatitis); koilonychia (spoon shaped deformity of fingernails)
Anemia of chronic disease
ineffective use of iron from macrophage stores in bone marrow
Which inflammatory cytokines inhibit iron mobilization?
lactoferrin, IL-1, TNF-a
Anemia of renal disease
decreased renal production of EPO leads to anemia: treat with recombinant EPO
How do erythrocytes appear in anemia of renal disease?
normocytic, normochromic, scalloped cell membranes (Burr cells) - can be fragmented/schistocytes if due to malignant hypertensions
Myelophthisic anemia
anemia associated with marro winfiltration: hypo proliferative anemia
What does the body do in an attempt to maintain blood cell production in myelophthisic anemia?
extramedullary hematopoisesis develops: mostly in spleen and liver
How do cells of myelophthisic anemia appear?
bone marrow infiltration causes moderate to severe normocytic anemia with anisopoikiocytosis and teardrop cells
Anemia of lead poisoning
lead interferes with several enzymes involved in heme synthesis
Megaloblastic anemia
impaired DNA synthesis because of vit B12 or folic acid deficiency - nuclear development delayed by cytoplasm matures normally
Which drugs can cause megaloblastic anemia?
chemotherapeutic agents (methotrxate, hydroxyurea) and antiretroviral drugs (5-azacytidine)
Where is folate absorbed?
jejunum
What lab value is elevated in folate and vitamin B12 deficiency?
Lactate dehydrogenase because of massive intramedullary destruction of red cell precursors
Schilling test
suggests the cause of B12 deficiency by measuring radio labeled vit B12 absorption, with or without intrinsic factor
How do folate deficiency and B12 deficiency differ clinically?
folate develops rapidly, B12 over years. Neuro symptoms with B12 (posterior and lateral column demyelination)
Thalassemia
congenital anemia caused by deficient global chain synthesis
Where is thalassemia most common?
Mediterranean and malaria endemic areas
How many alpha genes are there? Where are they located?
4 genes, each on chromosome 16 (4x4 = 16)
Beta thalassemia usually caused by what?
point mutation
Pathology of b-thalassemia
microcytic and hypochromic anemia - form unstable alpha tetramers that precipitate in the cytoplasm of developing erythroid precursors
What is characteristic of all forms of beta-thalassemia (how you’re able to tell the difference between alpha-thalassemia)
modest increase in HgbA2 (delta genes are upregulated)
Alpha thelassemia usually caused by what?
deletions
Heinz bodies
denatured hemoglobin - unstable hemoglobins H (B4) and Bart’s (gamma4) that precipitate in the cytoplasm
alpha thalassemia trait
two genes affected, mild microcytic anemia, up to 5% Hgb Bart
Mediterranean alpha thalassemia trait
single alpha gene deleted from each chromosome (SE asia, both genes from the same chromosome
Hemoglobin H disease
3 genes affected: moderate microcytic anemia: Hbg Bart up to 25% - Heinz bodies appear
Hemozygous alpha-thalassemia
all four genes affected: hydrous fettles, incompatible with life
What causes hemolytic anemia?
hemolysis (hehe)
Extravascular hemolysis
monocyte/macrophage system in spleen and a little liver is involved
intravascular hemolysis
RBCs destroyed while circulating
What are hemolytic anemias characterized by?
compensatory increase in red cell production and release
What are lab findings commonly associated with hemolysis?
increased LDH, increased bilirubin, decreased haptoglobin, free hemoglobin in blood and urine
How is the RBC membrane linked to the cytoskeleton?
spectrin (dimer of alpha and beta subunits); ankyrin (band 2.1) anchor spectrin to transmembrane proteins, and spectrin is bound to to actin and glycophorin by protein 4.1
hereditary spherocytosis
diverse group of inherited disorders of RBC cytoskeletons in which spectrin or another cytoskeletal component (ankyrin, protein 4.2, band 3) is deficient
What is a vertical defect?
deficiency of any cytoskeletal proteins (lipid bilayer uncoupled form the underlying cytoskeleton)
What does erythrocyte membrane defects lead to?
extravascular hemolysis
What is the genetics of hereditary spherocytosis?
AD
What is the pathology of hereditary spherocytosis (HS)?
normocytic anemia, hyperchromic cells, polychromes and reticulocytosis
Clinical features of HS
splenomegaly caused by chronic extravascular hemolysis - jaundiced, gallstones
When is transfusion needed with HS?
aplastic crisis (sudden decline in hemoglobin and reticulocites)
What usually causes aplastic crisis?
parvovirus B19
What is the risk with splenectomy
renders patient susceptible to infection - esp strep
Hereditary elliptocytosis (HE)
diverse group of inherited disorders affecting the erythrocyte cytoskeleton
What is the pathogenesis of HE (hereditary elliptocytosis)?
elliptical or oval RBCs due to defects in assemble of spectrum, spectrin-ankyrin binding, protein 4.1 and glycophorin C
Acanthocytosis
defect within the RBC membrane lipid bilayer and features irregularly spaced spiny projections of the surface - may be associated with hemolysis
Pathophysiology of acanthocytosis
MCC chronic liver disease - increased free cholesterol deposites in cell membranes
Pathology of acanthocytosis
irregular spiny surface projectiosn and central dense cytoplasm
Which enzyme defect can pre-dispose circulating RBCs to hemolysis?
glucose-6-phosphate dehydrogenase (G6PD) - catalyzes conversion of glucose-6-phosphate to 6-phosphogluconate - important because erythrocytes generate energy mainly by glycolysis
What are G6PD deficiency cause RBCs to be sensitive to?
oxidative stress (includes oxidant drugs such as the antimalarial primaquine)
What happens when G6PD RBCs are exposed to oxidative stress?
Heinz bodies appear with supra vital staining - bite cells appear because spleen bites parts off
What are most clinically relevant hemoglobinopathies caused by?
point mutations in the b-globin chain gene
Sickle cell disease
abnormal hemoglobin HgbS causes RBCs to sickle upon deoxygenation
How does HgbS heterozygosity protect against malaria?
infected erythrocytes selectively sickle and are removed from circulation by spleen and liver macrophages - DESTROY THE LITTLE SHIT
What is the molecular pathogenesis of sickle cell disease?
point mutation in the B-globin chain gene (valine for glutamic acid) which makes an unstable molecule that polymerizes like a bitch upon deoxygenation
What is the pathology of sickle cell disease?
severe normocytic or macrocytic anemia: howell-jolly bodies = nuclear remnants evident in most patients and reflect hyposplenism because of ischemic loss of splenic tissue
What happens in an aplastic crisis?
bone marrow fails to compensate for high level of red cell loss - hemoglobin level drop rapidly with no reticulocyte response (usually due to parvovirus B19)
Sequestration crisis
sudden pooling or erythrocytes esp in spleen decreases circulating blood volume and lowers hemoglobin levels
clinical manifestations of sickle cell disease
increased CO = cardiomegaly and CHF; acute chest syndrome; splenomegaly; neurologic issues vascular obstruction; retinal hemorrhage = blindness; increased bilirubin; cutaneous ulcers; handfoot syndrome in children
Why don’t sickle cell trait sickle?
HgbA in their RBCs prevents HgbS polymerization
What causes a milder form of sickle cell disease?
double heterozygosity for HgbS and HgbC - often develop retinopathy though
Hemoglobin C disease
homozygous inheritance of a structurally abnormal hgb, which increases erythrocyte rigidity and causes mild chronic hemolysis
Pathology of HgbC homozygosity
mild normocytic anemia
Hemoglobin E disease
homozygosity for a structurally abnormal hemoglobin, leading to a thalassemia-like defect that is associated with mild chronic hemolysis (unstable B-globin mRNA)
Warm antibody autoimmune hemolytic anemia
warm autoantibodies optimally bind their antigens at 37; IgG directed against erythrocyte membrane antigens (ie Rh group proteins) - RBCs are removed by macrophages of the reticuloendothelial system
Hapten mechanism Warm antibody autoimmune hemolytic anemia
drug such as penicillin attaches to RBC surface - elicited antibodies that react with erythrocyte itself
immune complex mechanism Warm antibody autoimmune hemolytic anemia
drug (quinidine) reacts with specific circulating antibody to form immune complexes which then bind to RBC membranes
Autoantibody mechanism Warm antibody autoimmune hemolytic anemia
drug (alpha-methyldopa) elicits antibodies (hemolysis occurs in the ABSENCE of the initiating drug)
Warm antibody autoimmune hemolytic anemia pathology and clinical features
normocytic or occasionally microcytic anemia - spherocytes and polychromasia
Direct Coombs test
helps to distinguish immune from nominee spherocytosis - patients RBCs are incubated with antihuman Ig - agglutination indicate antibody is present on cell surface
Cold antibody autoimmune hemolytic anemia
maximal reactivity at 4C due to mostly infections - so peripheral
What are cold antibodies? What are they directed against?
IgMs against I/i antigens on red cells
What are labs for cold agglutinins?
falsely low RBC counts and hematocrit, falsely elevated MCV and MCHC - direct Coombs test positive
What is the pathophysiology of cold hemolysin disease?
biphasic IgGs directed against P antigens on red cells - antibody binds erythrocytes at low temp and fixes compliment - intravascular hemolysis occurs when it warms back up
When does paroxysmal cold hemoglobinuria (PCH) - also called cold hemolysin disease - occur?
most often after viral illness
Lab values for paroxysmal cold hemoglobinuria/cold hemolysin disease
anemia, decreased haptoglobin, and hemoglobinuria due to intravascular hemolysis - Coombs test positive for complement
Hemolytic disease of the newborn
incompatibility of blood types between a mother and her developing fetus - mother lacks antigen present on fetal RBCs - IgG can cross placenta (usually Rh negative mother and Rh positive fetus)
What is characteristic of DIC?
abnormalities in coagulation and thrombocytopenia
What is characteristic of TTP?
thrombocytopenia alone
How does hypersplenism cause anemia?
spelomegaly causes pooling of blood and delayed transit of blood and delayed transit of blood cells through the splenic circulation and then prolonged exposure leads to premature destruction by macrophages
How do thermal burns cause anemia?
intravascular RBC hemolysis - membranes are disrupted and fragmented at temperatures over 49 degrees
Which infectious organisms cause RBC lysis?
plasmodium and babesiosis
polycythemia
an increase in RBC mass - when hematocrit is greater than 54% in men and 47% in women - this causes exponential increase in blood viscosity
relative polycythemia
occurs in dehydration - plasma volume is decreased - red cell mass is normal
primary polycythemia
autonomous, EPO-independent proliferation of erythroid cells caused by an acquired, clonal, HSC disorder
secondary polycythemia
EPO stimulation of erythropoiesis to compensate for general tissue hypoxia
Normal platelet count
150-350X10^3
TPO: what is it and where it is produced
stimulates thrombopoisesis and produced by the liver
What do dense granules contain?
ADP (potent aggregating molecule) - also ATP, calcium, histamine, serotonine, epi
What do alpha granules express on their membranes? What do they contain
adhesive proteins P-selectin on their membranes and contain fibrinogen, vWF, fibronectin and thrombospondin - also chemokine platelet factor 4, neutrophil0activating peptide 2, PDGF, TGF-a
What does collagen bind?
GpIa/IIa and GpVI
What does vWF bind?
Gp Ib/IX
How does aggregation of platelets occur?
fibrinogen receptor Gp IIb/IIIa crosslinking
thromboxane A2
provides positive feedback to activate additional platelets via their surface receptors
Which complex initiates coagulation?
tissue factor (TF) and factor VIIa
What does thrombin activate?
factors XI, VII, and V
What activates protein C? What does protein C do?
anticoagulant complex of alpha thrombin-thrombomodulin - protein C inactivates VIIIa and Va
antithrombin III
inhibits thrombin activity - also cleaves activated factors IXa, Xa, XIa, XIIa
Plasminogen activators
produced by endothelial cells near the thrombus to activate circulating plasminogen to plasmin and initiate thrombolyysis
What are the two plasminogen activators?
tissue plasminogen activator and urokinase-type plasminogen activator
What do platelet abnormalities results in clinically?
petechiae and purpuric hemorrhages in skin and mucous membranes
Senile purpura, purpura simplex, scurvy
senile: age-related atrophy of supporting connective tissues. purpura simplex: women during menses - deep dermis and resolves quickly. scurvy: vit c deficiency impairs collagen synthesis
Hereditary hemorrhagic telangiectasia
autosomal dominant disorder of blood vessel walls (venules and capillaries) in which arteriovenous malformation and telangiectasis (dilated, tortuous small blood vessels) form in solid organs, mucous membranes, and dermis
What is the underlying defect in HHT (hereditary hemorrhagic telangiectasia)
dilation and thinning of vessel walls due to inadequate elastic tissue and smooth muscle - mutations in ENG or ALK1
Clinical features HHT (telangiectasias)
punctate reddish spots on the lips and nose, recurrent hemorrhages, anemic
Henoch-Schonlein purpura
allergic purpura - vascular disease that results from immunologic damage to blood vessel walls (viral infections in children and drugs/chronic in adults)
What is Henoch-Schonlein purpura characterized by?
leukocytoclastic vasculitis - perivascular iniltration of neutrophils and eosinophils, fibrinoid necrosis of vessel walls and platelet plugs in vascular lumens - IgA and complement complexes circulate in the blood and deposit in vessel walls
Dhole-Like bodies
slightly abnormal neutrophils morphologically with blue cytoplasmic inclusions
thrombocytopenia
platelet counts under 150,000
Heparin-induced thrombocytopenia (HIT) type II
HEPARIN IS A HAPTEN immunologically mediated, caused by acquired IgG antibodies against platelet factor 4-heparin complexes - severe consumptive thrombocytopenia, platelet activation and thus a hyper coagulable state
Heparin-induced thrombocytopenia (HIT) type I
HEPARIN ITSELF induces platelets to aggregate
Glanzmann thrombasthenia
AR - defect in platelet aggregation caused by quantitative or qualitative abnormality in the gylcoprotein complex IIb/IIIa
What is the most frequent complication of hemophilia A?
degenerative joint disease caused by repeated bleeding into many joints
Factor IX
vitamin K dependent protein produced in the liver
What three things does vWF bind?
platelet glycoprotein receptors (Gp Ib/IX), Gp IIb/IIIa for platelet aggregation, and factor VIII (in plasma for protection)
Type I vWD (vWF disease)
AD: quantitative deficiency in vWF - all multimers are reduced
Type II vWD
qualitative defects in vWF - interations of vWF and blood vessel wall defective
Type III vWD
AR - vWF activity is absented plasma factor VIII levels are less than 10% of normol
How does liver disease effect coagulation?
coagulation factors are produced by liver (II, V, VII, IX, X) - also has a key role in vit K absorption. PT, PTT prolonged (PT more affected)
Vitamin K
essential cofactor in gamma carboxylation of glutamic acid residues - activating II, VII, IX, and X
What are acquired inhibitors of coagulation factors?
circulating anticoagulants - IgG autoantibodies - usually against factor VII and vWF
Factor V Leiden
mutation in factor V renders it resistant to inhibition to APC (activated protein C)
Mild neutropenia
number of neutrophils is adequate to defend against microorganisms
moderate neutropenia
patients become vulnerable to microbial infections (severe risk is high)
What are the principal causes of neutropenia?
decreased production: irradiation, drug induced (including alcohol), viral infections, congenital, cyclic. ineffective production: megaloblastic anemia, myelodysplastic syndromes. increased destruction: isoimmune neonatal and autoimmune
What drugs lead to immune0mediated neutrophil destruction?
sulfonamides, phenylbutazone, indomethacin
What are clues to a benign (or reactive) nature of leukemia reaction (which can otherwise be mistaken for leukemia - CML)
- segmented neutrophils and fewer neutrophilic myeloid precursors 2. leukocyte alkaline phosphatase activity is HIGH (low in CML) 3. WBC under 50,000 4. reactive neutrophils often contain Dohle bodies (large blue cytoplasmic inclusions)
Neutrophilia absolute neutrophil count
above 7000
Eosinophil growth factor
IL-5
Where do eosinophils hang out?
migrate from blood to gut, respiratory tract, and skin (where allergic reactions happen)
When does hypereosinophilia happen?
mast cell disease, tumors (hodgkin and non-hodgkin lymphoma), myeloproliferative disorders
What happens in hypereosinophilia?
accumulation of eosinophils in tissues leads to necrosis, particularly in the myocardium - grave prognosis - need aggressive corticosteroid therapy
What do basophils do when stimulated?
synthesize leukotrienes and other mediators
When does basophilia occur?
in immediate-type hypersensitivity reactions and with chronic myeloproliferative neoplasms
What does monocytosis characterize?
both malignant and inflammatory conditions
What are the symptoms of mast cell proliferative disease?
release of mast cell granules (inflammatory mediators histamine, heparin, eosinophil and neutrophil chemotactic factors, proteases) - causes flushing, pruritus, hives
Aplastic anemia
disorder of pluripotential hematopoietic stem cells that leads to bone marrow failure - marrow is hypocellular and all blood cell lineages are decreased -> bad prognosis
What causes aplastic anemia?
injury to hemtopoietic stem cells
Which cell lineages are decreased in aplastic anemia?
myeloid, erythroid, and megakaryocytic - relative increase in marrow lymphocytes and plasma cells
How does bone marrow appear on pathology in aplastic anemia?
large increase in fat cells
What is the most common hereditary bone marrow failure syndrome? What is the associated gene?
Fanconi anemia: FANC gene (subtypes A, C, G, D2) - usually repair DNA
Which cell lineages are affected by Fanconi anemia?
all hematopoietic cells
What is the difference between Fanconi anemia and idiopathic aplastic anemia?
fanconi patients will not respond to immunosuppressive treatments (like they will with idiopathic aplastic anemia)
What is the treatment of choice for Fanconi anemia?
HSC transplantation
Pure Red Cell aplasia?
selective marrow suppression of committed erythroid precursors (unknown etiology)
What is pure red cell aplasia most often due to?
viral infection (parvovirus B19) - acute or thymic lesions - chronic
What are the receptors for parvovirus on red cell membranes?
P antigens
What is the pathology of pure red cell aplasia?
overall marrow cellularity is normal, but erythroid precursors are absent or arrested in blast phase - increased EPO
Paroxysmal Nocturnal hemoglobinuria
an acquired clonal stem cell disorder characterized by episodic intravascular hemolytic anemia due to increased RBC sensitivity to complement-mediated lysis
What gene mutation causes paroxysmal nocturnal hemoglobinuria?
PIG-A (on X chromosome) - disrupts synthesis of GPI which anchors many proteins to RBC membranes
What is the pathogenesis of paroxysmal nocturnal hemoglobinuria?
PIG-A mutation disrupts GPI synthesis which anchors many proteins to RBC membranes - consequent loss makes RBCs more susceptible to lysis by complement
Myeloproliferative neoplasma
clonal stem cell disorders - increased proliferation of one or more myeloid lineages (grnaulocytes, erythrocytes, megakaryocytes, or mast cells)
What are character features of all subtypes of myeloproliferative neoplasms?
bone marrow hypercellularity with effective hematopoietic maturation and increased numbers of red cells, granulocytes and/or platelets - also typically have bone marrow fibrosis and splenomegaly
CML
chronic myelongenous leukemia - philadelphia chromosome BCR/ABL fusion gene
What is the BCR/ABL fusion gene?
philly chromosome seen in CML - active tyrosine kinase central to pathogenesis of CML - autophosphorylates and activates downstream signaling pathways that trigger cell proliferation, differentiation, survival and adhesion
CML chronic phase
leukocytosis consisting of neutrophils in all stages of maturation with a peak of mylocytes and mature neutrophils
CML accelerated phase
disease progression with persistent or increasing WBC count, splenomegal, thrombocytopenia, additional chromosomal abnormalities, 20% blood basophila, and/or 10-19% blasts that are unresponsive to treatment
CML blast phase
evloution to acute leukemia: 20% or more blasts, extra medullary proliferation, clusters of blasts in bone marrow. poor prognosis
What is treatment for CML?
imatinib - tyrosine kinase inhibitor
polycythemia vera
myeloproliferative neoplasm arising from a clonal HSC and characterized by autonomous production of RBCs, not responsive to EPO
What are the criteria for polycythemia vera?
increased RBC mass, JAK2 mutation (no EPO elevation and hypercellular marrow - minor criteria)
Primary myelofibrosis
clonal myeloproliferative neoplasm in which prominent megakaryopoisesis and granulopoisesis accompany marrow fibrosis - extra medullary hematopoiesis present in fully developed disease
Essential thrombocythemia
megakaryocytes proliferate without resonant - blood platelet counts increased
How does the pathology of essential thrombocythemia appear?
increased numbers of large, hyperlobulated, “stag-horn-shaped” megakaryocytic with abundant mature cytoplasm form cohesive clusters or sheets in the marrow
Mastocytosis
clonal hematopoietic disorder in which neoplastic mast cells accumulate in certain tissues - mainly skin and bone marrow - depletion of fat and normal hematopoietic elements in marrow
How does mastocytosis appear?
cutaneous: single or multiple lesions - tan-brown, cutaneous nodule in newborns
How does the spleen appear in mastocytosis?
nodular aggregates of mast cells with accompanying dense fibrosis in both red and white pulp
What are the clinical features of mastocytosis?
anaphylactic episodes - pruritus, flushing, hypotension, asthmatic symptoms and secondary anemia
Myelodysplastic syndromes
peripheral blood cytopenias accompany a hypercellular marrow with ineffective hematopoiesis -
What does myelodysplastic syndrome progress to 30-40% of the time?
AML
AML diagnosis
more than 20% myeloblasts in the blood or bone marrow
Acute promyelocytic leukemia
t(15;17)
What is AML considered if there is less than 20% blasts?
MDS (myelodysplastic syndrome) or MPN (myeloproliferative neoplasm) category
Auer Rods - what are they and what are they a sign of?
coalesced primary granules: appear eosinophilic, slender cytoplasmic inclusion. specific for myeloid lineage and preclude a diagnosis of lymphoblastic leukemia
What is cytochemical stained to classify AML cases
Auer rods, myeloperoxidase, Sudan black, nonspecific esterase (NSE)
Clinical features of AML?
most occur in adults - leukopenia, thrombocytopenia, anemia (progressive accumulation in the marrow of immature myeloid cells that cannot differentiate and mature further)
Gene fusion in APL
PML/RARA
How do patients with APL present?
DIC because senescent leukemic cells degranulate and activate the coagulation cascade
How is APL treated?
with ATRA - induces maturation of the tumor cells and prevents both degranulation and DIC
Myeloid sarcoma
extramedulllary solid tumor of myeloblasts and mono blasts
MALT
mucosa-associated lymphoid tissue - aggregates of organized lymphoid tissue present in extra nodal sites including gut, lungs, skin
What do Precursor B-cell acute lymphoblastic leukemias express
CD10 and CD19 - LACK CD20 (mature B cells) and Lchains
What do plasma cells no longer express on their cell membranes?
CD20
MCC reactive lymphocytosis
infectious mononucleosis due to EBV
Bone marrow plasmacytosis greater than 10% typically associated with what?
plasma cell neoplasm
Posterior auricular lymph nodes enlarged in….
rubella
occipital lymph nodes enlarged in……
scalp infection
posterior cervical lymph nodes enlarged in……
toxoplasmosis
axillary lymph nodes enlarged in……
infections of the arms or chest wall
inguinal lymph nodes enlarged in……
venereal infections and infections of the legs
Follicular hyperplasia characteristic
starry sky pattern - scattered benign macrophages with abundant pale cytoplasm containing pyknotic nuclear and cytoplasmic debris
Toxoplasmosis
prominent follicular hyperplasia and small collections of epithelioid macrophages in interfollicular regions and around the hyperplastic follicles (mixed pattern of reactive lymph node hyperplasia)
Sinus histiocytosis
an increase in macrophages lining nodal sinuses - derive from blood monocytes
Dermatopathic lymphadenopathy
lipid, melanin, and hemosiderin drain from affected skin to regional lymph nodes - T cell proliferation caused by chronic skin diseases
MC childhood leukemia
precursor B-cell ALL
Associated genetic/chromosomal abnormality b-lymphoblastic leukemia/lymphoma
t(9;22) translocation
Associated genetic/chromosomal abnormality T-lymphoblastic leukemia/lymphoma
TCR genes translocate to sites involving MYC
Associated genetic/chromosomal abnormality follicular lymphoma
t(14;18) - inactivation of p53; activation of MYC
Associated genetic/chromosomal abnormality mantle cell lymphoma
t(11;14)
Associated genetic/chromosomal abnormality marginal zone lymphoma
t(11;18)
Associated genetic/chromosomal abnormality burkitt lymphoma
t(8;14) MYC
Associated genetic/chromosomal abnormality plasma cell myeloma
clonal rearrangements involving Ig H and L genes - IgH translations with cyclin D
What are clinical manifestations of precursor B-cell ALL leukemia?
proliferate in marrow and displace normal elements resulting in anemia, thrombocytopenia, and neutropenia - bone pain and arthralgia
B-ALL prognosis
excellent yay
What is the earliest T-cell antigen?
CD7
Most frequent leukemic lymphoma
diffuse large B-cell lymphoma (followed by follicular)
What favors development of large B-cell lymphoma or Burkitt lymphoma?
immunodeficiency
Low grade B-cell lymphomas tend to develop in who? Burkitt lymphoma?
Bcell = autoimmune disease. Burkitt = EBC
Marginal zone lymphomas
where late-stage memory B cells reside - outermost compartment of lymphoid follicles (which also give rise to CLL)
What are examples of mature B-cell lymphomas?
B-cell CLL, follicular lymphoma, extra nodal marginal zone B-cell lymphoma (MALT), lymphoplasmacytic lymphoma
With the B-cell lymphomas, which are curable and which are incurable?
curable = aggressive lymphomas that progress rapidly - curable with conventional therapies. non curable - indolent lymphomas that follow a prolonged clinical course
B-cell CLL
common, mature CD5+ Bcell tumor - small lymphocytes - single basophilic nucleoli - CLL = only effects bone/bone marrow. lymphadenopathy or solid tumor called SLL
Where does Bcell CLL/SLL infiltrate?
splenic white and red pulp and portal areas of the liver
What are the clinical features of B-cell CLL/SLL?
asymptomatic - abnormal CBC with absolute lymphocytosis - immune deficiencies of B cells, some T cells
Richeter syndrome - how does it appear
transformation from Bcell CLL to diffuse large b-cell lymphoma. appears as rapidly enlarging mass, worsening systemic symptoms, high lactate dehydrogenase level in serum
Common complications of B-cel CLL/SLL
transformation to prolymphocytic leukemia (MC) and Richter syndrome (transformation to diffuse large B-cell lymphoma)
Follicular lymphoma
mature-B-cell lymphoma of follicle center B cell (germinal center cells)
Follicular cell genetic abnormality
14:18 = bcl-2 under control of IgH promoter - Bcl-2 overexpression (inhibitor of apoptosis usually)
Clinical features of follicular lymphoma
generalized adenopathy - painless and may have waxing and waning course - this is incurable
Mantle cell lymphoma
CD5+ mature B-cell tumors presenting a picture of monotonous small to medium sized lymphocytes
Mantle cell lymphoma chromosome abnormality
11:14 - overexpression of cyclin D1 - cell cycle dysregulation now. incurable
Characteristic feature of mantle cell lymphoma for pathology
striking monotony of lymphoma cells with respect to size and shape
What cell marker are MCL cells positive for?
cyclin D1 (what helps to distinguish it from other lymphomas)
Marginal zone lymphomas
mature B-cell tumor that arises in lymph nodes, spleen and extra nodal B cells (MALT) - memory B cells
What is associated with a maltoma?
h. pylori gastritis - treatable with antibiotic therapy alone :0
What distinguishes maltoma from B-CLL/SLL and mantle cell lymphoma?
negative for CD5, CD23, and cyclin D - most express IgM
lymphoplasmacytic lymphoma
mature b-cell neoplasm containing small lymphocytes, plasmacytoi lymphocytes and plasma cells - involve bone marrow and sometimes spleen/lymph nodes
What is the plasma cell marker of lymphoplasmacytic lymphoma? pathologic marker?
CD138 plasma cell - Dutcher bodies (immunoglobulin pseudo inclusions in the cell)
Similarity between small B-cell lymphomas
incurable
Hairy cell leukemia
clonal B-cell neoplasm small to medium sized - involve bone marrow and peripheral blood - arise from late activated memory B cell - have marked splenomegaly
Hairy cell leukemia pathology
do not disturb the normal bone marrow architecture - have a “fried egg appearance” cell - spares lymph nodes but involves liver and spleen
What do hair cell leukemia cells produce?
TRAP - tartrate-resistant acid phosphatase
Diffuse large b-cell lymphoma
aggressive but curable b-cell tumor - most common - association with EBV
Pathology of diffuse large b-cell lymphoma
lymphoma cells are twice the size of a normal lymphocyte - commonly presents at extra nodal sites esp GI tract
How do diffuse large b-cell lymphoma patients present?
with a rapidly growing tumor in nodal and/or extranodal sites - symptoms reflect the site of involvement
Burkitt lymphoma
most rapidly growing malignancy (so responds well to intensive chemotherapy)- chromosomal translocation involves MYC - presents at extra nodal site
Who do B-cell lymphomas afflict?
more males than females
How does sporadic Burkitt lymphoma present as compared to endemic burke lymphoma?
sporadic: abdominal mass involving ileocecum. endemic: EBV - involves jaw and facial bones
How do cells appear under microscope for burkittt lymphoma?
macrophages ingesting cellular debris of apoptotic tumor cells = “starry sky” - have lipid vacuoles in deeply basophilic tumor cell cytoplasm
Plasma cell neoplasia
clonal expansion of plasma cells
Risk factors for plasma cell neoplasia
genetic predisposition, ionizing radiation, chronic antigenic stimulation
Plasma cell myeloma
malignancy of plasma cells in which serum contains an M-protein - bone marrow based and multifocal (incurable still)
Plasma cell myeloma pathology
destructive bone lesions - lytic or “punched out” appearance - show clusters, nodules, or sheets of plasma cells in bone marrow core
High levels of M-protein in serum cause what?
erythrocyte rouleaux - RBC stick together end to end
How can you tell the difference between a normal plasma cell and a myeloma cell?
myseloma cells lack CD19 and do not express CD20
What is the heavy chain in plasma cell myeloma typically?
IgG or IgA (IgD and IgE are uncommon and aggressive - sometimes called plasma cell leukemia)
Major risk factors for T-cell neoplasia
HTLV-1 and EBV
How can you tell the difference between an immature T-cell neoplasm and a mature T-cel neoplasm?
mature T cell neoplasm lacks TdT
Clinical features of peripheral T-cell and NK-cell tumors
more widely disseminated and more aggressive than B-cell neoplasms - respond poorly to chemo
Adult T-cell leukemia/lymphoma
ATLL - caused by HTLV - Caribbean and Japan - long latency period
ATLL pathology
usually widespread at presentation (involves lymph nodes, spleen, bone marrow, peripheral blood and skin) - have clonal T-cell receptor gene rearrangements and have clonal integrate HTLV-1
Membrane markers ATLL
expresses CD25 and CD4 but absent CD7
Clinical features ATLL
systemic with multiorgan manifestations, hypercalcemia, skin most important extra nodal site
Mycosis Fengoides
most common form of primary cutaneous T-cell lymphoma - characterized by infiltration of epidermis by malignant CD4. 3 stages - eczematous stage, plaque stage, tumor stage
Sezary syndrom
variant of MF - triad of erythroderma, generalized lymphadenopathy, circulating lymphoma cells in blood
What distinguishes MF from inflammatory diseases?
clonal T-cell receptor gene rearrangements
Anaplastic large cell lymphoma
mature T-cell tumors - CD30 lymphoid activation marker - nodal and extranodal sites (skin)
Genetic abnormality anaplastic large cell lymphoma
translocation involving ALK gene = good prognosis. ALK negative ALCL = more aggressive
Hallmark cells of anaplastic large cell lymphoma
irregular shaped nuclei, abundant cytoplasm with distinct eosinophilic area near the nucleus (also express CD30)
Angioimmunoblastic T-cell lymphoma
aggressive peripheral T-cell lymphoma - neoplastic T-cell infiltrates expand the parametrical regions of lymph nodes and are associated with a striking proliferation of high endothelial venues
What is present in nearly all cases of angioimmunoblastic t-cell lymphoma?
EBV even though it infects only B cells. idk
Classical Hodgkin Lymphoma
inflammatory background and composed of mononuclear hodgkin cells and multinucleate reed-sternberg cells (owl’s eyes). the neoplastic cells in HL are derivatives of germinal center B cells
What occurs in >98% of hodgkin/reed sternberg cells?
a clonal Ig gene rearrangement
Clinical features hodgkin lymphoma
nontender peripheral adenopathy in a single lymph node or group of nodes (usually cervical and mediastinal)
Posttransplant lymphoproliferative disorder
occur in people treated with immunosuppressive regimens because they have received solid organ, bone marrow or stem cell allografts
What is the key risk factor for posttransplant lymphoproliferative disorder?
seronegativity for EBV at the time of transplantation (usually caused by EBV)
Clinical features of PTLD (posttransplant lymphoproliferative disorder)
present with nonspecific symptoms (lethargy, malaise, weight loss, fever
Hemophagocytic disorders
immunologic defect that results in immune dysregulation with consequent increases in certain cytokines leading to inadequately regulated T-cell and macrophage activation
Criteria for diagnosis of hemophagocytic disorders
- fever 2. splenomegaly 3. anemia 4. thrombocytopenia 5. hypertriglyceridemia 6. hypofibrinogenemia
Inherited hemophagocytic disorders vs acquired hemophagocytic disorders
inherited: PFR1 gene in children. acquired: viral infections (primary infections with EBV, CMV, HIV, parvovirus), malaria, E.coli, histoplasmosis
T cell domain of spleen. B cell domain of spleen
T cell - periarteriolar lymphoid sheath. B cell - follicles and a perifolicular marginal zone
Howell-Jolly bodies
remnants of nuclear DNA
What can be removed from splenic macrophages without destroying the erythrocytes?
- Howell-Jolly bodies 2. Heinz bodies 3. sideritic granules (iron)
How does the spleen appear in sickle cell anemia?
modestly enlarged with thickened, fibrotic capsule which causes a “sugar-coated” appearance
Thymoma
neoplasms of thyme epithelial - most are benign - encapsulated, firm and gray to yellow tumor divided into lobules
What do thymomas have a coincidence with?
myasthenia gravis
paraneoplastic syndromes
tumor-associated clinical manifestations that occur distant to the tumor and are caused by the secretion of tumor cell products such as hormones, cytokines, growth factors, and tumor antigens
paraneoplastic pruritus
itching lasting longer than 6 weeks
sweet syndrome
an acute febrile neutrophilic dermatosis characterized by abrupt onset of papular skin lesions, accompanied by systemic symptoms: fever, arthralgia, malaise, headache and myalgia
When is sweet syndrome normally seen?
acute myeloid leukemia and myelodysplastic syndromes
paraneoplastic pemphigus
mucocutaneous disease presenting with painful oral and mucosal ulcerations, with concomitant blistering skin lesions
