Study your flashcards anywhere!

Download the official Cram app for free >

  • Shuffle
    Toggle On
    Toggle Off
  • Alphabetize
    Toggle On
    Toggle Off
  • Front First
    Toggle On
    Toggle Off
  • Both Sides
    Toggle On
    Toggle Off
  • Read
    Toggle On
    Toggle Off
Reading...
Front

How to study your flashcards.

Right/Left arrow keys: Navigate between flashcards.right arrow keyleft arrow key

Up/Down arrow keys: Flip the card between the front and back.down keyup key

H key: Show hint (3rd side).h key

A key: Read text to speech.a key

image

Play button

image

Play button

image

Progress

1/622

Click to flip

622 Cards in this Set

  • Front
  • Back
  • 3rd side (hint)
Proerythroblasts, lymphoblasts, myeloblasts, monoblasts, and megakaryoblasts share what precursor cell type?
pluripotent hematopoeitic stem cells
Reticulocytes and proerythroblasts are precursors for what type of blood cell?
erythrocyte (RBC)
Lymphoblasts are the precursors for what two blood cell types?
T-cells and B-cells
Plasma cells develop from what immediate precursor blood cell type?
B-cells
Monocytes develop from what immediate precursor blood cell type?
monoblasts
Platelets develop from what immediate precursor blood cell type?
megakaryocytes
Neutrophils, eosinophils, and basophils differentiate from what common precursor blood cell type?
myeloblasts
Promyelocytes, myelocytes, metamyelocytes, and stab cells are precursors for what three granulocytes?
neutrophils, eosinophils and basophils
Give the WBC differential in order from highest to lowest.
Neutrophils> Lymphocytes> Monocytes> Eosinophils > Basophils
(Neutrophils Like Making Everything Better)
What is the name of the precursor of an erythrocyte?
reticulocyte
What type of blood cell is anucleate and biconcave?
erythrocytes (RBCs)
Erythrocytes have a large surface area-to-volume ratio, which is important for what?
Easy gas exchange (oxygen and carbon dioxide)
What is the source of energy for erythrocytes?
glucose
What is the source of energy for erythrocytes?
120 days
Name two ways that erythrocytes use glucose as a source of energy.
90% is used anaerobically and degraded to lactate, while 10% is used in a hexose monophosphate shunt
What is the function of the chloride-bicarbonate antitransport in the erythrocyte?
To transport carbon dioxide from the periphery to the lungs for elimination (RBCas have carbonic anhydrase which allow for conversion of CO2 and H2O --> HCO3- which is then exported into the plasma via the antiporter--Cl- enters the RBC to maintain charge neutrality.)
Where is the chloride-bicarbonate antiport located on the erythrocyte?
in the cell membrane
The physiologic chloride shift is involved in the transport of what substance?
Carbon dioxide from the periphery to the lungs for elimination
What is an immature erythrocyte called?
reticulocyte
What does the term erythrocytosis mean?
Polycythemia; an increased number of RBCs
What does the term anisocytosis mean?
Cells of varying sizes
What does the term poikilocytosis mean?
cells of varying shapes
Granulocytes and mononuclear cells are what kind of blood cells?
leukocytes
Name three types of granulocytes.
Neutrophils, eosinophils, basophils
Name two types of mononuclear cells.
monocytes and lymphocytes
What is the main function of leukocytes?
To defend against infection
How many leukocytes are normally found per microliter or blood?
4,000 to 10,000 per microliter
What is the origin of platelets?
They are small cytoplasmic fragments derived from megakaryocytes (bud off)
What is the function of platelets?
Primary hemostasis; form primary platelet plug for example, they help prevent leakage of RBCs from damaged vessels
How do platelets mediate primary hemostasis?
They are activated by endothelial injury- bind to vWF via GPIb-IX receptor; after that, they aggregate with other platelets and interact with fibrinogen to form a hemostatic plug
What two types of granules do platelets contain?
alpha-granules- vWF and fibrinogen
dense granules- ADP, Calcium
What are the contents of the dense granules of platelets?
ADP and Calcium
What are the contents of the α granules of platelets?
vWF and fibrinogen
Where are platelets stored?
Approximately 1/3 of the platelet pool is stored in the spleen
What is the life span of a platelet?
8-10 days (so you would need to stop anti-platelet therapy 10 days before surgery)
What sign on physical exam would be indicative of platelet dysfunction?
Petechiae on the skin
(mucocutaneous bleeding)
What is the main role of basophils in the body?
to mediate allergic response
Basophils are normally what percentage of white blood cells?
< 1%
The nucleus of a basophil has what kind of shape?
bi-lobed
Where are basophils normally found in the body?
blood (Basophil Blood Bilobed)
Basophils can be stained with what types of stain?
basic stains
Basophil granules contain which substances?
histamine, heparin, leukotrienes (LTD4) and other vasoactive amines
What is the main role of mast cells in the body?
To mediate allergic reactions
Mast cells resemble what type of granulocyte both structurally and functionally?
basophils
What substances are released when mast cells degranulate?
histamine, heparin and eosinophilic chemotactic factors
What immunoglobulins bind to mast cells?
IgE
Compare and contrast the basophil and mast cell.
Basophils and mast cells are structurally and functionally similar. Mast cells are found in tissue whereas basophils are found in blood.
What is the mechanism of action of cromolyn sodium?
prevents mast degranulation (used in the tx of asthma)
What is cromolyn sodium used for?
Prevent the hyperreactivity of airways found in asthma by preventing mast cell degranulation
Mast cells are associated with what type of hypersensitivity reactions?
type 1 hypersensitivity (allergy)
What granulocytes normally comprise between 1% and 6% of all leukocytes?
eosinophils
The nucleus of an eosinophil has what type of shape?
bi-lobed
What substances do eosinophils produce?
histaminase and arylsulfatase (help limit the reaction following mast cell degranulation)
What is the main target for the phagocytic activity of eosinophils?
antigen-antibody complexes
What is the function of histaminase and arylsulfatase?
helps limit the reaction following mast degranulation
What are the 5 major causes of eosinophilia?
Neoplasms, Allergy, Asthma, Collagen Vascular Diseases, Parasites (invasive)
NAACP
What is the function of eosinophils?
Defends against helminthic and protozoan infections
What substance found in eosinophils defends against helminthic and protozoan infections?
major basic protein
Neutrophils represent _____ of WBCs.
40-75%
What is the appearance of granules found in neutrophils?
Large, spherical, azurophilic granules (lysosomes)
What do the granules in neutrophils represent?
lysosomes
What are the contents of the granules in neutrophils?
Hydrolytic enzymes, lysozyme, myeloperoxidase, and lactoferrin
Name two functions of neutrophils.
Acute inflammatory response, phagocytosis
What is the appearance of neutrophils found in folate and B12 deficiency?
hyper-segmented polys
Monocytes represent _____ of WBCs.
2-10%
What is the name of the differentiated form of a monocyte?
macrophage
Where do monocytes differentiate?
in the tissues
True or False: Macrophages are found in circulation.
False; monocytes are found in circulation and differentiate into macrophages in tissue
Describe the appearance of monocytes.
Large, kidney-shaped nucleus; frosted glass cytoplasm
What are the primary functions of macrophages?
To phagocytose bacteria, cell debris, and senescent RBCs and to scavenge damaged cells and tissues
What is a secondary function of macrophages?
Can function as antigen-presenting cells (APC) via MHC II
Macrophages have a _____ (long/short) life in tissues.
long
What type of cell is the precursor of macrophages?
circulating blood monocytes
Which cytokine causes activation of macrophages?
gamma-interferon
What professional antigen-presenting cell is a main inducer of the primary antibody response?
Dendritic cell
What do dendritic cells express on their surface?
MHC II and Fc receptor
What are dendritic cells in the skin called?
Langerhans cells
Describe the appearance of lymphocytes.
Round, densely staining nucleus with small amount of pale cytoplasm
What is the function of the B lymphocytes?
Produce antibodies- involved in humoral immunity
What is the function of the T lymphocytes?
Manifest the cellular immune response and regulate B lymphocytes and macrophages
B lymphocytes are part of the _____ (cell-mediated/humoral) immune response.
Humoral
Where do B lymphocytes originate?
Stem cells in bone marrow
Where do B lymphocytes mature?
Bone marrow (B lymphocyte = Bone marrow)
Where do B lymphocytes migrate once mature?
Peripheral lymphoid tissue (follicles in lymph nodes, white pulp of spleen, uncapsulated lymphoid tissue)
What occurs when B cells encounter an antigen?
Differentiate into plasma cells and produces antibodies
True or False: B cells have antigenic memory.
true
Can B cells function as an APC?
Yes, via the MHC II on their surface
Which CD molecules are found on B cell surface?
CD19 and CD 20
Describe the appearance of the plasma cell.
Off-center nucleus, clock-face chromatin
Which organelles are abundant in plasma cells?
Rough endoplasmic reticulum and Golgi apparatus
Why do plasma cells have abundant RER and well-developed golgi apparatus?
They produce large amounts of antibodies; RER and Golgi are integral to protein secretion
What is the precursor cell and the inciting event leading to the production of plasma cells?
When B cells encounter an antigen, they differentiate into plasma cells
Which cancer results from uncontrolled proliferation of plasma cells?
Multiple myeloma
T lymphocytes originate from stem cells located in the _____ _____, but then they mature in the _____.
Bone marrow; thymus; remember T cells mature in the Thymus
Name the three types of cells into which T cells differentiate.
Cytotoxic T cells, helper T cells, and suppressor T cells
T cells with major histocompatibility complex I and CD8 are called _____ T cells.
Cytotoxic (MHC × CD = 8; MHC I × CD8 = 8)
T cells with major histocompatibility complex II and CD4 are called _____ T cells.
Helper (MHC × CD = 8; MHC II × CD4 = 8)
T lymphocytes mediate the _____ (cellular/humoral) immune response.
T lymphocytes mediate the _____ (cellular/humoral) immune response.
The majority of circulating lymphocytes are _____ (T/B) cells.
T cells (approximately 80%)
Which type of T cell expresses CD3?
Both helper and cytotoxic T cells express CD3
What antigen(s) and antibody(s) do people with type A blood group have?
A antigen on RBC surface and B antibody in plasma.
What antigen(s) and antibody(s) do people with type B blood group have?
B antigen on RBC surface and A antibody in plasma
What antigen(s) and antibody(s) do people with type AB blood group have? What special property do these people have?
A and B antigens on RBC surface and no antibodies in plasma = "universal recipient"
What antigen(s) and antibody(s) do people with type O blood group have? What special property do these people have?
Neither A nor B antigens on RBC surface, A and B antibodies in plasma = "universal donor"
What is the significance of "Rh+" or "Rh-" blood types?
People who are positive have Rh antigen, and people who are negative do not.
What negative result can occur when an Rh- mother who has given birth to a Rh+ child, has a second Rh+ child?
Erythroblastosis fetalis = hemolytic disease of the newborn
How does erythroblastosis fetalis occur?
An Rh- mother is exposed to Rh+ blood (often during birth) and makes anti-Rh IgG that can cross the placenta during subsequent pregnancy, causing hemolysis of the new fetus' blood cells.
How is erythroblastosis fetalis prevented?
Rh antigen immunoglobulin is given to the mother after delivery to prevent her from developing natural antibodies to Rh--preventing future erythroblastosis
What can happen if someone is transfused with blood of the wrong type?
immunological response, hemolysis, renal failure, shock and death
Anti-AB antibodies, which are (IgG/IgM) (do/do not) cross the placenta, while anti-Rh antibodies, which are (IgG/IgM) (do/do not) cross the placenta.
IgM; do not; IgG; do
What is the initial step of the extrinsic pathway?
Activation of factor VII (by tissue factor = thromboplastin = factor III)
What is the initial step of the intrinsic pathway?
Activation of factor XII (with exposure to subendothelial collagen, basement membrane and activated platelets-contact)
What is the first step that is common to both the intrinsic and extrinsic pathway?
Activation of factor X
Name three substrates that are necessary for the activation of factor VII.
Tissue factor, calcium, and phospholipid
What factors are unique to the intrinsic pathway?
XII, XI, IX, VIII
What factors are unique to the extrinsic pathway?
VII
What are the functions of thrombin in the coagulation cascade?
Activation of factor V, VIII, XIII and cleavage of fibrinogen to fibrin monomers
What is the function of fibrin?
Creates a mesh that stabilizes the platelet plug
What substance degrades fibrin plugs?
plasmin
What mediates the connection between subendothelial collagen and platelets?
GpIb on platelet and vWF on subendothelial collagen
How do platelets aggregate?
Fibrinogen connects platelets by attaching to GpIIb/IIIa on adjacent platelets
Where is vWF found?
Inside platelets (alpha granules) and endothelial cells
What substances relevant to coagulation are found in platelets?
Thromboxane A2, fibrinogen, vWF, ADP, and calcium
What substances relevant to coagulation are found in endothelial cells?
Thromboplastin (tissue factor), tPA, PGI2, vWF
What leads to the expression of GpIIb/IIIa on the surface of platelets?
Activation of ADP receptor
How is protein C activated?
Thrombin binds to Thrombomodulin on the surface of endothelial cells and then this complex activates protein C
What is the pathogenesis of factor V Leiden?
There is a mutation in factor V, rendering it unable to be degraded by protein C, leading to a hypercoaguable state
What type of clots are associated with prothrombin gene mutation?
Venous clots
How would a patient with antithrombin III deficiency react to administration of heparin?
The patient would not have the expected increase in PTT after heparin administration because heparin's mechanism of action is dependent on AT III
Why does protein C or S deficiency lead to a hypercoaguable state?
There is an inability to inactivate factors V and VIII
What is the risk associated with administering warfarin in the setting of protein C or S deficiency?
Hemorrhagic skin necrosis
What are the three steps of platelet plug formation?
adhesion, aggregation, and swelling
What molecules mediate adhesion in the formation of a platelet plug?
Platelet GpIb attaches to subendothelial collagen via vWF
What molecules mediate aggregation in the formation of a platelet plug?
TxA2 released by platelets mediates aggregation while PGI2 and NO released by endothelial cells inhibit aggregation
How does aspirin prevent clot formation?
Aspirin inhibits cyclooxygenase in the platelets, thereby preventing TxA2 formation and thus aggregation of platelets
What molecules mediate swelling in the formation of a platelet plug?
ADP binds to receptor on platelet membrane leading to GpIIb/IIIa insertion onto surface of platelets, allowing platelet cohesion
Which ion, released from activated platelets, helps stabilize the platelet plug?
calcium
What enzyme is involved in vitamin K activation?
epoxide reductase
What coagulation factors use vitamin K as a cofactor?
factor II, VII, IX, X, Protein C and Protein S
Why do coagulation factors need to interact with activated vitamin K to function?
The interaction with activated vitamin K gives them a gamma-carboxyl group (which is negatively charged) that allows them to interact with calcium
How does warfarin act as an anti-coagulant?
It inhibits epoxide reductase, thereby inhibiting the activation of vitamin K- and its use by factors II, VII, IX, X
Why are neonates at risk for life-threatening hemorrhage?
Neonates lack enteric bacteria that produce vitamin K; hence they can be deficient in the vitamin K-dependent coagulation factors
Name three anticoagulant factors.
Antithrombin III, protein C, plasminogen (fibrinolytic)
How does antithrombin III act as an anticoagulant?
It inactivates factors II, VII, IX, X, XI
How does protein C act as an anticoagulant?
Activated protein C (APC) cleaves and inhibits Va and VIIIa
How does plasminogen act as an anticoagulant?
Plasminogen is activated by tPA to plasmin which cleaves the fibrin clot
Which is tPA used for clinically?
As a thrombolytic in cases of acute stroke or MI within hours of clot formation
What is the role of heparin in anticoagulation?
Potentiates the effect of antithrombin III
What is the relationship between vWF and factor VIII?
vWF carries/protects factor VIII; this is why you can see an increase in PTT in certain variants of von Willebrand's disease
What part of the fibrinolytic system also activates the complement cascade by cleaving C3 to C3a?
Plasmin
Kallikrein links the coagulation cascade to the kinin cascade through its activation of _____ and to the fibrinolytic system through its activation of _____.
Bradykinin; plasminogen
High-molecular-weight kininogen is a precursor of _____ in the kinin cascade and a cofactor in the activation of factor _____ in the coagulation cascade.
Bradykinin; XII
What does plasmin create when it interacts with fibrin clots?
Fibrin split products
What are the effects of bradykinin activating the kinin cascade?
Vasodilation, vascular permeability and pain
What factor converts prekallikrein to kallikrein and factor XI to XIa and indirectly links the coagulation cascade with the kinin cascade and fibrinolytic system?
Factor XIIa
What is the blood group of an individual with A antigen on his or her RBCs and B antibody in his or her plasma?
Group A
What is the blood group of an individual with B antigen on his or her RBCs and A antibody on his or her plasma?
Group B
What is the blood group of an individual with A and B antigens on his or her RBCs?
Group AB (universal blood recipient, univeral plasma donor)
What is the blood group of an individual with neither A nor B antigens on his or her RBCs and A and B antibodies in his or her plasma?
Group O (universal blood donor, universal plasma recipient)
What is the blood composition of an individual who is a universal recipient of blood products?
A and B antigen on the RBCs
What is the blood composition of an individual who is a universal donor of blood products?
Neither A nor B antigens on the RBCs and A and B antibodies in the plasma
What are the consequences of a nonmatched blood transfusion?
Hemolysis and a massive immune reaction that may lead to renal failure and death in severe cases
AB individuals are the "universal recipient" because of an absence of which substance in the plasma?
Antibodies to ABO blood group antigens
What are the complications associated with an Rh- mother giving birth to an Rh+ baby?
During birth, the mother may be exposed to Rh+ blood from the fetus and will make IgG antibodies against Rh factor; in subsequent pregnancies, if the baby is Rh+, IgG antibodies can cross the placenta, leading to hemolysis of the Rh+ fetal blood
What type of antibodies are produced against the ABO blood groups?
IgM (cannot cross the placenta)
What type of antibodies are produced against Rh factor?
IgG
If a mother is blood type O and her fetus is blood type B, will the fetus be at risk for hemorrhagic disease of the newborn?
No; antibodies against ABO blood groups are IgM and do not cross the placenta
Can IgG antibodies against Rh factor cross the placenta?
Yes, this is the pathogenesis of hemolysis of fetal blood (erythroblastosis fetalis)
What shape do normal RBCs have on a peripheral smear?
biconcave disc about the size of a lymphocyte nucleus
A blood smear filled with spherocytes is associated with what two different pathologies?
hereditary spherocytosis and autoimmune hemolysis
A blood smear filled with elliptocytes is associated with what pathology?
Hereditary elliptocytosis
A blood smear filled with macro-ovalocytes is associated with what two pathologies?
Megaloblastic anemia and marrow failure
Hypersegmented polymorphonuclear leukocytes are associated with what type of anemia?
Megaloblastic anemia as a result of vitamin B12 and folate deficiencies
A blood smear filled with teardrop-shaped RBCs is associated with what pathology?
Myeloid metaplasia with myelofibrosis
A blood smear filled with target cells is associated with what four pathologies?
Hemoglobin C disease, Asplenia, Liver disease, and Thalassemia (remember: HALT, the hunter said to its target)
A blood smear filled with helmet cells/schistocytes is associated with what three pathologies?
Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, microvascular damage, and disseminated intravascular coagulation
A blood smear filled with Burr cells is associated with what pathology?
Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome
A blood smear filled with acanthocytes (spiny appearance) is associated with what pathology?
Abetalipoproteinemia
A blood smear filled with sickle cells is associated with what pathology?
Sickle cell anemia
What fours diseases are associated with basophilic stippling on blood smear?
Thalassemia, Anemia of chronic disease, Iron deficiency, Lead poisoning (remember: TAIL)
What is a spur cell?
RBC with a spiny appearance that is associated with liver diseases and abetalipoproteinemia; also called acanthocytes.
What are Heinz bodies?
Heinz bodies are accumulations of denatured hemoglobin in RBCs due to the oxidation of iron
What diseases are associated with Heinz bodies?
α-Thalassemia, G6PD deficiency
What are Howell-Jowell bodies?
Nuclear remnants found in RBCs
When are Howell-Jowell bodies seen?
In patients with asplenia or functional hyposplenia
What are five causes of microcytic anemia?
TAILS- Thalassemia, Anemia of Chronic Disease, Lead Poisoning, Sideroblastic anemia
What lab findings would you expect in iron deficiency anemia?
Low serum iron, high TIBC, and low ferritin
What blood smear findings would you expect to see in thalassemias?
target cells
What MCV qualifies for microcytic anemia?
< 80fL
What blood smear findings would you expect to see in vitamin B12 and folate deficiency?
Hypersegemented PMNs
Name three causes of macrocytic anemia.
Vitamin B12 deficiency, folate deficiency, drugs that inhibit DNA synthesis
Why does reticulocytosis lead to macrocytic anemia?
Reticulocytes are larger than mature RBCs; a higher percentage of reticulocytes leads to a higher MCV
What MCV qualifies for macrocytic anemia?
MCV > 100 fL
Name some causes of normocytic, normochromic anemia.
Acute hemorrhage, G6PD deficiency, pyruvate kinase deficiency, RBC membrane defects, bone marrow disease, hemoglobinopathies, autoimmune hemolytic anemia, anemia of chronic disease
What lab values suggest hemolysis as the cause of normocytic anemia?
Decreased haptoglobin (if intravascular hemolysis), increased LDH
How do you differentiate between autoimmune and non-autoimmune hemolysis?
Positive direct coombs test suggests autoimmune hemolysis
What lab values are suggestive of anemia of chronic disease?
Low TIBC, high ferritin, high storage of iron in macrophages in bone marrow (by bone marrow biopsy with prussian blue stain)
What is the pathogenesis of microcytic anemias?
Any defect in hemoglobin synthesis
What are five diseases that result in microcytic anemias?
Iron deficiency, anemia of chronic disease, thalassemia, lead poisoning, and sideroblastic anemia
What is the defect in iron deficiency that leads to microcytic anemia?
Decreased iron availability and thus decreased heme synthesis
What is the defect in anemia of chronic disease that leads to microcytic anemia?
There is decreased release of iron to transferrin (from ferritin) and thus decreased availability for heme synthesis
What is the defect in thalassemias that leads to microcytic anemias?
There are mutations in the globin genes that lead to reduced globin synthesis
What is the defect in lead poisoning that leads to microcytic anemias?
Lead inhibits ALA dehydrase and ferrochelatase in the synthesis of heme
What heme synthesis substrates accumulate in urine in a patient with lead poisoning?
protoporphorin and ALA (aminolevulinic acid)
What enzyme is affected in acute intermittent porphyria?
Uroporphyrinogen I synthase = porphobilinogen deaminase
Macrocytic anemia arises from an impairment of what?
DNA synthesis
What 2 deficiencies can cause a macrocytic megaloblastic anemia?
folate and vitamin B12
Name 5 causes of non-megaloblastic macrocytic anemia.
1. liver disease (target cells, acanthocytes)
2. hypothyroidism
3. alcoholism
4. reticulocytosis--bone marrow responding to anemia-- so this is actual a normocytic anemia with inc retics--> hemolysis or hemorrhage
5. drugs (AZT, 5-Fluorouracil, and hydroxyurea (tx for sickle cell anemia))
what drugs can cause a non-megaloblastic macrocytic anemia?
AZT, 5-fluorouracil, and hydroxyurea (derepresses fetal hemoglobin production--used in tx of sickle cell anemia)
what are some findings in megaloblastic anemia caused by vitamin B12 deficiency?
hypersegmented neutrophils, glossitis (common among B vitamin deficiencies), inc homocysteine and methylmalonic acid, dec B12
What is aplastic anemia?
Pancytopenia characterized by severe anemia, neutropenia, and thrombocytopenia caused by failure of development or destruction of multipotent myeloid stem cells-- hypocellular bone marrow with fatty infiltration
What are iatrogenic causes of aplastic anemia?
drugs (benzene, chloramphenicol, alkylating agents, antimetabolites) or radiation
What are infectious causes of aplastic anemia?
viral agents like parvovirus B19, HIV, EBV, and acute hepatitis
What is a genetic cause of aplastic anemia?
Fanconi's anemia (genetic defect in DNA repair) - often progresses to AML-- also have short stature, and increased incidence of tumors/leukemia.
What diagnostic procedure is necessary for diagnosis of aplastic anemia?
bone marrow biopsy
Name seven signs or symptoms that are associated with aplastic anemia.
Fatigue, malaise, pallor, purpura, mucosal bleeding, petechiae, and infection; these manifestations are associated with the depletion of progenitors of all blood cell lines
What are pathologic features of aplastic anemia on peripheral smear and on bone marrow biopsy?
Peripheral blood smear- pancytopenia with normal cell morphology
bone marrow- hypocellular with fatty infiltration
Name four treatments for aplastic anemia.
Bone marrow transplant, granulocyte colony-stimulating factor, RBC and platelet transfusion, or immunosuppressive regimens (if autoimmune etiology)
Name three common triggers for sickling in patients with sickle cell anemia.
infection, dehydration, and acidosis (low O2)
What type of blood dyscrasia is characterized by a mutation resulting in a single amino acid replacement of glutamic acid with valine in the β chain?
Hemoglobin S mutation; causing sickle cell anemia if homozygous and sicke cell trait if heterozygous
True or False: Patients with sickle cell trait (hemoglobin S heterozygotes) have higher morbidity and mortality rates associated with malaria infection than those without hemoglobin S.
False; heterozygotes are relatively malaria resistant as compared with those without the HbS mutation
Name the bacterium that is classically associated with osteomyelitis in patients who are homozygous for the hemoglobin S mutation.
salmonella
In patients who are homozygous for the hemoglobin S mutation, continued scarring of a certain organ causes progressive shrinkage so that, by adolescence, only a small amount of fibrous tissue remains. Name the organ and the name of the process by which it shrinks.
Spleen; autosplenectomy
(it gets infarcted so it is about the size of a thumb by age 18-- see Howel Jolly bodies in the blood)
In patients who are homozygous for the hemoglobin S mutation, parvovirus B19 infection is classically associated with what result?
aplastic crisis
People who are homozygous for hemoglobin S are at increased risk for infection with which type of organism: encapsulated bacteria, gram-positive rods, gram-negative rods, fungi, helminths, nonenveloped viruses, or spore-forming bacteria?
Encapsulated bacteria; due to their lack of a functional spleen
(must receive pneumovax for Streptococcus pneumoniae= pneumococcus)
In patients who are homozygous for the hemoglobin S mutation, what type of crisis is associated with episodes of hypoxic injury and infarction associated with severe pain in the affected region?
Vaso-occlusive crisis (also called pain crisis)
True or False: Hemoglobin C defect is similar to the hemoglobin S mutation in that both involve a mutation in the α chain.
False; both involve a mutation in the β chain
True or False: Patients with hemoglobin C disease or hemoglobins S and C disease have more severe disease than do patients with sickle cell anemia.
False; patients with sickle cell anemia have more severe disease
What percentage of African-Americans have the hemoglobin S trait and sickle cell disease?
sickle cell trait = 8%
sickle cell disease = 0.2%
genetic counseling!!
What causes a "crew cut" appearance on x-ray of the skull of patients with sickle cell disease?
marrow expansion by increased hematopoeisis
What are the sickled cells in sickle cell anemia?
Crescent-shaped RBCs; RBCs are distorted due to abnormal hemoglobin polymers
For hemoglobin, how many copies of the α-globin genes are there in a normal genotype?
four
Where is α- thalassemia most prevalent?
Africa and Asia (remember Alpha thalassemia- Africa and Asia)
In what populations is β-thalassemia most prevalent?
Mediterranean populations
(Italians and Greeks)
True or False: In patients with α-thalassemia, there is a compensatory increase in other globin chains as a result of the deficiency in α-globin chains.
False; this is why patients with this disease present with anemia
What is the primary deficiency in patients with α-thalassemia?
The underproduction of the α-globin chain as a function of the number of affected α genes (one to four) that a patient has
What happens to patients with α-thalassemia in whom four α-globin genes are affected by disease?
Hydrops fetalis and intrauterine fetal death (they have hemoglobin barts- which is a tetramer of gamma chains)
In adults with α-thalassemia, what causes the accumulation of hemoglobin called hemoglobin H disease?
Excess unpaired β chains caused by the deficiency of α chains form tetramers known as hemoglobin H (this results from 3 a globin genes being deleted)
Adults with severe α-thalassemia (ie, they are missing three copies of their α-globulin gene) produce an excess of what type of hemoglobin?
Hemoglobin H, which consists of excess unpaired β chains that form tetramers
How many α genes do adults have in the most severe form of α-thalassemia?
One α gene (as compared with four in normal patients; having no α genes is lethal in utero)
True or False: Hemoglobin S disease/β-thalassemia heterozygotes have mild to moderate disease.
True; because they have decreased β chain production, this leads to a decrease in the amount of hemoglobin S that is produced, leading to less sickling and vaso-occlusion-- less of the messed up globin chain!
The β chain is underproduced in cases of β-thalassemia _____ (major/minor), and it is absent in cases of β-thalassemia _____ (major/minor).
minor; major
What type of hemoglobin increases and partially compensates in patients with β-thalassemia?
fetal hemoglobin (HbF = alpha2, gamma2) and hemoglobin A2 (HbA2 = alpha2, delta2)
What is the usual treatment for severe anemia in cases of β-thalassemia major?
blood transfusions
In β-thalassemia major and other blood dyscrasias, what is the cause of skeletal deformities?
Marrow expansion from increased erythropoiesis
In patients with β-thalassemia, cardiac failure may occur as a result of what?
Hemochromatosis as a result of the accumulation of excessive iron from blood transfusions
In patients who are homozygous for the hemoglobin S mutation, which renal complication may occur?
Renal papillary necrosis due to sickling
Newborns who are homozygous for the hemoglobin S mutation are initially asymptomatic due to _____ (increased/decreased) hemoglobin F and _____ (increased/decreased) hemoglobin S.
increased; decreased
What is the genetic defect in sickle cell anemia?
Single amino acid replacement (point mutation) in β chain (glutamic acid is changed to a valine)
What are complications associated with sickle cell anemia?
Aplastic crisis, autosplenectomy, encapsulated organism infection, Salmonella osteomyelitis, pain/vaso-occlussive crisis, renal papillary necrosis, splenic sequestration crisis
Why are sickle cell patients at higher risk for encapsulated organism infections?
Patients undergo autosplenectomy at a young age, rendering them unable to remove these organisms from circulation
What are two therapies for sickle cell anemia?
Hydroxyurea and bone marrow transplantation
How does hydroxyurea aid in the treatment of sickle cell anemia?
It increases the concentration of circulating HbF, which does not sickle in low oxygen states
What is the difference between HbC and HbS?
HbC has a different β chain mutation and thus a milder form of sickle cell anemia- HbC does not cause sickling by itself-- it just predisposes to sickling if HbS is present
What is the makeup of hemoglobin in HbH?
β-4Tetramer, lacks 3 α chains
What is the makeup of hemoglobin in Hb Barts?
γ-4Tetramers, lacks all four α chains in utero
What is the difference between β-thalassemia major and β-thalassemia minor?
In β-thalassemia major, the beta chain is absent; in β-thalassemia minor, the β chain is underproduced
Which thalassemia requires blood transfusions?
β-Thalassemia major results in severe anemia that requires transfusions
What is a common complication of treatment for β-thalassemia?
Cardiac failure secondary to hemochromatosis; blood transfusions results in an iron overload state
What is a radiological finding in β-thalassemia?
"Crew cut" skull; this is due to marrow expansion which gives the appearance of cortex lifting on x-ray
Do newborns present with symptoms of sickle cell anemia?
No; since they have a higher concentration of HbF, the sickling that occurs during a deoxygenated state is not clinically significant in newborns
What is the phenotype of a patient who has both HbC and HbSC mutations?
A less severe sickle cell anemia
What type of anemia is characterized by increased serum bilirubin levels (jaundice, pigment gallstones) and increased reticulocytes (marrow compensating for anemia)?
Hemolytic anemia; due to increased destruction of RBCs, there is more bilirubin in circulation; bone marrow attempts to compensate by increasing erythropoeisis and releasing reticulocytes into circulation
If the hemolysis is intravascular, what clinical finding is expected?
decreased haptoglobin (which binds up free hemoglobin) and increased urine hemoglobin (hemoglobinuria)
If extravascular hemolysis is suspected, what clinical finding should occur?
jaundice
What are three types of autoimmune anemia?
Warm agglutinins, cold agglutinins, and erythroblastosis fetalis
What is the process by which RBCs are destroyed in warm autoimmune anemia?
There is increased destruction of RBCs in the spleen and in the liver by Kupffer cells because the RBCs are coated with IgG--extravascular hemolysis
What type of antibody is responsible for warm autoimmune hemolytic anemia?
IgG (remember: Warm weather is GGGreat)
What conditions predispose a patient to warm hemolytic anemia?
chronic disease-- SLE, CLL or drugs (e.g. alpha-methyldopa used to treat HTN in pregnancy)
What conditions predispose a patient to cold hemolytic anemia?
mycoplasma pneumonaie infections, or infectious mononucleosis (EBV)
What type of antibody is responsible for cold autoimmune hemolytic anemia?
IgM IgM (remember: Cold ice cream…MMM)
Describe the direct Coombs' test.
Anti-Ig Ab is added to the patient's RBCs; if the RBCs are coated with the antibody (IgG for warm and IgM for cold), the RBCs will agglutinate, yielding a positive test
Describe the indirect Coombs' test.
Normal RBCs (not from the patient) are added to patient's serum; if serum has anti-RBC surface Ig, the control RBCs will agglutinate
True or False: Autoimmune hemolytic anemias are Coombs' negative.
False; they are Coombs' positive
What is erythroblastosis fetalis, and why does it occur?
This condition is seen in newborns as a result of Rh or other blood antigen incompatibility with that of the mother; it occurs when the mother's antibodies attack fetal RBCs (when Rh- mother has Rh+ child, develops Anti-Rh Abs. that attack her next born Rh+ child)
What blood cell test can be used to confirm hereditary spherocytosis?
Osmotic fragility test-- spherocytes are very fragile and will lyse when different concentrations of saline are added to solution
True or False: Patients with hereditary spherocytosis will be Coombs' positive.
False; they will be Coombs' negative because this is not an immune-mediated disease but rather a structural one (membrane defect--intrinsic cause of hemolysis)
What is the defect in patients with hereditary spherocytosis?
A spectrin, band 3.1 or ankyrin defect that results in small and round RBCs that are more fragile and susceptive to hemolysis
What are blood smear findings associated with hereditary spherocytosis?
Small RBCs with no central pallor, increased MCHC, increased RDW
True or False: Howell-Jolly bodies are seen in hereditary spherocytosis.
They will be present if the patient has undergone a splenectomy-- which is the recommended treatment for hereditary spherocytosis--since the spleen is removing the defective RBCs leading to a normocytic anemia
What will occur in a patient with hereditary spherocytosis who is infected with parvovirus B19?
aplastic crisis because parvovirus B19 suppresses erythropoeisis
What is the defect in paroxysmal nocturnal hemoglobinuria?
There is a defect in an anchoring protein/decay accelerating factor which renders the RBCs more susceptible to intravascular hemolysis by complement
What protein is deficient in paroxysmal nocturnal hemoglobinuria?
GPI anchor/decay-accelerating factor
What urinalysis abnormality is expected in paroxysmal nocturnal hemoglobinuria?
Increased urine hemosiderin
and hemoglobin (might pee red in the morning)
What type of hemolytic anemia is characterized by the presence of schistocytes (helmet cells) on blood smear?
Microangiopathic anemia
How can systemic lupus erythematosus be a cause of microangiopathic anemia?
The immune complex aggregates with platelets, which creates intravascular thrombi
In what patients is microangiopathic anemia usually seen?
Patients with DIC, TTP/HUS, SLE, or malignant hypertension
How are RBCs damaged in patients with microangiopathic anemia?
Mechanical trauma occurs as RBCs are forced through narrowed vessels
Schistocytes are a common feature of microangiopathic anemia. What are schistocytes?
RBC fragments that are created by traumatic injury to RBCs
Advair Dsikus
Fluticasone/Solumeterol
Asthma
Describe DIC.
Activation of the coagulation cascade leading to microthrombi and global consumption of platelets, fibrin, and coagulation factors
Name seven causes of disseminated intravascular coagulation.
Sepsis (gram-negative), Trauma, Obstetric complications, acute Pancreatitis, Malignancy, Nephrotic syndrome, Transfusion (remember: STOP Making New Thrombi!)
How does disseminated intravascular coagulation affect the laboratory findings for prothrombin time, partial thromboplastin time, fibrin split products, and platelets?
increased PT and aPTT, increased fibrin split products (D-dimer), and decreased platelets and fibrinogen as they are being used up in forming micro thrombi
For patients with disseminated intravascular coagulation, what defects will be seen in RBCs on a blood smear?
schistocytes and helmet cells from damage to RBCs trying to flow through narrowed/microangiopathic vessels
A patient with a somewhat diminished total iron binding capacity, a somewhat diminished serum Fe2+ level, no change in percent transferrin saturation, and an elevated ferritin level has what type of anemia: iron deficiency, anemia of chronic disease, pregnancy/OCP use, or iron overload?
anemia of chronic disease
A patient with an elevated total iron binding capacity, a diminished serum Fe2+ level, decreased percent transferrin saturation, and a low ferritin level has what type of blood disorder: iron deficiency, anemia of chronic disease, pregnancy/OCP use, or iron overload?
iron deficiency anemia
A patient with a low total iron binding capacity, an elevated serum Fe2+ level, and an elevated ferritin level, and a very high percent transferrin saturation has what type of iron disorder: iron deficiency, anemia of chronic disease, pregnancy/OCP use, or iron overload?
Iron overload, such as hemochromatosis (TIBC is low because all the spots on transferrin are mostly taken up!)
A patient with an increased total iron binding capacity, a normal serum Fe2+ level, normal ferritin level, and decreased percent transferrin saturation has what type of anemia: iron deficiency, anemia of chronic disease, iron overload, or pregnancy/OCP use?
pregnancy/OCP use
What is the role of ferritin in iron transport?
It is the primary iron storage protein of the body
What is the role of transferrin in iron transport?
To transport iron in blood
What is the primary abnormal lab value in iron deficiency anemia?
There is low serum iron which results in high TIBC, low ferritin, and low percent transferrin saturation
What is the primary abnormal lab value in anemia of chronic disease?
There are high ferritin levels because the body has adapted a mechanism that allows the cells to store iron and prevents pathogens from acquiring circulating iron; thus there is low serum iron and transferrin/TIBC
What is the primary abnormal iron lab value in hemochromatosis?
There is high serum iron; leading to low TIBC, high ferritin and high percent transferrin saturation
What substrates accumulate in urine in acute intermittent porphyria?
AminoLevulenic Acid (ALA) and porphobilinogen
What enzyme is affected in porphyria cutanea tarda?
urophorphyrinogen decarboxylase
What substrate accumulates in urine in porphyria cutanea tarda?
uroporphyrin (tea colored urine)
What are five symptoms of acute intermittent porphyria?
5 Ps
Painful abdomen
Pink urine
Polyneuropathy
Psychological disturbances
Precipitated by drugs
What are the two substrates needed in the initial step of hemoglobin synthesis?
succinyl CoA and glycine (vitamin B6 is the cofactor for the rate limiting enzyme ALA synthase which converts these substrates to ALA)
What enzyme catalyzes the first step of hemoglobin synthesis?
aminolevulinic acid synthase (ALA synthase)
What cofactor is needed for the first step of hemoglobin synthesis?
vitamin B6 = pyridoxine (thus B6 deficiency can cause a microcytic/sideroblastic anemia)
Where does the first step of hemoglobin synthesis take place?
mitochondria of RBCs
What is the product of the first step of hemoglobin synthesis?
δ-Aminolevulinic acid
What enzyme catalyzes the transformation of δ-ALA to porphobilinogen?
ALA dehydratase
What four intermediates are formed in the cytosol during hemoglobin synthesis?
Porphobilinogen, pre-uroporphyrinogen, uroporphyrinogen III, coproporphyrinogen
(not necessary to know according to Goljan)
What intermediate is iron incorporated into during hemoglobin synthesis?
protoporphyrin
Where in the cell is iron incorporated into protoporphyrin?
mitochondria
What enzyme catalyzes the incorporation of iron into protopophyrin?
ferrochelatase (inhibited by lead--microcytic anemia due to lead poisoning)
What is the product of the addition of iron to protoporphyrin?
heme!
True or False: Aplastic anemia can cause platelet deficiencies and result in a bleeding disorder.
true
True or False: Immunosuppressive drugs can cause bleeding disorders as a result of platelet deficiency.
true
Why is there a platelet deficiency in patients with idiopathic thrombocytopenic purpura?
In ITP, there is production of antiplatelet antibodies that coat platelets. This targets them for destruction in the spleen, leading to decreased platelet counts in the periphery
Hemophilia A is caused by a deficiency of what factor?
factor VIII (intrinsic pathway of coagulation)
Hemophilia B is caused by a deficiency of what factor?
factor IX (intrinsic pathway of coagulation)
In von Willebrand's disease, the deficiency of von Willebrand factor causes what two results?
vWF is responsible for the adhesion of platelets to subendothelial collagen and for carriage of factor VIII. If vWF is deficient or absent, there is decreased platelet adhesion and decreased factor VIII activity.
What is the most common inherited bleeding disorder?
vonWillebrand's disease
what is the inheritance pattern of vonWillebrand's disease?
autosomal dominant (thus it is the most common inherited bleeding disorder!)
In _____ (idiopathic/thrombotic) thrombocytopenic purpura, there is peripheral platelet destruction and antiplatelet antibodies.
idiopathic (aka immune thrombocytopenic purpura)
In _____ (idiopathic/thrombotic) thrombocytopenic purpura, increased platelet aggregation leads to thrombosis, which results in schistocytes.
thrombotic (microangiopathic- normocytic anemia)
Name five etiologies of platelet dysfunction/decreased platelet counts.
DIC, TTP-HUS, ITP, drug induced thrombocytopenia, aplastic anemia
What are clinical signs of platelet disorders.
Microhemorrhages: mucous membrane bleeding, epistaxis, petechiae, purpura, increased bleeding time-- this is because it is a defect in primary hemostasis which presents in this manner. secondary hemostasis is more characterized by joint and soft tissue bleeds.
What is the pathogenesis of ITP?
In ITP, there is production of antiplatelet antibodies that coat platelets; this targets them for destruction in the spleen, leading to decreased platelet counts in the periphery
What is the pathogenesis of TTP?
There is a deficiency in a metalloproteinase (ADAMTS13) which yields abnormally large vVF, favoring platelet aggregation. Intravascular clots cause formation of schistocytes. Excess consumption of platelets leads to bleeding such as purpura
What are the clinical signs of coagulopathies?
Macrohemorrhages: hemarthroses, easy bruising, increased PT and/or PTT
(problem is with secondary hemostasis so there is more joint and soft tissue bleeds- remember pt with hemophilia--joint bleeds--arthritis)
What is the name of the hemorrhagic disease that is caused by a defect of platelet adhesion associated with decreased glycoprotein Ib?
Bernard-Soulier disease
What is the name of the hemorrhagic disease that is caused by a defect of platelet aggregation associated with decreased glycoprotein IIb/IIIa?
Glanzmann's thrombasthenia
Which category of hemorrhagic disorders is associated with decreased platelet count, increased bleeding time, and no changes in prothrombin or partial thromboplastin times?
Thrombocytopenia (primary hemostasis/platelet plug formation abnormality)
Name two hemorrhagic disorders that are associated with increased partial thromboplastin time and no changes in platelet count, bleeding time, or prothrombin time.
Hemophilia A and hemophilia B
Which hemorrhagic disorder is associated with increased bleeding time and partial thromboplastin time and no changes in platelet count or prothrombin time?
von Willebrand's disease
(remember that vWF is a carrier for factor VII-- increased aPTT)
Which hemorrhagic disorder is associated with decreased platelet count and increased bleeding time, prothrombin time, and partial thromboplastin time?
disseminated intravascular coagulation (DIC) --also involves fibrinolysis--elevated D-dimer
Which hemorrhagic disorder is associated with no changes in platelet count or bleeding time, but increased prothrombin and partial thromboplastin times?
vitamin K deficiency
Which hemorrhagic disorder is associated with decreased platelet count, increased bleeding time, and no changes in prothrombin and partial thromboplastin times?
Bernard-Soulier disease
Which hemorrhagic disorder is associated with elevated bleeding time but no changes in platelet count, partial thromboplastin time, and prothrombin time?
Glanzmann's thrombasthenia
What coagulation findings are seen in thrombocytopenia?
Decreased platelet count, increased bleeding time, normal PT and PTT
What coagulation findings are seen in hemophilia A and B?
Increased PTT
What coagulation abnormalities are expected in von Willebrand's disease?
Increased bleeding time and increased PTT (if factor VIII levels are decreased)
What coagulation abnormalities are seen in DIC?
Increased bleeding time, PT, and PTT; decreased platelet count
What coagulation abnormalities are seen in vitamin K deficiency?
Increased PT and PTT
What coagulation abnormalities are seen in Bernard-Soulier disease?
Decreased platelet count, increased bleeding time
What coagulation abnormalities are seen in Glanzmann's thrombasthenia?
Increased bleeding time
Defects in platelet plug formation result in what laboratory abnormality?
Increased bleeding time
How does Glanzmann's thrombasthenia result in increased bleeding time?
There is a defect in GpIIb/IIIa leading to a defect in platelet aggregation
How does Bernard-Soulier disease result in increased bleeding time?
There is a defect in GpIb leading to a defect in platelet-to-collagen adhesion
How does von Willebrand's disease lead to increased bleeding time?
With decreased functional vWF, there is a defect in platelet-to-collagen adhesion
How does DIC and thrombocytopenia lead to increased bleeding time?
In DIC, platelets are consumed due to systemwide clot formation; thrombocytopenia, by definition, is decreased platelet count
Defects in the intrinsic pathway leads to increased _____ (PT/PTT).
PTT
Defects in the extrinsic pathway leads to increased _____ (PT/PTT).
PT
Name three defects associated with the intrinsic pathway.
Hemophilia A, hemophilia B, and von Willebrand's disease
(affecting factors VIII and IX)
What is the histological appearance of malignant plasma cells in multiple myeloma?
"Fried egg" appearance
What is the most common primary tumor that arises within the bone of adults > 40-50 years old?
multiple myeloma
What are Bence Jones proteins?
Immunoglobulin light chains found in urine that are associated with multiple myeloma
Name five common complications of multiple myeloma.
hyperCalcemia (bone lytic lesions), Renal insufficiency, Anemia and predisposition to infections (bone marrow crowding), Bone pain, primary amyloidosis (light chains)
Does multiple myeloma cause hypocalcemia or hypercalcemia?
hypercalcemia
True or False: A common complication of multiple myeloma is liver dysfunction caused by the absorption of Bence Jones protein.
False; renal insufficiency (not liver dysfunction) is a common complication due to the immunoglobulin light chains excreted in the urine (Bence Jones proteins), which are toxic to renal tubules
True or False: Multiple myeloma is often associated with a primary amyloidosis.
true; AL amyloidosis (amyloid from light chains)
True or False: Multiple myeloma often is associated with anemia.
true
What is the leading cause of death in multiple myeloma?
Infection; the decreased production of normal immunoglobulin makes patients susceptible to recurrent bacterial infections
What is the difference between multiple myeloma and Waldenstrom's macroglobulinemia with respect to bone lesions and protein electrophoresis?
Multiple myeloma: M protein spike on electrophoresis and bone lytic lesions; Waldenstrom's (IgM): hyperviscosity symptoms and M spike without bone lytic lesions
On the blood smear of a patient with multiple myeloma, the RBCs are stacked like poker chips. What is this called?
Rouleaux formation
A 65-year-old man has a monoclonal immunoglobulin spike on serum protein electrophoresis. He is asymptomatic. What is the likely diagnosis?
Monoclonal gammopathy of undetermined significance (MGUS) (1% per year risk of progression to multiple myeloma)
What immunoglobulins are produced in large quantities in multiple myeloma?
IgG (55%) or IgA (25%) (IgM gives the diagnosis of Waldenstrom's macroglobulinemia)
True or False: Leukemias result in a decreased number of circulating WBCs in the blood.
False; leukemias result in an increased number of WBCs
True or False: Common complications of leukemia are cell infiltrates in the liver, spleen, and lymph nodes.
true
Name three common complications of marrow failure in patients with leukemia.
Anemia (decreased RBCs), infection (decreased WBCs), and hemorrhage (decreased platelets)
Name five characteristics of acute lymphoblastic leukemia.
It commonly presents in children, it involves lymphoblasts (pre-B or pre-T), it often spreads to the central nervous system and testes, it is often responsive to therapy, and leukemic cells are positive for TdT (marker of pre-T and pre-B cells)
Name a leukemia that commonly presents in adults and that involves myeloblasts.
Acute myelogenous leukemia
Name three characteristics of acute myelogenous leukemia.
It commonly presents in adults, it involves myeloblasts, and it is associated with Auer rods
What leukemia is associated with Auer rods?
Acute myelogenous leukemia
What is the treatment for M3 type of AML?
All-trans retinoic acid (vitamin A)
What does all-trans retinoic acid do in AML?
Induces differentiation of circulating myeloblasts
What is the marker of pre-T and pre-B cells?
Tdt
Name a leukemia that is associated with the Philadelphia chromosome (t[9;22], bcr-abl).
Chronic myelogenous leukemia
Which leukemia is morphologically and genetically indistinguishable from small lymphocytic lymphoma?
Chronic lymphocytic leukemia
What type of anemia is associated with CLL?
Warm autoimmune anemia
What cells in the periphery are classically associated with chronic lymphocytic leukemia?
Smudge cells
Describe the clinical course of CLL.
This disease presents in older adults with lymphadenopathy, hepatosplenomegaly, and otherwise few symptoms; and it follows an indolent course
What cell types are increased in CML?
Neutrophils, metamyelocytes, basophils
What is a possible complication of CML with respect to disease course?
It may accelerate and transform to AML or ALL, also known as a "blast crisis"
True or false: CML is associated with a low leukocyte alkaline phosphatase level.
True; leukocyte alkaline phosphatase is high in leukemoid reaction
What is the treatment of choice of CML?
Imatinib (anti-bcr-abl)
Which leukemia is a mature B-cell tumor in the elderly and associated with cells that have filamentous, hair-like projections and stains tartrate-resistant acid phosphatase (TRAP) positive?
Hairy cell leukemia
Which leukemia is most common in patients < 15 years old?
Acute leukocytic leukemia
Which leukemia is most common in patients 30-60 years old?
Chronic myelogenous leukemia
Which leukemia is most common in patients > 60 years old?
Chronic leukocytic leukemia
What is a complication of treatment of acute promyelocytic leukemia (M3)?
Treatment of AML M3 with all-trans retinoic acid can lead to release of Auer rods, which can lead to DIC
What are Auer rods?
Peroxidase-positive cytoplasmic inclusions found in granulocytes and myeloblasts in patients with acute promyelocytic leukemia
The presence of what type of cell is pathognomonic for Hodgkin's disease?
Reed Sternberg cells
What is the CD profile of Reed-Sternberg cells?
CD15+ and CD30+
True or False: The presence of Reed-Sternberg cells is sufficient for the diagnosis of Hodgkin's disease.
False; Reed-Sternberg cells are necessary, but they alone are not sufficient for a diagnosis of Hodgkin's disease
Lacunar cells are variants of Reed-Sternberg cells that are found in what variant of Hodgkin's disease?
nodular sclerosing (65-75% of all Hodgkin's cases- more common in women than men--only type that is more common in women)
Which type of lymphoma involves Reed-Sternberg cells?
hodgkin's lymphoma
Which lymphoma is more likely to be localized to a single group of nodes: Hodgkin's or non-Hodgkin's?
hodgkin's lymphoma
Which lymphoma is more likely to spread contiguously: Hodgkin's or non-Hodgkin's?
hodgkin's lymphoma
Which lymphoma rarely spreads extranodally: Hodgkin's or non-Hodgkin's?
Hodgkin's lymphoma
Which lymphoma is more likely to have constitutional ("B") signs and symptoms such as low-grade fever, night sweats, and weight loss: Hodgkin's or non-Hodgkin's?
Hodgkin's lymphoma
Which lymphoma is more likely to have mediastinal lymphadenopathy: Hodgkin's or non-Hodgkin's?
Hodgkin's lymphoma
Which lymphoma has a bimodal distribution of young and old: Hodgkin's or non-Hodgkin's?
hodgkin's lymphoma
What virus is associated with 50% of Hodgkin's lymphoma?
EBV (epstein barr virus-- causes mononucleosis-- highly assoc with Burkitts lymphoma in young African kids)
How do Reed-Sternberg cells relate to prognosis in Hodgkin's lymphoma?
There is better prognosis with fewer Reed-Sternberg cells. (Similarly, there is better prognosis with increased lymphocytes)
Which lymphoma is more often associated with HIV and immunosuppression: Hodgkin's or non-Hodgkin's?
Non-Hodgkin's
Non-Hodgkin's lymphoma usually involves which lymphocyte lineage?
B-cell
Which type of Hodgkin's lymphoma is most common, has collagen banding and lacunar cells, and affects more women than men?
nodular sclerosing (65% to 75% of all Hodgkin's cases)
Which two types of Hodgkin's lymphoma have the most favorable prognosis?
Nodular sclerosing (65% to 75% of all Hodgkin's cases) and lymphocyte predominant (6% of all Hodgkin's cases)
Which type of Hodgkin's lymphoma has an intermediate prognosis and is marked by numerous Reed-Sternberg cells and lymphocytes?
Mixed cellularity (25% of all Hodgkin's cases)
Which type of Hodgkin's lymphoma has a poor prognosis and is most often found in older men with disseminated disease?
Lymphocyte depleted (rare)
Which type of Hodgkin's lymphoma has a poor prognosis and has few Reed-Sternberg cells or lymphocytes present?
Lymphocyte depleted (rare)
Which type of Hodgkin's lymphoma is most common in males < 35 years of age?
Lymphocyte predominant
How does the ratio of lymphocytes to Reed-Sternberg cells to correlate with prognosis of Hodgkin's lymphoma?
The higher the lymphocyte to Reed-Sternberg cell ratio, the better the prognosis
Name three characteristics of small lymphocytic lymphoma.
It occurs in adults, it involves B cells, and it is indistinguishable from chronic lymphocytic leukemia except that it involves a focal mass (it also is assoc with warm antibody hemolytic anemia (extravascular-- antibodies coat RBCs and they are removed by the spleen), Peripheral blood smear will show smudge cells
What is the most common form of non-Hodgkin's lymphoma in adults?
follicular (small cleaved cells)
Which variant of non-Hodgkin's lymphoma is associated with t(14;18)/bcl-2 expression?
follicular lymphoma (small cleaved cells)
What is the function of bcl-2?
it inhibits apoptosis allowing the cells to live longer
From what class of lymphocytes is follicular lymphoma derived?
B cells
Which variant of non-Hodgkin's lymphoma is associated with t(8;14)/c-myc expression?
Burkitt's lymphoma
What chromosomal translocation is associated with Burkitt's lymphoma?
t (8;14)
What is the gene product of the translocation associated with Burkitt's lymphoma?
c-myc oncogene moves next to heavy-chain Ig gene and is thus produced in large quantities
What infectious etiology is associated with Burkitt's lymphoma?
Epstein Barr Virus (EBV)
What is the histological appearance of Burkitt's lymphoma?
Sheets of lymphocytes interspersed with macrophages ("starry-sky" appearance)-- macs are the stars in the sky of lymphocytes
What lesion is associated with the endemic form of Burkitt's and where is this lymphoma endemic?
Jaw lesions, Africa
What lesion is associated with the sporadic form of Burkitt's lymphoma?
Pelvic or abdominal lesions (remember the patient in the classroom with Burkitts and they thought it ovarian cancer since it was in that region)
Which form of non-Hodgkin's lymphoma can be derived from either B or T cells?
diffuse large cell lymphoma (20% of the time it is of mature T cell origin)
Name a variant of non-Hodgkin's lymphoma that occurs most often in children, that involves immature T cells, and that has a very aggressive course.
Lymphoblastic lymphoma
(also T-ALL- acute lymphoblastic leukemia if more in blood/marrow than tissues)
What is the common presentation of lymphoblastic lymphoma?
anterior mediastinal mass and acute lymphoblastic lymphoma
What two forms of non-Hodgkin's lymphoma are more prominent in children?
lymphoblastic lymphoma and Burkitt's lymphoma
What translocation is associated with mantle cell lymphoma?
t (11;14)
What cell surface marker is unique to the malignant cells in mantle cell lymphoma?
CD5+
Mantle cell lymphoma usually affects _____ (adults/children) and generally has a _____ (poor/good) prognosis.
adults; poor (often affects older males)
Name the abnormal protein and the chromosomal translocation that are associated with chronic myelogenous leukemia.
bcr-abl fusion protein, and t (9;22) = "Philadelphia chromosome"
Name the abnormal protein and the chromosomal translocation that are associated with Burkitt's lymphoma.
c-myc; t(8;14)
Name the abnormal protein and the chromosomal translocation that are associated with follicular lymphomas.
bcl-2; t(14;18)
Name the chromosomal translocation associated with promyelocytic leukemia (M3).
t (15;17)
Name the chromosomal translocation that is associated with mantle cell lymphoma.
t (11;14)
What is the result of the t(8;14) translocation in Burkitt's lymphoma?
c-myc oncogene activation
What is the result of the t(14;18) translocation in follicular lymphoma?
bcl-2 activation
What is the significance of the translocation in M3 type of AML with respect to treatment?
The cancer is responsive to all-trans retinoic acid
Name the chromosomal translocation that is associated with Ewing's sarcoma.
t(11;22)
What are two signs indicating leukemoid reaction?
Increased WBC count with a left shift (more immature cells -e.g. 80% bands on diff), and increased levels of leukocyte alkaline phosphatase
Define histiocytosis X.
Proliferative disorders of dendritic cells (Langerhans cells) from the monocyte lineage
What findings of histiocytosis X are most commonly seen on electron microcscopy?
Birbeck granules ("tennis rackets")
What surface proteins are expressed by defective cells in histiocytosis X?
S-100 and CD1a
Histiocytosis X is known by what other three names?
Letterer-Siwe Disease, Hanns- Schuller-Christian disease, and eosinophilic granulomas
What are the relative levels of RBCs, WBCs, and platelets in polycythemia vera?
increase in all three lines
What are the relative levels of RBCs, WBCs, and platelets in essential thrombocytosis?
Increase in platelets, no change in RBC and WBC levels
What are the relative levels of RBCs, WBCs, and platelets in myelofibrosis?
Decreased in RBCs with variable levels of WBCs and platelets
What are the relative levels of RBCs, WBCs, and platelets in CML?
Decrease in RBCs, increase in WBCs and platelets
What myeloproliferative disorder is associated with the Philadelphia chromosome?
chronic myelogenous leukemia (CML)
What myeloproliferative disorders are associated with the JAK2 mutation?
Polycythemia vera (always), essential thrombocytosis (30-50%), myelofibrosis (30-50%)
What is the basic pathophysiology of polycythemia vera?
Abnormal clone of stem cells are sensitive to growth factors due to the JAK2 mutation
What precursor is particularly sensitive to growth factors in essential thrombocytosis?
megakaryocytes (precursor of platelets)
What pathological finding is found in myelofibrosis?
Fibrotic obliteration of bone marrow (may see dacrocytes in peripheral blood smear)
What is the role of bcr-abl in CML?
Leads to increased cell division and inhibition of apoptosis
What is the role of JAK2 mutation in myeloproliferative disorders?
It is involved in hematopoietic growth factor signaling
What is the mechanism by which heparin anticoagulates?
It catalyzes the activation of antithrombin III and reduces thrombin and factor Xa
Name a positively charged molecule that binds negatively charged heparin and can be used for the rapid reversal of heparin anticoagulation.
protamine sulfate
Compare enoxaparin and heparin.
Enoxaparin is more specific for factor Xa, has higher bioavailability, and 2-4 times longer half-life- it can be given subQ and does not require lab mornitoring
True or False: Enoxaparin, which is a low-molecular-weight heparin, is easily reversible.
False; enoxaparin is not easily reversible (it is not as big HMH-so there is not as much of a negative charge for the protamine sulfate to bind to)
What are some benefits with respect to administration of enoxaparin?
Can be administered subcutaneously and does not need monitoring (also less risk of HIT)
Name four toxicities of heparin.
bleeding, thrombocytopenia (HIT), osteoporosis, and drug-drug interactions
True or False: The use of heparin is contraindicated during pregnancy.
False; heparin does not cross the placenta and thus can be used during pregnancy (warfarin in contraindicated)
True or False: The impact of heparin therapy can be monitored by following a patient's partial thromboplastin time.
true
What is heparin-induced thrombocytopenia?
A disease that occurs when heparin binds platelets, causing autoantibody production that destroys platelets and over-activates the remaining ones, resulting in a thrombocytopenic, hypercoagulable state
A 70-year-old woman is given prophylactic heparin while hospitalized for pneumonia. Five days later she develops deep vein thromboses. What disease is the likely cause of her sudden thrombocytopenic, hypercoagulable state?
heparin induced thrombocytopenia
What are the clinical uses for heparin?
Immediate anticoagulation for pulmonary embolism, stroke, acute coronary syndrome, MI, DVT
Lepirudin and bivalirudin are _____ derivatives that directly inhibit _____ and used as an alternative to _____.
hirudin; thrombin; heparin (use these if HIT develops)
What is the clinical indication for lepirudin or bivalirudin use?
Used as an alternative to heparin for anticoagulating patients with HIT
What is the mechanism by which warfarin anticoagulates?
It interferes with normal synthesis and the gamma-carboxylation of the vitamin K-dependent clotting factors II, VII, IX, and X and proteins C and S
What are the vitamin K-dependent clotting factors that are affected by warfarin?
Factors II, VII, IX, and X and proteins C and S
True or False: The primary impact of warfarin on the clotting cascade is on the intrinsic pathway by increasing partial thromboplastin time.
False; its primary impact on the clotting cascade is on the extrinsic pathway by increasing prothrombin time
What is the therapy of choice for patients who require chronic anticoagulation: heparin or warfarin?
warfarin
Name four toxicities of warfarin.
bleeding, skin/tissue necrosis, drug-drug interactions, teratogenic
True or False: The use of warfarin is contraindicated during pregnancy.
true- warfarin crosses the placenta- use heparin instead, which does not cross the placenta
How is warfarin metabolized?
by the CYP-450 pathway
_____ (Heparin/Warfarin) is a large, acidic, anionic polymer structure, whereas _____ (heparin/warfarin) is a small, lipid-soluble molecule.
heparin; warfarin
_____ (Heparin/Warfarin) is administered orally, whereas _____ (heparin/warfarin) is administered parenterally (intravenously or subcutaneously).
warfarin; heparin
The site of action of _____ (heparin/warfarin) is the blood, whereas the site of action of _____ (heparin/warfarin) is the liver.
heparin; warfarin
The onset of action of _____ (heparin/warfarin) is rapid (seconds), whereas the onset of _____ (heparin/warfarin) is slow and limited by the half-lives of normal clotting factors.
heparin; warfarin
_____ (Heparin/warfarin) inhibits coagulation in vitro, whereas _____ (heparin/warfarin) does not.
heparin; warfarin
Describe the treatment of acute warfarin overdose.
IV vitamin K and fresh frozen plasma (which has the clotting factors in it that have had their production impaired by warfarin--II, VII, IX, and X)
_____ (Heparin/warfarin) crosses the placenta and is teratogenic, whereas _____ (heparin/warfarin) does not and thus can be used during pregnancy.
warfarin; heparin
What is the treatment of acute heparin overdose?
protamine sulfate
How is the effect of heparin monitored?
aPTT (prolonged partial thromboplastin time indicated therapeutic heparin levels)
How is the effect of warfarin monitored?
Prolonged PT/INR indicates therapeutic warfarin levels
(goal is for INR to be between 2 and 3)
Streptokinase, urokinase, tissue plasminogen activator, and anisoylated plasminogen streptokinase activator complex are examples of what type of drugs?
thrombolytics
What is the primary mechanism of action of thrombolytics?
They directly or indirectly aid the conversion of plasminogen to plasmin, which is the major fibrinolytic enzyme that cleaves thrombin and fibrin clots
What are the clinical uses of thrombolytics?
Early MI, early ischemic stroke
What is the primary toxicity of thrombolytics?
bleeding
Name five contraindications for thrombolytics that are related to increased risk of bleeding.
Patients with active bleeding, a history of intracranial bleeding, recent surgery, known bleeding disorders, or severe hypertension
What is the pharmacologic treatment for thrombolytic toxicity?
aminocaproic acid; inhibitor of fibrinolysis
What is the mechanism for tissue plasminogen activator and urokinase?
They are thrombolytics that directly accelerate the cleavage of plasminogen to plasmin
What effect do thrombolytics have on prothrombin time: increase, decrease, or no change?
increased
What effect do thrombolytics have on partial tromboplastin time: increase, decrease, or no change?
increased
What effect do thrombolytics have on the platelet count: increase, decrease, or no change?
no change
How does abciximab downregulate platelet aggregation?
Abciximab is a monoclonal antibody that binds to the glycoprotein receptor IIb/IIIa on activated platelets, thereby preventing aggregation (so that fibrinogen cannot form a bridge between platelets)
On platelets, what binds to the glycoprotein receptor IIb/IIIa, which facilitates aggregation?
fibrinogen
What factor binds to the glycoprotein receptor Ib on platelets, which facilitates binding to collagen exposed by breaks in endothelium?
von Willebrand factor
When vascular injury occurs, what endothelial substance becomes exposed and binds to the glycoprotein receptor Ia on platelets, which promotes adhesion and aggregation? (This substance also binds von Willebrand factor.)
collagen- may also include other extracellular matrix products (subendothelial collagen is exposed)
Activated platelets release what two granule products that promote adhesion and aggregation? (The action of these products is inhibited by aspirin and clopidogrel.)
thromboxane A2 (TxA2) and adenosine diphosphate (ADP)
In addition to thromboxane A2 and adenosine diphosphate, activated platelets release what two vasoactive amines that are important in the inflammatory process?
5-Hydroxytryptamine (serotonin) and histamine
What is the mechanism of action of aspirin as an anticoagulant?
Aspirin acetylates and irreversibly inhibits cyclooxygenase-1 and cyclooxygenase-2 to prevent the conversion of arachidonic acid to thromboxane A2 (thus preventing platelet aggregation and vasoconstriction mediated by TXA2)
What is the effect of aspirin on bleeding time, prothrombin time, and partial thromboplastin time?
increased bleeding time, NO effect on PTT, or PT
Name five common toxicities of aspirin.
gastric ulceration, bleeding, hyperventilation, Reye's syndrome, and tinnitus (CNVIII)
True or False: Aspirin's action on cyclooxygenase is irreversible.
true (for the life of the platelet--10 days-- must stop aspirin 10 days before surgery)
Name four clinical uses for aspirin.
antipyretic, anti-inflammatory, analgesic, and anti-platelet
What is the mechanism of antiplatelet action for clopidogrel and ticlopidine?
They inhibit platelet aggregation by irreversibly blocking adenosine diphosphate receptors, and they inhibit fibrinogen binding by preventing glycoprotein IIb/IIIa expression (since ADP causes their expression)
What is a severe toxicity of the antiplatelet drug ticlopidine?
neutropenia
What are three common clinical uses of clopidogrel and ticlopidine?
Acute coronary syndrome, coronary stenting, and reducing the incidence or recurrence of thrombotic stroke
What antiplatelet drugs act by blocking adenosine diphosphate receptors and preventing glycoprotein IIb/IIIa expression?
clopidogrel and ticlopidine
Clopidogrel inhibits the binding of what substance by preventing the expression of glycoprotein IIb/IIIa?
fibrinogen
Name a monoclonal antibody that binds the glycoprotein IIb/IIIa receptor on activated platelets and that prevents aggregation.
abciximab
What are clinical uses of abciximab?
Acute coronary syndromes, percutaneous transluminal coronary angioplasty
Name the two most common toxicities of abciximab.
bleeding and thrombocytopenia
What antineoplastic drugs affect nucleotide synthesis?
1. alkylating agents, cyclophosphamide and cisplatin
by cross-linking DNA
2. Dactinomycin and Doxorubicin by intercalating DNA
3. Etoposide buy inhibiting topoisomerase II (cuts DNA in order to unwind it)
How do alkylating agents and cisplatin work?
Cross-link DNA
What antineoplastic drugs intercalate DNA?
dactinomycin and doxorubicin (adriamycin)
How does etoposide work?
inhibits topoisomerase II
What antineoplastic drugs work by inhibiting cellular division?
vinca alkyloids and paclitaxel
How do vinca alkaloids work?
inhibit microtubule formation
How does paclitaxel work?
inhibits microtubule disassembly
What occurs during stage G0 of the cell cycle?
resting, cell is quiescent/not dividing
What occurs during stage G1 of the cell cycle?
The synthesis of components that are needed for DNA synthesis
What occurs during stage S of the cell cycle?
DNA synthesis
What occurs during stage G2 of the cell cycle?
The synthesis of components that are needed for mitosis
What occurs during stage M of the cell cycle?
mitosis--cell division
During what stage of the cell cycle does the synthesis of the components needed for DNA synthesis occur?
G1
During what stage of the cell cycle does DNA synthesis occur?
S
During what stage of the cell cycle does the synthesis of the components needed for mitosis occur?
G2
During what stage of the cell cycle does quiescence (resting) occur?
G0
During what stage of the cell cycle do the vinca alkaloids and taxols work?
mitosis (M)
During what stage of the cell cycle do the antimetabolites work?
S (synthesis)
During what stages of the cell cycle does etoposide work?
S and G2
During what stage of the cell cycle does bleomycin work?
G2
What is the mechanism of action of methotrexate?
It is a folic acid analog that inhibits dihydrofolate reductase, thereby decreasing thymidine synthesis and thus DNA and protein synthesis
What drug can be used to reverse the myelosuppression caused by methotrexate toxicity?
leucovorin (folinic acid)
Name toxicities of methotrexate.
myelosuppression, teratogen, macrovesicular fatty liver, mucositis
Which cancers can be treated with methotrexate?
leukemia, lymphoma, choriocarcinoma, sarcoma
What are non-oncologic uses of methotrexate?
abortions, ectopic pregnancy, rheumatoid arthritis, and psoriasis
What S-phase-specific antimetabolite is a pyrimidine analog that covalently complexes folic acid and inhibits thymidylate synthase?
5-fluorouracil
5-Fluorouracil works by inhibiting thymidylate synthase, thereby resulting in decreased deoxythymidine monophosphate and thus decreased _____ synthesis, which leads to decreased _____ synthesis.
DNA; protein
True or False: Leucovorin can reverse the myelosuppression caused by both methotrexate and by 5-fluorouracil.
False; leucovorin can reverse the myelosuppression caused by methotrexate but not that caused by 5-fluorouracil
Name two toxicities of 5-fluorouracil.
myelosuppression and photosensitivity
True or False: 5-Fluorouracil is often used synergistically in combination with methotrexate.
true
What cancers can be treated with 5-FU?
colon cancer another solid tumors, basal cell carcinoma (topical)
What is a treatment for 5-FU toxicity?
thymidine (leucovorin does NOT work)
What is the mechanism of action of 6-mercaptopurine?
purine analog that Blocks de novo purine synthesis
6-Mercaptopurine works by blocking de novo ______ synthesis and is activated by _____-_____ _______.
purine; hypoxanthine-guanine phophoribotransferase (HGPRTase)
What antimetabolite drug is metabolized by xanthine oxidase and used to treat leukemia and certain lymphomas?
6-mercaptopurine-- which is why you cannot give it with allopurinol which is a xanthine oxidase inhibitor used to treat gout
True or False: 6-Mercaptopurine toxicity is decreased by allopurinol.
False; its toxicity is increased by allopurinol since it inhibits xanthine oxidase which causes more 6-MP to build up
Why is 6-mercaptopurine's toxicity increased with allopurinol?
6-MP is metabolized by xanthine oxidase; allopurinol is a xanthine oxidase inhibitor, thus increasing serum levels of 6-MP
6-Mercaptopurine can be toxic to which three organs (or organ systems) of the body?
bone marrow, GI, liver
What is the mechanism of action of cytarabine?
it inhibits DNA polymerase
What are the three major toxicities of cytarabine?
leukopenia, thrombocytopenia, and megaloblastic anemia (pancytopenia)
What are the clinical uses for cytarabine?
AML, ALL, and high grade non-Hodgkin lymphoma
What is the mechanism of action of cyclophosphamide and ifosfamide?
They are alkylating agents; they covalent cross-link DNA at guanine N-7
True or False: The alkylating agents cyclophosphamide and ifosfamide require bioactivation by the liver.
true
What are the two major toxicities of cyclophosphamide and ifosfamide?
myelosuppression and hemorrhagic cystitis (hematuria)--partially prevented by taking MESNA with it
What can help prevent hemorrhagic cystitis that is associated with cyclophosphamide?
mesna
What are the clinical uses of cyclophosphamide?
Non-hodgkin lymphoma, breast and ovarian cancer- can also be used as an immunosuppressant
Name four examples of nitrosureas.
carmustine, lomustine, semustine, and streptozoxin
What are the clinical uses for nitrosureas?
brain tumors like glioblastoma multiforme
What property of nitrosureas makes them useful in the treatment of brain tumors?
crosses the blood brain barrier
What is the mechanism of action of nitrosureas?
DNA alkylation
What is the major toxicity of nitrosoureas?
Central nervous system toxicity (eg, dizziness, ataxia)
What are the clinical uses of dactinomycin?
Wilm's tumor, Ewing's sarcoma, rhabdomyosarcoma (remember: ACTinomycin D is used for childhood tumors; children ACT out)
What is the major toxicity of dactinomycin (actinomycin D)?
myelosuppression
True or False: Dactinomycin (actinomycin D) works by blocking de novo purine synthesis.
False; dactinomycin (actinomycin D) intercalates DNA
Name the two major toxicities of bleomycin.
pulmonary fibrosis and skin changes (minimal myelosuppression)
True or False: A major toxicity of bleomycin is myelosuppression.
False; bleomycin causes minimal myelosuppression
Name two clinical uses for bleomycin.
testicular cancer and Hodgkin lymphoma (part of ABVD treatment)
What is the mechanism of action of bleomycin?
Induces formation of free radicals, which cause breaks in DNA strands
What two cancer drugs generate free radicals and noncovalently intercalate in DNA as their primary mechanism of action?
Doxorubicin (Adriamycin) and daunorubicin
What are adverse effects of doxorubicin (Adriamycin) and daunorubicin?
Cardiotoxicity, myelosuppression, marked alopecia, and toxic extravasation
What are the clinical uses of doxorubicin (Adriamycin) and daunorubicin?
Part of the ABVD regimen for Hodgkin's lymphoma, myelomas, sarcomas, solid tumors of lung, ovary, and breast
What is the mechanism of doxorubicin (adriamycin) and daunorubicin?
intercalates in DNA-->creates breaks in DNA--> dec replication
Name a late S to G2-phase-specific cancer drug that inhibits topoisomerase II and increases DNA degradation.
etoposide
Name three toxicities of etoposide.
Myelosuppression, GI irritation, and alopecia
Name three clinical uses for etoposide.
small cell carcinomas of the lung, testicular carcinoma and prostate carcinoma
What are the names of the two M-phase-specific alkaloids that bind to tubulin and block the polymerization of microtubules so that mitotic spindles cannot form?
Vincristine and vinblastine (remember the mnemonic: "Microtubules are the vines of your cells")
True or False: Etoposide is an M-phase-specific alkaloid that binds to tubulin and blocks the polymerization of microtubules so that mitotic spindles cannot form.
False; this is the mechanism of vincristine and vinblastine; etoposide is a S to G2-phase-specific agent that inhibits topoisomerase II and that increases DNA degradation
What are the clinical uses of vincristine and vinblastine?
Hodgkin lymphoma, Wilm's tumor, and choriocarcinoma
Name two toxicities of vincristine.
Neurotoxicity (areflexia, peripheral neuritis) and paralytic ileus
Name a toxicity of vinblastine.
Bone marrow suppression (remember: vinBLASTine BLASTs Bone marrow [suppression])
What is the mechanism of action for busulfan?
it alkylates DNA
What is busulfan used to treat?
CML and it is uses for ablation of bone marrow prior to a hematopoetic stem cell transplant
Name two major toxicities of busulfan.
pulmonary fibrosis and hyperpigmentation
Name two major toxicities of busulfan.
Used to ablate host bone marrow
What is the name of the M-phase-specific agent that binds to tubulin and that hyperstabilizes polymerized microtubules so that mitotic spindles cannot break down (ie, so that anaphase cannot occur)?
PacliTAXel (and other TAXols)- remember it is TAXing to stay polymerized
What phase of the cell cycle is inhibited by the taxols?
anaphase (microtubule structure cannot disassemble)
Name two clinical uses for paclitaxel.
breast and ovarian cancer (remember it is TAXing to be a woman)
Name two toxicities of paclitaxel and the other taxols.
myelosuppression and hypersensitivity
What is the mechanism of action of cisplatin and carboplatin?
Cross-link DNA
What are the clinical uses of cisplatin and carboplatin?
bladder, ovary, testicle, and lung carcinomas
Name two major toxicities of cisplatin and carboplatin.
nephrotoxicity and acoustic nerve damage
Which drug inhibits ribonucleotide reductase, acting during the S phase to decrease DNA synthesis?
hydroxyurea
What are the three clinical uses for hydroxyurea?
CML, melanoma, sickle cell disease (increases HbF- alpha 2, gamma 2)
Name two toxicities of hydroxyurea.
bone marrow suppression and GI upset
What is the most commonly used glucocorticoid in cancer chemotherapy?
prednisone
What cancers have prednisone as part of their treatment regimen?
hodgkin lymphoma (MOPP regimen), and CLL
True or False: One of the proposed mechanisms for prednisone is that it triggers cell apoptosis; it may even work on nondividing cells.
true
True or False: In addition to being an anticancer drug, prednisone is an immunosuppressant used to treat autoimmune diseases.
true
Name toxicities of prednisone.
cushing-like symptoms: osteoporosis, hyperglycemia, peptic ulcers, acne, cataracts, psychosis, hypertension, immunosuppression
Name two selective estrogen receptor modulator that are used to treat breast cancer and to prevent osteoporosis.
tamoxifen and raloxifene
What is the primary mechanism of action of tamoxifen and raloxifene?
They are selective estrogen receptor modulators that block binding of estrogen to estrogen-receptor-positive cells
True or False: Tamoxifen may decrease the risk of endometrial carcinoma via partial agonist effects.
False; tamoxifen increases this risk
Tamoxifen and raloxifene are receptor-_____ (agonists/antagonists) in breast whereas they are receptor-_____ (agonists/antagonists) on bone.
antagonists; agonists in the bone (thus may prevent osteoporosis)
What is a toxicity of tamoxifen?
Hot flashes; induce a pseudo-menopausal state
also tamoxifen may increase the risk of endometrial carcinoma via partial agonist affect (raloxifene does NOT carry this risk as it is an antagonist at the endometrial level)
What are the clinical uses of SERMs?
breast cancer (in estrogen receptor-positive tumors) and prevention of osteoporosis
What is the name of the monoclonal antibody against HER-2 (erb-B2)?
trastuzamab (herceptin)
What is the clinical use of trastuzumab (Herceptin)?
metastatic breast cancer
What is the proposed mechanism of action of herceptin?
Helps kills breast cancer cells that overexpress HER-2, possibly through antibody-dependent cytotoxicity
What is the major toxicity of trastuzumab (Herceptin)?
cardiotoxicity
Name the monoclonal antibody that is used against the Philadelphia chromosome bcr-abl tyrosine kinase.
imantinib (gleevac)
What are the clinical uses for imatinib (Gleevec)?
chronic myelogenous leukemia and GI stromal tumors
What is the major toxicity of imatinib (Gleevec)?
fluid retention