Hematology/Oncology Flashcards
B12 deficiency may present with a ________ anemia and ___________ (finding). The most common cause of B12 deficiency is ________, which may be confirmed with a ___________.
macrocytic; peripheral neuropathy
Pernicious anemia; positive intrinsic factor antibody
Iron deficiency is a common cause of _________ anemia. Although usually a benign condition in premenopausal women, it may be related to _________ in men and postmenopausal women.
microcytic
occult GI malignancy
Approach to anemia: 1st 2 steps
1 reticulocyte count (RC) (hi = Red cell destruction and blood loss; low = decreased RBC production)
2 if low RC, measure MCV - Microcytosis: MCV 100 µm3.
Low RC, microcytic anemia DDx (4)
Iron deficiency
Thalassemia
Anemia of chronic disease
Sideroblastic anemia (usually hereditary)
Low RC, macrocytic anemia DDx (8)
B12 (cobalamin) deficiency Folate deficiency Alcohol abuse Liver disease Myelodysplastic syndrome Hypothyroidism, severe Sideroblastic anemia (acquired) Drug effects
Low RC, normocytic anemia DDx (6)
Anemia of chronic disease Anemia of renal failure Aplastic anemia Multiple myeloma Myelophthisis Hypothyroidism
Anemia of chronic disease (ACD) is caused by ________ (2). The three major categories of disease associated with ACD are _________.
iron trapping in the reticuloendothelial system and suppression of erythropoiesis, perhaps mediated by cytokines such as interleukin-1
infection, malignancy, and inflammatory disease (e.g., rheumatoid arthritis)
The characteristic feature of sideroblastic anemia is the presence of ____________, which represents abnormal iron accumulation in the mitochondria.
ringed sideroblasts in the bone marrow
Myelodysplastic syndrome (MDS) is a stem cell disorder characterized by _____________, usually presenting as _________. It occurs most often in the elderly.
an arrest in maturation of all blood cells
a pancytopenia
Myelophthisis refers to __________, usually leading to _________.
It may be secondary to _________ (3).
extensive marrow infiltration that inhibits bone marrow function
a pancytopenia
metastatic carcinoma, leukemia, or chronic infection (e.g., tuberculosis).
Thalassemia is an inherited defect in _________ gene. Mutations result in lack of, or decreased production of, a globin chain. Lack of ___ of the two β genes or ______ of the four α genes leads to ________, usually an asymptomatic microcytic anemia.
either the α-or the β-globin
One, two
the thalassemia trait
Findings seen in marked iron deficiency anemia include: (3)
Atrophic glossitis
Angular cheilitis (scaling at corners of mouth)
Koilonychia (spoon nails)
- Formula for corrected RC
- cutoffs for decreased RBC production vs. hemolysis or blood loss.
Corrected RC = RC × (Patient’s Hematocrit ÷ Expected Hematocrit)
A corrected RC of ≤2% = decreased RBC production; >3% = hemolysis or blood loss.
An anemia that has a dimorphic population has a high ________ (measured value); this can help to distinguishing which two common types of microcytic anemia?
RDW
iron deficiency anemia (high RDW) and thalassemia (low RDW)
Megaloblastic anemia findings on peripheral smear (2)
Hypersegmented PMNs
Ovalocytes
Target cells on peripheral smear are assoc with (3):
Liver disease, thalassemia, hemolysis
Bilobed PMNs on periph smear are assoc with (1):
Myelodysplastic syndrome
Teardrop cells on periph smear are assoc with (1):
Myelophthisis
Schistocytes on periph smear are assoc with (1)
Microangiopathic hemolytic anemia
An elevated RBC count in the presence of a microcytic anemia is suggestive of _________.
thalassemia
All pure microcytic anemias are associated with a low ______ (1) and the most useful initial tests are ___________ (1).
RC
Iron studies
_________ may be elevated with inflammation, so a normal _______ level does not rule out iron deficiency in the presence of chronic disease. However, iron deficiency is extremely uncommon when the ________ level is >150 µg per L. (All the same answer)
Ferritin
Macrocytic anemias are subclassified into those with and without ______________.
impaired deoxyribonucleic acid (DNA) synthesis (megaloblastic anemias = impaired).
Megaloblastic anemias include ________ (3)
B12 deficiency, folate deficiency, and drug effects.
Patients with myelodysplasia often have extremely high ______ levels.
B12
__________ may be elevated in all megaloblastic anemias because of ineffective erythropoiesis.
Lactate dehydrogenase (LDH)
________ is the most common cause of normocytic anemia.
Anemia of chronic disease
Aplastic anemia is characterized by ________(2)
pancytopenia and a zero RC.
The anemia of renal failure may be present in a patient with an estimated glomerular filtration rate (GFR) less than _______.
50
Iron studies: Fe, TIBC, and ferritin levels in each of: Iron deficiency Thalassemia Anemia of chronic disease Sideroblastic anemia
Fe - TIBC - ferritin
Iron deficiency: ↓↑↓
Thalassemia: N N N
Anemia of chronic disease↓↓↑
Sideroblastic anemia ↑ N N/↑
Pernicious anemia is related to the lack of ________ (1)
intrinsic factor (IF)
Syndrome where bacterial overgrowth reduces the B12 available for absorption?
blind intestinal loop syndrome
Schilling test: results which indicate 4 different etiologies
Able to Absorb B12 After Oral Administration of:
- B12 only = Inadequate diet
- B12 and intrinsic factor = Pernicious anemia
- B12 after administration of antibiotics = Blind loop syndrome
- Failure to absorb B12 in all of above tests = malabsorption/ileal disease (eg Crohn’s)
Indications for bone marrow biopsy to determine etiology of anemia: (3)
Pancytopenia (suggesting aplastic anemia or marrow infiltration)
Macrocytic anemia of unknown etiology (to rule out myelodysplasia)
Findings suggestive of sideroblastic anemia or myelophthisis
Hemolysis may be caused by extraerythrocytic factors (usually _________) or intrinsic defects in the RBC (often _______). (Acquired or inherited)
Acquired, inherited
Intravascular hemolysis results in release of hemoglobin, which is quickly bound to the serum protein _________. Next, the hemoglobin-_________ complex is cleared by the reticuloendothelial (RE) system, and the ________ level rapidly falls to low or undetectable levels. Once intravascular hemoglobin overloads the __________ capacity, it is filtered by the kidney and reabsorbed in the proximal tubule. (All the same answer)
These tubular cells are sloughed off into the urine and are detected as urine _________. Finally, when proximal tubular reabsorption is overwhelmed (only in severe hemolysis), _________ can be detected. This is suggested by a positive occult blood reading on urine dipstick, but no ______ are seen on urinalysis.
haptoglobin
hemosiderin
hemoglobinuria
RBCs
Extravascular space (organs) where extravascular hemolysis may occur (2)
Spleen, liver
In extravascular hemolysis, RBCs are removed by the ________ and ____________; therefore, little hemoglobin is released into the bloodstream. Haptoglobin may be ______, and urine hemosiderin and hemoglobinuria are usually ________. (Hi/lo)
Spleen and reticuloendothelial system
Low; not present
Microangiopathic hemolytic anemia (MAHA) DDx (4)
Intravascular; Extraerythrocytic Factors
Disseminated intravascular coagulation (DIC)
Hemolytic uremic syndrome (HUS)
Thrombotic thrombocytopenic purpura (TTP)
Cardiac valve hemolysis
Immune-Mediated Hemolytic Anemia DDx (2 groups)
Extraerythrocytic Factors
Warm antibody (hematologic malignancy, connective tissue disorders, drugs) (extravascular) Cold antibody (lymphoma, mycoplasma, mononucleosis) (intravascular)
Infections causing hemolytic anemia DDx (3)
Extraerythrocytic Factors; Intravascular & Extravascular
Malaria
Babesiosis
Clostridial toxin
Hemolytic anemia assoc with splenomegaly (2)
Extraerythrocytic Factors; Extravascular
Infiltrative diseases
Portal hypertension
DDx Hemolytic anemia due to RBC defects: Hemoglobinopathies (1), Enzyme Defects (2), membrane defects (2)
Hemoglobinopathies (Extravascular)
Sickle cell disease
Enzyme Defects (Intravascular) Pyruvate kinase deficiency Glucose-6-phosphate dehydrogenase (G6PD) deficiency
Membrane Defects
Hereditary spherocytosis and elliptocytosis (extravascular)
Paroxysmal nocturnal hemoglobinuria (intravascular)
Sickle cell disease:
- pattern of inheritance?
- A mutation in the ______ hemoglobin chain results in production of hemoglobin ___, which polymerizes in the deoxygenated state and causes red cells to form sickle-shaped cells. This leads to vaso-occlusion in the microvasculature, which causes pain and organ dysfunction.
AR
Beta; S;
G6PD deficiency:
- pattern of inheritance
- G6PD is the enzyme responsible for generation of _______ in the red blood cell, which protects against oxidative stress. Loss of this enzyme leads to oxidation of hemoglobin and hemolysis.
X-linked trait
NADPH
Paroxysmal nocturnal hemoglobinuria (PNH)
- due to Extraerythrocytic Factors or RBC defect?
- acquired or inherited?
- affects which cells?
- Which Gene is mutated?
- result of mutation - why does hemolysis occur?
RBC defect Acquired Stem cell disorder PIG-A Mutation results in lack of a glycosylphosphatidylinositol (GPI) anchor in RBCs, and Lack of certain GPI dependent receptors leads to an increased sensitivity to complement-mediated hemolysis.
Certain drugs are associated with warm-antibody hemolytic anemia: (4)
Methyldopa
Quinine
Sulfonamides
Penicillin
________ often precedes the hemolysis in G6PD deficiency and can be due to __________ (3).
An oxidative stress
infection, ingestion of fava beans, or certain drugs (Sulfonamides, Nitrofurantoin, Methylene blue, Dapsone, Primaquine)
Hemolytic anemia assoc with fever suggests which etiologies? (2)
Presence of an infectious or microangiopathic etiology
The key laboratory features of hemolysis include: (5)
Elevated indirect bilirubin Elevated lactate dehydrogenase (LDH) Increased reticulocyte count Decreased haptoglobin Urine hemosiderin may be present (especially with intravascular hemolysis).
Elevated LDH and indirect bilirubin may be seen in patients with ineffective hematopoiesis (e.g., B12 deficiency) and in hemolytic anemia. What other test tells these two apart?
The reticulocyte count is low in patients with ineffective hematopoiesis
Hemolytic anemia with schistocytes on smear (more than 5 per HPF) indicate which group of pathologies? What other lab finding is most prominent within this group compared to other groups?
Microangiopathic hemolytic anemia (MAHA) - Causes include DIC, HUS, and TTP.
Thrombocytopenia
How to tell Disseminated intravascular coagulation (DIC), Hemolytic uremic syndrome (HUS), and Thrombotic thrombocytopenic purpura (TTP) apart on labs?
PT is elevated in DIC but is normal in TTP and HUS. Renal failure is an important feature of HUS but is also seen in other microangiopathic etiologies.
RBC hemolysis usually results in which cell morphologies? (2)
However, a large number of one of these morphologies is related to two specific pathologies - what are they?
Target cells and spherocytes.
However, large numbers of spherocytes are limited to hereditary spherocytosis and warm-antibody hemolysis.
Elliptocytes (RBC morphology) are seen in ______ (2).
hereditary elliptocytosis and severe iron deficiency
DDX for Intracellular parasites in RBC seen on smear (2)
Malaria
Babesiosis
Once examination of the smear eliminates _________ (3), a Coombs test should be performed.
- indirect vs direct Coombs test?
MAHA, intraerythrocytic infections, and sickle cell
An indirect Coombs’ test looks for an antibody in the patient’s serum that can agglutinate normal RBCs. A direct Coombs’ test is the definitive test for immune-mediated hemolysis, searching for the presence of the antibody directly on the patient’s own RBCs.
A direct Coombs’ test may be further classified by the type of antibody associated with the hemolysis. Most warm-antibody hemolysis is mediated by ______, and therefore _______ will be detected on the RBC surface. Cold-antibody hemolysis is mostly ______ mediated, and therefore ______ will be detected on the cell surface.
IgG; IgG and C3
IgM; only C3 (IgM binds to the RBC and fixes complement at lower temperatures but then dissociates from the RBC)
Test (1) used for Dx in each of the following cases:
- membrane defects (eg hereditary spherocytosis)
- Paroxysmal nocturnal hemoglobinuria (PNH)
- G6PD deficiency
- Sickle cell disease
- Osmotic fragility test (abnormal cells lyse more easily)
- flow cytometry to detect cells deficient in the GPI anchor protein.
- fluorescent spot test, which measures generation of the reduced form of NADPH
- hemoglobin electrophoresis, which demonstrates hemoglobin S.
Drug that may cause a pseudolymphoma syndrome
phenytoin (Dilantin)
DDx adenopathy plus each of the following assoc Sx:
Weight loss, night sweats (3)
Sore throat (2)
Genital lesion (2)
Pets, especially cats (2)
History of travel to the southwestern United States (1) or the midwestern United States (1)
History of IV drug use or high-risk sexual behavior (1)
Weight loss, night sweats (lymphoma, metastatic cancer, tuberculosis)
Sore throat (mononucleosis, pharyngitis)
Genital lesion (syphilis, chancroid)
Pets, especially cats (cat-scratch disease, toxoplasmosis)
History of travel to the southwestern United States (coccidioidomycosis) or the midwestern United States (histoplasmosis)
History of IV drug use or high-risk sexual behavior (HIV)
Skin lesion and pattern of adenopathy that is highly suggestive of sarcoidosis
Erythema nodosum (tender, red subcutaneous nodules) with hilar adenopathy
Adenopathy plus a maculopapular rash involving palms and soles is seen in ________.
syphilis
Pattern of adenopathy in secondary syphilis
bilateral epitrochlear adenopathy
Pattern of adenopathy in cat scratch disease
Unilateral adenopathy proximal to the cat bite or scratch (usually epitrochlear or axillary)
Location of adenopathy: DDx for each: Generalized (6) Cervical (5) Inguinal (4) Supraclavicular (2) Hilar adenopathy (5) Axillary (1)
Generalized: HIV infection Lymphoma Hypersensitivity reaction (including phenytoin) Systemic lupus erythematosus (SLE) Toxoplasmosis Secondary syphilis
Cervical: Mononucleosis Lymphoma Pharyngitis Toxoplasmosis Sarcoidosis
Inguinal: Syphilis Herpes simplex Lymphogranuloma venereum Chancroid
Supraclavicular:
Mediastinal or pulmonary malignancy (right)
Abdominal malignancy (left)
Hilar adenopathy: Sarcoidosis (bilateral) Lymphoma Tuberculosis Bronchogenic carcinoma (unilateral) Fungal infection (bilateral)
Axillary: breast cancer
- Cervical adenopathy in a young patient is often __________
- characteristic CBC finding
- test for confirming Dx
mononucleosis
Lymphocytosis, with atypical lymphocytes
Heterophile antibody to confirm Dx; may be negative early in the disease
Hilar adenopathy: how to tell sarcoidosis from lymphoma or bronchogenic cancer.
When to investigate hilar adenopathy further?
Patients with hilar adenopathy related to lymphoma or bronchogenic cancer usually have associated symptoms; sarcoidosis is asymptomatic hilar adenopathy.
If the adenopathy is associated with a mass or effusion, it must be investigated further.
Often, adenopathy resolves after a period of observation, making biopsy unnecessary. Early biopsy should be considered when the following features are present: (4)
Lymph node >2 to 3 cm in diameter without findings suggestive of mononucleosis
Adenopathy in association with an abnormal chest radiograph (hilar adenopathy, pulmonary mass or cavity)
Supraclavicular adenopathy (especially in the older patient)
Axillary adenopathy without signs of upper extremity infection (consider breast malignancy in women and lymphoma in both sexes)
Additional tests that may be performed to assist in diagnosis related to adenopathy (if indicated) include: (4)
Purified protein derivative (PPD) skin test for tuberculosis
Toxoplasma titers
HIV antibody testing
Rapid plasma reagin (RPR) to rule out syphilis
Sarcoidosis Bx shows ___________
noncaseating granulomas
Supraclavicular adenopathy may represent malignancy. The left supraclavicular node (Virchow’s node) drains _________ and therefore may be enlarged in _______ (3) cancer.
the abdominal cavity
gastric, colon, or ovarian
The thrombolytic system, in which the fibrin-cleaving protein ________ is a central component, is responsible for remodeling and removing existing fibrin clots.
When is the thrombolytic system activated?
plasmin
The thrombolytic system is activated from the time the coagulation system begins clot formation, providing close regulation of hemostasis.
Clots are composed of ______ (2)
Fibrin and platelets
The most common hemorrhagic disorders in adults are _________ (acquired/hereditary) and include: (3)
Acquired
Vitamin K deficiency/anticoagulant therapy
Coagulopathy associated with liver disease
Disseminated intravascular coagulation (DIC)
Vitamin K deficiency/warfarin Tx leads to decrease of which coagulation factors/regulators? (6)
II, VII, IX, and X and the coagulation regulators protein C and protein S.
Severe liver failure can result in a bleeding tendency because of factor deficiency, but Factor _____, produced by the endothelium, is preserved in liver disease.
VIII
DIC:
- which diseases can trigger? (4)
- mechanism?
- features/findings (3)
- sepsis, trauma/tissue injury, neoplasms, and obstetric catastrophes
- accelerated, unregulated activation of the coagulation cascades. Small thrombi and emboli; eventually leads to depletion of coagulation factors and platelets.
- severe coagulation defect comprised of thrombocytopenia, decreased fibrinogen, and decreased factor levels.
inherited bleeding disorders (2)
von Willebrand disease (vWD) and hemophilia
vWD is the result of a deficiency or defect in von Willebrand factor; what are the roles of this factor? (2)
vW factor is a carrier for factor VIII and a cofactor for platelet adhesion.
Hemophilia: pattern of inheritance? Hemophilia A vs B? How can it affect joints?
X-linked disease caused by the lack of factor VIII (hemophilia A) or factor IX (hemophilia B).
Chronic bleeding into joints, as is seen in hemophilia, can lead to joint deformity.
Which drugs are associated with immune-mediated platelet destruction? (2)
sulfa and beta-lactam antibiotics
Platelet disorders usually manifest as __________ (deep/superficial) bleeding involving which areas of the body? (4)
Disorders involving plasma coagulation factor defects generally manifest as ________ (deep/superficial) bleeding, affecting which areas of the body? (2)
superficial; the skin, mucous membranes, and gastrointestinal (GI) and urinary tracts
deeper; joints and body cavities (e.g., peritoneum).
Typical skin findings (2) and timing of platelet disorder bleeding
Petechiae and small ecchymoses.
Bleeding occurs immediately after trauma because of the inability to form a platelet plug. Bleeding within the oral mucous membranes (wet purpura) is associated with an increased risk of more serious bleeding.
Bleeding disorders: things to look for on phys exam (4)
Skin lesions, timing of bleeding, liver disease, splenomegaly
Timing of coagulation factor defect bleeding
Because platelet function is unaffected, abnormal bleeding does not manifest immediately after trauma but can be delayed hours to days.
Bleeding due to platelet disorder DDx (2 groups)
Abnormal function (uremia, vWD, decreased cyclooxygenase activity related to aspirin or nonsteroidal anti-inflammatory drugs [NSAIDs])
Thrombocytopenia (immune destruction, DIC, splenic sequestration, marrow failure)
Bleeding due to coag factor disorder DDx (5 groups)
Defective factors (hemophilia, dysfibrinogenemia)
Consumption of coagulation factors (DIC)
Vitamin K deficiency (insufficient dietary intake, intestinal malabsorption, chronic liver disease)
Interference with vitamin K activity (warfarin administration)
Interference with activated coagulation factors (heparin administration)
Bleeding due to abnormal activity of fibrinolytic pathway DDx (2 groups)
Exogenous plasminogen activator (tPA or streptokinase administration during acute MI)
Abnormal regulation of fibrinolysis (plasmin inhibitor deficiency)
With normal platelet function, clinical or spontaneous bleeding usually does not occur until the platelet count is <_______ per mm3.
20,000
The aPTT assesses the _______ limb of the coagulation pathway whereas the PT assesses the _________ limb. Which is used to monitor heparin, warfarin?
aPTT=activated partial thromboplasmin time; assesses intrinsic limb (factors VIII, IX, XI, and XII, high molecular weight kininogen and prekallikrein); monitor heparin
(Heparin binds to the enzyme inhibitor antithrombin III (AT), causing its activation and subsequent inactivation of thrombin and other proteases involved in blood clotting, most notably factor Xa.)
PT=prothrombin time=time it takes plasma to clot after addition of tissue factor; converted to INR; monitors extrinsic limb (factor VII and tissue factor-dependent); monitor warfarin
(The speed of the extrinsic pathway is greatly affected by levels of functional factor VII in the body. Factor VII has a short half-life and the carboxylation of its glutamate residues requires vitamin K.)
A possible defect in a coagulation factor that leads to an abnormal PT or PTT can be screened for by using which test? How does it work?
1:1 mixing study: add normal plasma to the patient’s plasma and repeat the PT/PTT; Normalization by the addition of normal serum indicates a factor deficiency, whereas a continued prolongation indicates the presence of a coagulation inhibitor.
DDx for Prolonged PTT only (3)
heparin administration, classic hemophilia (factors VIII or IX deficiency), some cases of vWD
DDx for Prolonged PT only (3)
warfarin administration, vitamin K deficiency, factor VII deficiency (factor with shortest half-life)
Factor ____ has the shortest half-life and therefore is the first to show deficiency in conditions such as liver disease
VII
DDx for Prolonged PTT and PT (6)
factor II, V, and X deficiency, severe vitamin K deficiency, higher dose warfarin administration, severe liver disease, DIC, dysfibrinogenemia
When both PT and aPTT are elevated, the level and function of ________ should be tested. Which test can be used?
fibrinogen Thrombin time (cleavage of fibrinogen to fibrin can be specifically tested by the thrombin time).
When the platelet count, PT, and aPTT are normal, _________ needs to be assessed.
the functional capacity of platelets
Potential causes of platelet dysfunction (2)
Uremia, antiplatelet medications (aspirin, clopidogrel).
Thrombocytopenia: Platelet Count, PT, aPTT, Thrombin Time, Fibrinogen, and Other Features
Platelet Count low PT N aPTT N Thrombin Time N Fibrinogen N Other Features N/A
DIC: Platelet Count, PT, aPTT, Thrombin Time, Fibrinogen, and Other Features
Platelet Count low PT high aPTT high Thrombin Time high Fibrinogen low Other Features: schistocytes on smear
Hemophilia A: Platelet Count, PT, aPTT, Thrombin Time, Fibrinogen, and Other Features
(Factor VIII deficiency) Platelet Count N PT N aPTT high Thrombin Time N Fibrinogen N Other Features: corrected by mixing study
vWD: Platelet Count, PT, aPTT, Thrombin Time, Fibrinogen, and Other Features.
Tests for Dx vWD? (2)
Platelet Count N PT N aPTT N or slightly high Thrombin Time N Fibrinogen N Other Features: abnormal ristocetin cofactor activity
Tests for Dx: measurement of vWF antigen and ristocetin cofactor activity (a functional measure of the ability of vWF to agglutinate platelets). Pts also usually have Hx of bleeding in surgery.
Vit K deficiency (diet, warfarin): Platelet Count, PT, aPTT, Thrombin Time, Fibrinogen, and Other Features
Platelet Count N PT high aPTT N Thrombin Time N Fibrinogen N Other Features: corrected by mixing study
Dysfibrogenemia: Platelet Count, PT, aPTT, Thrombin Time, Fibrinogen, and Other Features
Platelet Count N PT high aPTT high Thrombin Time high Fibrinogen N Other Features N/A
Thrombocytopenia: DDx for increased destruction (3) and decreased production (3)
Increased destruction:
- microangiopathic hemolytic anemias (HUS, TTP, and DIC).
- Idiopathic thrombocytopenic purpura (ITP): autoimmune destruction of platelets; isolated thrombocytopenia, often with platelet counts <20,000 per mm3. Large (i.e., young) platelets are seen on smear, and bone marrow biopsy demonstrates increased megakaryocytes (indicating accelerated destruction of platelets).
- medications (heparin, quinidine)
Decreased production: -Infiltrative bone marrow disorders -acute leukemias -myelodysplastic syndromes (all usually in the context of pancytopenia.)
Tx of bleeding disorder: Supportive care with transfusion of blood products can be initiated except in which cases?
In cases of excess consumption (DIC, TTP, HUS, heparin-induced thrombocytopenia), transfusion should be avoided because it adds “fuel to the fire.”
Fresh-frozen plasma: what does it contain? What are 2 disadvantages?
Fresh-frozen plasma contains all the needed coagulation factors and can be used to rapidly replenish factor deficiencies.
Its short half-life (4 hours) and risk of viral transmission are disadvantages.
Cryoprecipitate contains ___________ (3). It can be used for which 2 diseases/conditions?
vWF, factor VIII, and fibrinogen
vWD or hypofibrinogenemia
________ is specifically used for the Tx of hemophilia A.
Factor VIII concentrate
If a more rapid reversal of warfarin is required because of clinically significant bleeding or the need for immediate surgery, _______ can be administered.
fresh-frozen plasma
Thrombocytopenia or qualitative platelet defects that cause significant hemorrhage can be managed with __________ except in which case?
platelet transfusions; in the case of immune-mediated thrombocytopenia, platelet transfusions are avoided because the platelets are rapidly consumed
Leukemia that’s mainly a disease of children
ALL
Although it can be seen in the blast phase of CML
In an older classfication system, which leukemia was divided into eight subtypes?
AML
M0, M1, M2 are myeloblastic leukemias of varying differentiation, M3 is acute promyelocytic leukemia (APL) with its unique treatment and clinical features, M4 and M5 are monocytic variants, M6 is erythroleukemia, and M7 is megakaryocytic leukemia. Newer classification systems focus on the presence of preceding myelodysplastic syndrome (MDS) and chromosomal abnormalities.
Many cases of AML are preceded by ______, which is often associated with chromosomal abnormalities.
Other exposures related to devel of AML?
Myelodysplastic syndrome (MDS)
Radiation exposure: CML and AML
Chemotherapy: Use of alkylating agents or topoisomerase II inhibitors
Benzene exposure
Agent Orange (an herbicide used in the Vietnam War) has been associated with which leukemia?
Radiation exposure is associated with which 2 leukemias?
CLL
AML and CML
Which chromosomal anomaly is assoc with CML?
Tx of CML?
The Philadelphia chromosome, t(9;22), involves a fusion of the breakpoint cluster (BCR) gene on chromosome 22 with the ABL gene on chromosome 9. The resulting fusion protein is a constitutively activated tyrosine kinase.
Allogeneic SCT is the first-line treatment in young patients (age <40 years) with CML, achieving cure rates of approximately 50%.
Newer: Treat with imatinib mesylate (Gleevec), a specific inhibitor of the BCR-ABL tyrosine kinase.
Which is the most common leukemia in the US?
What is its Tx?
CLL
Benign; generally not treated unless there are complications (e.g., severe cytopenia, bulky adenopathy or organomegaly, severe systemic symptoms).
Standard treatment: fludarabine, a purine analogue, which often results in disease regression, but not a cure. Other options (combination) include an alkylating agent (e.g., chlorambucil, cyclophosphamide) and rituximab.
CLL can transform to a more aggressive disease, at which time the treatment resembles therapy for aggressive lymphoma (Richter transformation). This should be suspected if patient develops B symptoms (fever, night sweats, weight loss) or rapid enlargement of lymph node.
Chromosomal anomaly in acute promyelocytic leukemia (AML type M3)? What is its Tx?
t (15;17), involving the retinoic acid receptor-alpha and the PML genes, resulting in a fusion protein that blocks differentiation.
Administration of all-trans retinoic acid (ATRA) relieves this block and promotes differentiation.
Tx of APL: chemotherapy plus ATRA (remission in ~ 75% of patients, less toxicity). However, treatment produces newly differentiated WBCs that can lead to the retinoic acid syndrome (fever, pulmonary infiltrates, hypoxia) - Tx with corticosteroids.
Anomaly in CLL? Which karyotypes have a poor Px?
CLL = mature B-cell line (CD19+) that also expresses CD5 (usually a T-cell antigen). The cells appear to be resistant to apoptosis, resulting in prolonged life and elevated numbers of leukocytes. Certain karyotypes carry a poor prognosis (17p or 11q deletions).
There is significant overlap between the clinical features (eg painless adenopathy or splenomegaly) and treatment of indolent NHL and which leukemia?
CLL
On physical examination, a patient with leukemia may exhibit: (4)
Ecchymoses, petechiae (related to thrombocytopenia)
Lymphadenopathy, most often with CLL
Splenomegaly, seen in over 90% of CML, as well as hepatomegaly
Gingival hypertrophy (because of infiltration) can be seen in the monocytic (M4,M5) types of AML
Elevated WBC DDx (3)
Leukemia
Leukemoid reaction (may be caused by overwhelming infection or a paraneoplastic syndrome)
Demargination of neutrophils (physiologic stress, corticosteroids)
Examination of the peripheral smear in AML demonstrates _________ (2).
myeloblasts, usually with thrombocytopenia.
Blast cells have prominent nucleoli, large nuclear-to-cytoplasm ratio, and lack of granules.
Smear finding pathognomonic for AML?
An Auer rod, a bluish red rod seen in the blast cell.
In CML, the blood count shows _______. (2)
leukocytosis (sometimes with basophilia) and thrombocytosis.
The leukocytes in CML lack leukocyte alkaline phosphatase (LAP), in contrast to leukemoid reactions that have a high amount of staining for this enzyme.
The blood smear in CLL shows a lymphocyte predominance (>50% lymphocytes, absolute lymphocyte count >5000 per mm3), and the fragile lymphocytes in CLL are called ________.
smear or smudge cells; they are fragile cells and become flattened on the blood smear
Additional processes/pathologies/lab findings in CLL (2), APL (1), and AML (1)
Hemolytic anemia (CLL)
Idiopathic thrombocytopenic purpura (CLL)
Disseminated intravascular coagulation (APL)
Hyperuricemia (AML)
Patients who relapse after treatment for AML have a poor prognosis. A newer treatment for relapsed AML is ________.
gemtuzumab ozogamicin, a monoclonal antibody against CD33 linked to a chemotherapeutic agent. This may beneift up to 30% of patients.
Tx of AML?
Initial induction therapy to induce a complete remission, most commonly with an anthracycline (e.g., daunorubicin) and cytarabine (ara-C). ~70% remission.
Relapse is inevitable in AML, and allogeneic (human lymphocyte antigen-matched relative or unrelated donor) stem cell transplantation (SCT) can be used as consolidation therapy, or it can be performed after the first relapse.
Classic example of an indolent lymphoma, an aggressive lymphoma, and a highly aggressive lymphoma.
T-cell lymphomas, such as cutaneous T-cell lymphoma, account for ______% of the cases of NHL.
Follicular lymphoma (indolent), diffuse large B-cell lymphoma (aggressive), and Burkitt lymphoma (highly aggressive).
Which lymphoma has 2 peaks of incidence (wrt age) and when are they?
HL
the first in the second and third decades of life and another in the sixth.
Which virus has been linked to the development of adult T-cell leukemia/lymphoma?
Epstein-Barr virus (EBV) infection has been closely associated with which lymphomas? (2)
Human T-cell leukemia virus type-1
HL, and the African form of Burkitt lymphoma.
Follicular lymphoma translocation and result?
t(14;18) - leads to the upregulation of the Bcl-2 proto-oncogene, which is an inhibitor of apoptosis.
Mantle cell lymphoma translocation and result?
t(11;14) - results in production of cyclin D1, a protein involved in cell cycle regulation.
Burkitt lymphoma translocation and result?
t(8:14) - activates the c-myc proto-oncogene (a transcriptional activator).
What are the B symptoms?
What are other constitutional Sx present in lymphoma?
What is an unusual symptom in HL?
B symptoms = fever, night sweats, and weight loss.
Other constitutional symptoms, such as malaise, pruritus, and anorexia, may be present.
An unusual symptom seen in some patients with HL is increasing pain in lymph nodes with alcohol ingestion.
Lymphoma presentation and phys exam (node features)?
Pts present with painless lymphadenopathy (axillary, supraclavicular, and cervical nodes) and/or a mass.
On physical examination, lymph nodes are usually firm, freely mobile, and nontender. Splenomegaly may be present.
HL biopsy shows ________.
RS cell, a large cell with a bilobulated nucleus and “owl’s-eye” nucleoli.
Lymphoma staging?
Stage I—single lymph node group or single extranodal site
Stage II—two or more lymph node groups on same side of the diaphragm
Stage III—nodal involvement on both sides of the diaphragm, which may include the spleen (IIIS), a contiguous extra-nodal site (IIIE), or both (IIIES)
Stage IV—disseminated foci of involvement in one or more extralymphatic organs or tissues (such as bone marrow or liver)
The initial treatment of indolent lymphoma?
Resembles that for CLL - because these lymphomas are incurable, most patients are followed expectantly until symptoms or cytopenias appear.
Fludarabine is the first-line treatment, along with rituximab. High grade (grade 3) follicular lymphomas may be curable with systemic chemotherapy.
The standard chemotherapy for aggressive NHL is _______.
CHOP (cyclophosphamide, [hydroxydaunomycin] doxorubicin, vincristine [Oncovin], prednisone), which can be improved by the addition of rituximab (R-CHOP), especially in older patients.
Patients who do not respond to standard chemotherapy may be considered for additional multidrug regimens or SCT.
Tx of HL?
Limited-stage HL was previously treated with radiotherapy alone, but chemotherapy+radiotherapy is used more often now. Standard chemotherapy is ABVD: doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine. Bleomycin can cause long-term pulmonary toxicity, and doxorubicin can cause cardiomyopathy.
Advanced HD is also treated with ABVD. Failure to achieve remission or an early relapse is an indication for autologous stem cell transplantation (SCT).
BRCA1/2 lifetime risk of breast or ovarian ca
50%
Risk factors for breast ca (5)
Early menarche Late menopause Late age of first pregnancy Nulliparity Combination hormone replacement therapy (estrogen and progestin) increases the relative risk of breast cancer an estimated 25% after approximately 5 years. Unopposed estrogen in women with hysterectomies does not appear to confer a similar risk.
Breast mass DDx (4) and nipple discharge DDx (4)
Breast mass: Malignancy Cyst Fibroadenoma Fibrocystic changes
Nipple discharge: Malignancy Ductal papilloma Ductal ectasia Endocrinopathies, such as prolactinoma (especially if discharge is bilateral)
Subtypes of breast ca (ductal carcinoma) with better Px (2)
mucinous, tubular
Breast ca staging
Carcinoma in situ is considered stage 0. Tumors 5 cm are considered stage IIB if lymph nodes are negative. Large tumors with positive nodes, any tumor with fixed lymph nodes, and tumor infiltration into the skin or chest wall are classified as stage III. This includes inflammatory breast cancer, where tumor infiltration into skin lymphatics causes swelling, erythema, warmth, and peau d’orange appearance. Distant metastases (such as bone, lung, or liver) are classified as stage IV. Five-year survival in stage I is >80% but is reduced to 10% to 15% in stage IV breast cancer.
Aromatase inhibitors are used in which patient population?
Postmenopausal breast ca patients with steroid receptor-positive tumors.
Breast ca chemo regimens: which class of drugs is included in newer regimens?
Typical regimens:
cyclophosphamide, methotrexate, 5-FU (CMF);
cyclophosphamide, Adriamycin (doxorubicin), 5-FU (CAF);
and cyclophosphamide and doxorubicin (CA).
Regimens with an anthracycline (e.g., doxorubicin) appear to be superior to those regimens without an anthracycline (like CMF).
Newer regimens incorporate the taxanes; either
cyclophosphamide and doxorubicin (CA), followed by a taxane (paclitaxel or docetaxel),
or a combination treatment (cyclophosphamide, doxorubicin, paclitaxel).
These taxane-based regimens have shown some benefit in cancer-free survival compared to the standard CAF treatment.
Add trasruzumab if Her2 positive.
Prostate ca grading and staging
Gleason score: well differentiated (Gleason 2 to 4), moderately differentiated (Gleason 5 to 6), moderately to poorly differentiated (Gleason 7), and poorly differentiated (8 to 10). This grading system correlates with 15-year mortality from prostate cancer (approximately 6%, 9%, 24%, and 75%, respectively, for well to poorly differentiated adenocarcinoma)
Staging (using the tumor-node-metastasis [TNM] system) is also important in prostate cancer prognosis. Disease confined to the prostate is classified as nonpalpable (T1) or palpable (T2). Locally advanced disease is labeled as T3 or T4. Regional lymph node involvement (N0 or N1) is assessed at time of surgery but may also be suggested by radiologic studies. Metastatic disease (M1) often presents in the vertebral bodies. Bone scanning is recommended in some patients with prostate cancer at time of diagnosis but may be avoided in patients with a PSA <1%).
Drugs used in medical castration in prostate ca (2 classes)
LHRH AGONISTS (goserelin, leuprolide, triptorelin) act to suppress LH release by providing continued stimulation of the LH receptor (delivered by long-acting injections). Initial treatment may cause a “flare” in LH production and should be combined with nonsteroidal antiandrogens (flutamide, bicalutamide, nilutamide) to induce “complete androgen blockade” and to prevent a “flare.”
The most common site of prostate ca mets is:
vertebral body
