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613 Cards in this Set

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Define anemia.
A condition characterized by too few red blood cell or too little hemoglobin.
Define erythrocytosis.
A condition characterized by too many red blood cells.
Define leukocytosis.
A condition describing an abnormally high white blood cell count.
Define leukopenia.
A condition describing an abnormally low white blood cell count.
Define thrombocytosis.
A condition describing an abnormally high platelet count.
Define thrombocytopenia.
A condition describing an abnormally low platelet count.
What is EDTA's use?
Calcium chelator, rarely used to prevent clot formation.
Where is heparin stored?
Mast cells.
Why does heparin not cross the placenta and how is it given?
Heparin is a very large molecule (up to 30kD), so it cannot cross the placenta and is too large to be absorbed in the GI tract. Must be given parenterally.
What is the active ingredient in leech saliva & how does it work?
Hirudin. Directly binds to & inactivates thrombin.
Name the synthetic versions of hirudin.
Refludan, bivalirudin, desirudin, argatroban.
Why might you use a hirudin-based drug?
Patient has HIT-->no more heparin-based usage.
What are the low-MW heparins?
enoxaparin, dalteparin, and tinzaparin.
What is fondaparinux?
A heparin-like drug that acts only on factor Xa. However it is small enough to cross the placenta and cannot be bound by protamine sulfate.
What are the two physiological effects of heparin?
Clotting inhibition and activation of lipoprotein lipases.
How does heparin work?
Heparin binds to antithrombin & increases its ability to bind clotting factors by 1000x.
At low doses, affects mostly factor Xa.
At high doses, affects Xa, IXa, XIa, XIIa, XIIIa.
What does drotrecogin alfa do?
Degrades factors Va and VIIIa.
Also increases activity of plasminogen.
What is drotrecogin alfa used to treat?
Disseminated intravascular coagulation (DIC).
What is warfarin?
Coumadin. Vitamin K analog.
How does coumadin work?
Vitamin K analog that prevents activation of vitamin K. Inhibits synthesis of factors VII, IX, X, and pro-thrombin.
How does aspirin work as an anticoagulant?
Aspirin inhibits cyclooxygenase in platelets. This decreases prostaglandin formation, including thromboxane A2.
What is cilstazol and how does it work?
Cilostazol is a phosphodiesterase inhibitor that decreases platelet aggregation by inhibiting the breakdown of cAMP.
What is dipyridamole?
Dipyridamole is a phosphodiesterase inhibitor that decreases platelet aggregation by inhibiting the breakdown of cAMP.
What are the ADP inhibitors?
ticlopidine, clopidogrel, and prasugrel.
How do the ADP inhibitors work?
They are prodrugs that inhibit the binding of ADP to ADP receptors.
How do the fibrinogen receptr inhibitors work?
Bind to and inhibit fibrinogen receptors, thus preventing platelet aggregation.
What are the low MW heparins?
enoxaparin, dalteparin, tinzaparin.
Why would you use low MW heparins?
Longer half-life.
Causes less osteoporosis & HIT.
OD's cannot be treated as well by protamine sulfate.
What is fondaparinux?
A heparin like drug that acts only on factor Xa. It is small enough to cross the placenta & completely unbound by protamine sulfate.
What is hirudin?
The chemical in leech saliva that acts as an anticoagulant.
What are the synthetic analogs of hirudin?
Lepirudin, bivalirudin, desirubin, and argatroban.
Why would you use a hirudin analog for treatment of thombophilia?
If the patient has HIT.
What is drotrecogin alfa?
Activated protein C.
Used for treating DIC.
Degrades factors Va and VIIIa.
Increases activity of plasminogen.
How does warfarin/coumadin work?
It is a vitamin K analog-->prevents further clot formation but cannot break up clots.
Interferes w/synthesis of factors VII, IX, X and pro-thrombin.
Prevents activation of vitamin K.
What are the toxicities of warfarin?
High potential for drug & diet interactions.
Excessive bleeding can occur.
Can cross the placenta.
How does aspirin function as an anticoagulant?
Aspirin is an irreversible cyclooxygenase inhibitor that decreases prostaglandin formation, including thromboxane A2.
How do phosphodiesterase inhibitors function as anticoagulants?
Decrease platelet aggregation by inhibiting breakdown of cAMP.
What are the phosphodiesterase inhibitors?
cilostazol and dipyridamole
How do the ADP inhibitors function as anticoagulants?
Inhibit ADP binding to receptors.
What are the ADP inhibitors?
ticlopidine and clopidogrel and prasugrel.
What are possible toxicities of ticlopidine?
Neutropenia, agranulocytosis, and thrombocytopenic purpura.
How do the fibrinogen receptor inhibitors function?
Bind to and inhibit fibrinogen receptros to prevent platelet aggregation.
What are the fibrinogen receptor inhibitors particular good at doing?
Preventing white thrombi.
What is a potential toxicity of fibrinogen receptor inhibitors?
thrombocytopenia.
What are the fibrinogen receptor inhibitors?
abciximab, tirofiban, and eptifibatide.
What is eptifibatide?
A cyclic heptapeptide that is a fibrinogen receptor inhibitor.
What is tirofiban?
A non-peptide receptor blocker that is a fibrinogen receptor inhibitor.
What is anagrelide?
A platelet count reducer.
When might you use a thrombolytic agent?
To treat MIs and some types of strokes that are due to a clot rather than a bleed.
What is streptokinase?
A urine plasminogen activator which hydrolyzes fibrin & degrades fibrinogen and factors V and VIII.
What is urokinase?
A urine plasminogen activator which hydrolyzes fibrin & degrades fibrinogen and factors V and VIII.
What are hemostatic agents?
Agents that increase clotting by enhancing platelet formation.
What would you use hemostatic agents for?
In patients with bleeding problems.
What is aminocaproic acid?
A hemostatic agent that functions by inhibiting plasminogen activation by binding to it. May be given orally or by injection.
What is tranexamic acid?
A hemostatic agent that functions by inhibiting plasminogen activation by binding to it. May be given orally or by injection.
What is estrogen?
Acts a hemostatic agent that generally enhances clotting by increasing production of factors I, II, VII ,IX, and X. Also increases plasminogen.
What are the three phases of absorption of B12?
1. Binding of B12 to IF.
2. Transport to distal ileum where the B12-IF is bound in a Ca2+-dep. manner to membranes of microvilli.
3. NRG-dep. interiorization of B12; IF is left on surface where, briefly, it can bind a 2nd load of B12.
How is B12 transported from mucosal cells to body cells?
A transport protein such as transcobalamine II or B binder.
What is transcobalamine I or alpha-binder?
A binder present in serum that probably represents a storage form of B12.
What is the appearance of marrow & blood in megaloblastic anemia?
Very cellular, plasma clearance of Fe is rapid & uptake of Fe by marrow is prompt but incorporation of Fe into new RBCs is slow & incomplete.
What is a characteristic finding in the blood smear of patients w/megaloblastic anemia?
Increase in 5-lobed PMN's.
What changes are observed in the peripheral blood of patients with megaloblastic anemia?
Macrocytic, normochromic (unless Fe deficiency coexists) RBCs.
Hypersegmentated granulcytes.
Leukopenia and/or thrombocytopenia may occur.
What changes are observed in the bone marrow of patients w/megaloblastic anemia?
Megaloblastic erythroid precursors are larger than normal w/immature nuclei for stage of Hb production & a more open chromatin pattern.
Giant metamyelocytes may appear.
What chemical changes in body fluid may be observed in cases of megaloblastic anemia?
Bilirubin: mild increase.
Iron: mold-moderate increase.
LDH: moderate-marked increase.
Muramidase: moderal elevation.
What causes most megaloblastic anemias?
Deficiency of folate or B12.
What is the daily requirement of folate?
50-100micrograms.
How long do the reserves of folate in the body last?
3-4 months.
What is needed to absorb folate?
Conjugase must split glutamates from folic acid to form mono- or diglutamate folic acid.
Where is folic acid absorbed?
Small intestine.
How is folic acid transported w/in the body?
Found in serum in a # of forms including 5,10-MTHF or 5-MTHF.
What are the specific characteristics of folate deficiency?
Low RBCs and serum folate activity.
What is the order of appearance of changes in cases of folate deficiency.
Low serum folate-->hypersegmentation-->low RBC folate-->macroovalocytosis-->megaloblastic marrow-->anemia (19wks.)
What are the causes of folate deficiency?
Dietary deficiency
Malabsorption
Increased requirements for folate.
What is the daily requirement of B12?
2-5 micrograms/day.
How long will the body's stores of B12 last?
2-3years
What is necessary for absorption of B12?
Intrinsic factor.
Describe the prototypic patient with pernicious anemia.
Elderly, Northern European w/gray hair & jaundice.
What is pernicious anemia?
Megaloblastic anemia resulting from gastric atrophy, which results in absolute achlorhydria & lack of IF.
What is a particularly characteristic abnormality of pernicious anemia?
Neurologic disturbances including paresthesia, loss of position & vibratory sensation, irritability, psychosis, change in taste and smell.
What causes "megaloblastic madness"?
Pernicious anemia.
Demyelination of the posterior & lateral columns of the spnail cord.
Why is atrophy of tongue papillae a symptom of pernicious anemia?
Defect in cells which have a rapid turnover rate.
What is required for a dx of pernicious anemia?
Macrocytosis, hypersegmented PMN, megaloblastic alteration of marrow, low serum B12, absence of IF, achlorhydria that cannot be stimulated by histamine, and abnormal Schilling test.
What is the most reliable form of therapy for pernicious anemia?
Parenteral B12. Usually 100mg 1qm.
Describe the Schilling test.
Part I: Administer radiolabelled B12 & chase with large dose of cold B12. Measure amt. of radiolabelled B12 excreted in the urine. Abnormal<6% of dose excreted.
Part II: only done if Part I is abnormal. Radiolabelled B12 is given with IF. Determines if cause of deficiency is due to IF deficiency or another cause.
Describe acquired pernicious anemia.
Most common cause of B12 deficiency. Characterized by atrophic gastritis & histamine-fast achlorhydria. May be autoimmune.
Describe congenital/juvenile pernicious anemia.
Normal gastric mucosa with normal acid secretion but no IF.
Onset<2 years.
NO autoantibodies.
Which is a better measure of folate levels: serum folate or RBC folate.
Serum folate.
How are MMA levels affected by B12 or folate deficiencies?
Increased MMA in the case of cobalamine deficiency. No change in folate deficiency.
How are homocysteine levels affects by B12 or folate deficiencies?
Homocysteine levels increase in both B12 and folate deficient states.
Define leukemia.
A malignant disease arising from unregulated clonal proliferation of hematopoietic stem cells.
What type of leukemia has splenomegaly and hyperuricemia as common symptoms?
Acute lymphoblastic leukemia.
What leukemia more commonly has meningeal infiltration?
ALL.
What particular problem is a common/key feature of acute promyelocytic leukemia?
DIC.
What confirms the diagnosis of acute leukemia?
Blast cells >/= 20% in BM aspiration or biopsy.
What type of leukemia is characterized by Auer rods?
AML.
Which characteristics are more common in myeloid malignancies than lymphoid malignancies?
Older px, preexisting MDS or chemo, leukemia cutis, chloromas, and leukostasis.
Which characteristics are more common in lymphoid malignancies than myeloid malignancies?
Children, lymphadenopathy, spleno/hepatomegaly, CNS involvement, high LDH, high uric acid.
What is M3?
Promyelocytic leukemia (a type of AML)
Is AML more common in adults or children?
Adults.
What antigens are expressed in virtually all types of AML?
CD13 and CD33
What antigen is conspicuously absent from M3/APML?
HLA-DR.
What types of AML is CD14 unique to?
M4 and M5
What is indicated by the presence of CD11b?
M4,M5 AML with monocytic differentiation.
What antigens are seen only with M6 AML?
CD71 and glycophorin.
What antigens are found only in M7 AML?
CD41 and CD61
What are poor prognostic factors for AML?
Older age (>60)
Prior hematologic disorder (egMDS, MPD)
Leukemia caused by prior chemo
Poor initial response to chemo
Poor performance status
ADVERSE CYTOGENETICS
If a young person is in the "favorable/good" risk group for AML, what is the est. 5OS?
60%
If a young person is in the "intermediate" risk group for AML, what is the overall 5y survival rate?
40%
If a young person is in the poor prognositic group for AML, what is their overall survival at 5 yrs?
20%
What are the "favorable" cytogenetic abnormalities for AML?
t(8;21)(q22;q22)
inv(16)(p12q22)/t(16;16)(p13;q22)
t(15;17)(q22;q21)
What are the "intermediate" cytogenetic characteristics for AML?
Normal karyotype.
t(9;11)(p22;q23)
What are "poor" cytogenetic characteristics for AML?
Complex karyotype
11q23 abnormalities
-5
-7
If a old person is in the poor prognositic group for AML, what is their overall survival at 5 yrs?
0%
If a old person is in the "intermediate" risk group for AML, what is the overall 5y survival rate?
20%
If an older person is in the "favorable" group with AML, what is the 5OS?
40%
What is the standard induction regiment for patients with AML?
7+3
7d of continuous ARA-C + 3d of anthracycline
Etoposide may be added for 3 days (7+3+3)
How many patients achieve CR with the 7+3 induction therapy?
70-80%
For which AML patients is high-dose ARA-C indicated as consolidation therapy?
Younger patients, esp those with inv16 and t(18;21)
What is the cause of APL?
translocation (15,17) which fuses the genes for PML and RARA-->disables the RARA gene, causing a stop of maturation of the cells at the level of promyelocyte.
What is used to treat APL?
ATRA (all-trans-retinoic acid) combined with chemotherapy.
What is a possible complication of ATRA therapy?
"Retinoic acid syndrome" which can cause fluid collections and pleural effusions. Treat with dexamethasone.
What is the cure rate for patients with APL treated with ATRA+chemo?
80%+
Define "acute lymphoblastic leukemia."
A progressive & malignant disease of committed lymphopoietic stem cells that originates in lymphoid precursors of marrow, thymus & lymph nodes.
What characterizes ALL?
Presence of immature & abnormal lymphoblasts in the circulating blood & bone marrow.
What is the most common form of leukemia in children <15y?
ALL (80%)
What is the distribution pattern of ALL by age?
Bimodal.
What is a particular common finding in patients with ALL?
Lymphadenopathy, splenomegaly (80%) and hepatomegaly (70%)
What are the three WHO classification groups for ALL?
1. Precursor-B-cell ALL
2. Precursor T-cell ALL
3. Burkitt cell leukemia
What is TdT+ indicative of?
Is a required finding of diagnosis of all types of ALL except Burkitts.
What are two important cytogenetic abnormalities of precursor-B-cell ALL?
t(9;22)(q34;q11)->Bcr-Abl (Philadelphia chromosome)
t( v11q23) MLL rearranged.
What are the three steps in treatment of ALL?
Induction, consolidation, maintenance.
What is a common induction therapy for ALL?
3-5 drugs (prednisone, vincristine, daundorubicin, L-asparaginase, cyclophosphamide)
What is typical maintenance therapy for ALL?
Adults: same drugs as induction therapy in similar or greater intensity.
Children: methotrexate or 6-mercaptopurine.
What is needed in addition to induction chemo in patients w/ALL?
Prophylaxis for CNS leukemia.
What does prophylaxis for CNS leukemia in cases of CLL include?
CNS irradiation, intrathecal methotrexate or high dose systemic & intrathecal methotrexate.
What are the survival rates of ALL?
Children: 80%
Adults: 20-30%
What are favorable prognostic factors for ALL?
Age 3-10 or under 35
WBC<20000/mm3
Hyperdiploidy>50 chromosomes present
t4;11), t(9;22) absent
Free of disease in < 4 wks.
Prolonged initial remission
How much iron is lost by the body daily?
0.6-2.0mg
How much iron is in one ml of packed erythrocytes?
1mg
How much packed erythrocytes are in the human body?
30ml/kg of body weight
What are the two mechanisms through which dietary iron may be absorbed?
1. Ionic iron is absorbed, its absorption is limited to the divalent state. Iron must be split from its complex & reduced in the GI tract.
2. Iron complexed to heme can be taken into the mucosal cell where Fe is split off & transferred to plasma.
Where does iron absorption occur?
Proximal small bowel (duodenum & upper jejunum).
What is transferrin?
The molecule to which iron in plasma is bound. If its iron-binding capacity is exceeded, excess iron is stored in liver parenchymal cells.
What are two commonly used tests to evaluate iron status?
Serum iron and total iron binding capacity (TIBC).
What happens to senescent RBCs?
Removed by reticuloendothelial system where the hemoglobin molecule is broken down & the iron is transferred to transferrin in the plasma.
How do bone marrow normoblasts get iron to incorporate into new cells?
Bone marrow normoblasts have a high affinity for the transferrin-iron complex, which they take up and internalize, remove the Fe from the transferrin & return the transferrin to the plasma.
What is ferritin and what does it do?
Ferritin is a water-soluble molecule consisting of a protein shell (apoferritin) around a core of micelles of a hydrated iron oxide-phosphate complex. This is a storage form for iron!!
What is hemosiderin & what does it do?
Hemosiderin is an insoluble product containing a variety of molecules but always has some ferritin. This is a storage form for iron that is visible via light microscopy as blue staining material.
When is transferrin or serum iron low?
When the RES is depleted of iron or fails to release iron normally.
When is serum iron elevated?
When there is a rapid turnover of iron or when iron is not removed normally from the plasma.
What does serum ferritin correspond to?
Iron stores.
How do you accurately determine the presence/absence of iron in the RES?
Bone Marrow aspirate stained w/prussian blue.
What three things can be measured using ferrokinetics?
1. Plasma iron disappearance
2. Organ distribution of iron
3. Percent incorporation of radiolabelled iron into RBCs.
What is caused by inadequate hemoglobin synthesis by normoblasts?
Hypochromic anemia.
Symptoms include anemia, hypochromia (low MCHC) and microcytosis (low MCV).
What are the causes of hypochromic anemia?
1. Iron deficiency
2. Chronic inflammation or infection
3. Thalassemia
4. Sideroblastic anemia
5. Lead poisoning
What are the laboratory features of iron deficiency anemia?
Serum Fe: low
TIBC: high
RE: 0
Normoblast: 0
Ferritin: low
Abnormal HB: NL
What are the laboratory features of chronic illness-related anemia?
Serum Fe: NL-low
TIBC: low
RE: high
Normoblast: low
Ferritin: high
Minor HB: normal
What are the laboratory features of thalassemia-related anemia?
Serum Fe: normal to high
TIBC: normal
RE: normal to high
Normoblast: increased
Serum Ferritin: increased
Abnormal HB: increased
What are the laboratory features of sideroblastic anemia?
Serum Fe: increased
TIBC: normal
RE: increased
Normoblasts: veryvery increased
Serum ferritin: incrased
HB abn: normal
What are the laboratory features of sideroblastic anemia?
Serum Fe: increased
TIBC: normal
RE: increased
Normoblasts: very increased
Serum ferritin: increased
HB abn: normal
What is the timeline of development of iron deficiency anemia?
Mild, normocytic-normochromic anemia develops before microcytic, hypochromic RBCs.
What is the most common mechanism/cause of iron deficiency anemia?
Chronic blood loss.
What is necessary for a diagnosis of iron deficiency anemia?
Low serum iron w/elevated TIBC, low serum ferritn & absent bone marrow iron stores.
What is the therapy for iron deficiency anemia?
Oral iron, continued for 3-6 months.
What are the 2 mechanisms responsible for anemia of inflammation?
1. Impaired RES release of iron derived from senescent RBCs.
2. Inappropriately reduced erythropoietin response to anemia.
What is require for diagnosis of anemia of chronic inflammation?
Low serum Fe and TIBC, increased bone marrow (RES) iron with decreased numbers of Fe-containing normoblasts and increased serum ferritin.
What is the treatment for anemia of chronic inflammation?
Relief from inflammatory process.
What characterizes sideroblastic anemia?
Presence of ringed sideroblasts in the bone marrow & abnormalities in heme synthesis. Iron accumulates in the mitochondria that ring the nucleus.
What are the three categories of sideroblastic anemias?
1. Acquired, primary
2. Acquired, secondary
3. Hereditary
What are "acquired, primary" sideroblastic anemias?
Represent genotypic alterations in clones of bone marrow stem cells.
Observed in older people & often represent "pre-leukemia states"
What are "acquired, secondary" sideroblastic anemias?
Sideroblastic anemias that are reversible and associated w/a variety of clinical situations.
What is the hereditary nature of the hereditary sideroblastic anemias?
X-linked.
How does lead poisoning cause hypochromic anemia?
Inhibition of heme synthesis.
Lead can inhibit heme synthetase & amino levulinic acid dehydrase.
What is necessary to diagnose lead poisoning-related hypochromic anemia?
Basophilic stippling of RBCS, increased serum Fe, increased ferritin & bone marrow iron, increased serum & urine Pb concentrations.
What are some symptoms of lead poisoning related hypochromic anemia?
Children: encephalopathy & anemia.
Adults: peripheral neuropathy, abdominal colic, anemia.
What is hereditary hemochromatosis?
A rare inherited iron storage disease.
Iron accumulates in parenchymal tissue first NOT the liver.
What are manifestations of hereditary hemochromatosis?
Hyperpigmentation, enlarged liver, diabetes mellitus, hypo-gonadism, and cardiac failure.
What is needed to diagnose hereditary hemochromatosis?
Familial nature of disorder, elevated serum ferritin, and liver biopsy w/characteristic iron deposition.
Increases in serum Fe and TIBC are usually particularly HIGH.
What is the treatment for hereditary hemochromatosis?
Repeated phlebotomy to reduce iron stores.
How might acquired hemochromatosis or hemosiderosis occur?
Multiple transfusions or excessive oral intake of iron.
What differentiates acquired hemochromatosis from hereditary hemochromatosis?
In acquired, Fe accumulates in the RES before the parenchymal tissue.
In hereditary, Fe accumulates in the parenchymal tissue before the RES.
How is acquired hemochromatosis treated?
Iron chelators.
What characteristics of a peripheral blood smear are indicative of CML?
Cell precursors in the peripheral smear.
What characteristics of a peripheral blood smear are indicative of myelofibrosis?
The presence of NRBCs (nucleated), myelocytes, and circulating blasts.
If a person's blood work is normal except for an extremely elevated platelet count, what would you diagnose?
Essential thrombocythemia.
What laboratory results may indicate CML?
WBC: elevated
Blasts: in blood
Basophils: elevated
Platelets: varies, can be high or low, usually low in blast stage CML
Bone marrow: myeloid hyperplasia
Positive Ph chromosome of Bcr-abl
What mutation causes the bcr-abl mutation?
t(9;22)
How does imatinib function?
It blocks the ATP-binding pocket of the bcr-abl tyrosine kinase.
What are the second-gen tyrosine kinase inhibitors?
nilotinib and dasatinib.
What is the treatment for CML? The cure?
Imatinib can be used to treat CML.
The only cure remains allogeneic stem cell transplantation.
What are possible mechanisms of resistance to imatinib?
Bcr-abl OE
Gene amplification
Drug reflux mediated by P-glycoproteins
What is polycythemia?
Erythrocytosis-->increased RBC mass. Often manifests as elevated hemoglobin.
What is relative polycythemia?
A condition where the RBC mass appears high due to low plasma volume. Can often be "treated" by hydration.
What is absolute polycythemia?
A true increase in RBC mass.
What is polycythemia vera?
Low erythropoietin levels despite high RBC mass, due to increases erythropoiesis.
What can cause secondary erythrocytosis?
Smoking, high altitude, pulmonary disease, CV shunts, hemoglobinopathies.
What is needed for a diagnosis of polycythemia vera?
Elevated RCM (often manifested as high Hgb or hematocrit) AND arterial oxygen saturation >92%.
Other possible:
JAK2 mutation,
platelet ct.>400k,
WBC>12k,
LAP score>100,
Serum B12>900 or Serum unbound B12>2200
What is JAK2?
A cytoplasmic tyrosine kinase that is frequenctly constitutionally activated in polycythemia vera. Mutations in JAK2 are associated with many MPDs.
What are common clinical symptoms of polycythemia vera?
Fatigue, headache, pruritis, thromboembolic events, epigastric distress, SPLENOMEGALY. Left shoulder pain.
What is the median survival of polycythemia vera?
14 years.
What causes most deaths due to polycythemia vera?
Thombotic problems.
Sometimes transforms into myelofibrosis of acute leukemia (10-25%)
What is the treatment for polycythemia vera?
Phlebotomy is mainstay.
Aspirin may be given at low doses.
Agents to decrease risk of thromboembolic events include: hydroxyurea, anagrelide, IFN-alpha
What is myelofibrosis?
Extensive bone marrow fibrosis resulting in extensive hematopoietic activity outside the bone marrow.
What are clinical symptoms of myelofibrosis?
Anemia, bleeding/bruising, painful splenomegaly.
What might the labs show in a patient with myelofibrosis?
Anemia.
WBCs elevated
No Philadelphia chromosome
Peripheral smear: nucleated red blood cells, immature myeloid elements.
Bone marrow is hypercellular w/fibrosis and may be difficult to obtain.
What is the median survival of patients with myelofibrosis?
3 years.
What are the Lille criteria & what are they used for?
Lille critera: Hemoglobin<10, WBC<4K or >30K
Lille criteria help show indication of surivival time for Myelofibrosis.
What is the treatment for myelofibrosis?
Mostly supportive care. No standard of care because no regimen is effective.
Splenectomy may be considered but post-surgery mortality is high.
Reduced intensity allogeneic transplantation is indicated possibly if patient is younger or is symptomatic.
What is essential thrombocythemia?
Sustained increased platelet count (>1million)
Bone marrow shows elevation of all three cell types.
What is needed for a dx of thrombocythemia?
1. Sustained elevated platelet count (>450X109)
2. BMA showing proliferation of mainly of megakaryocytes
3. No WHO criteria for other myeloid neoplasm met.
4. Demonstration of clonal marker or no evidence of reactive thrombocytosis.
What are the causes of reactive thrombocytosis?
Iron deficiency anemia
Splenectomy
Acute hemolytic anemia
Chronic inflammation
Rebound after chemo
When might you treat essential thrombocythemia?
Platelet count >1.5x106/mm3
Past history of thrombosis/bleeding
Older px
Other co-morbid disorders (diabetes, hyper tension)
What is the treatment for essential thrombocythemia?
Goal is to lower platelet counts.
Pheresis if needed quickly.
Chemo+aspirin can be used
Also hydroxyurea nad anagrelide
What is hypereosinophilic syndrome?
Eosinophils infiltrate solid organs.
What is HES similar to?
CEL-chronic eosinophilic leukemia (more in blood than HES)
What damage may HES cause?
End-organ damage: cardiac, CNS & PNS, pulmonary, liver, kidneys, retina
What molecular abnormality is associated w/HES?
A large deletion on chromosome 4 which creates a fusion protein w/a kinase activity.
Target of imatinib.
What are amyloids?
Extracellular deposits of insoluble abnormal protein fibrils from misfolded, normally soluble precursor proteins that have red-green dichronism w/Congo Red in polarized light.
What are the three steps of amyloid formation?
1. Precursor protein produced that is qualitatively or quantitatively abnormal.
2. Protein undergoes quaternary change.
3. Protein is deposited in extracellular tissues & joins final amyloid deposit.
What are the three types of amyloid?
AL amyloid
AA amyloid
Familial amyloid
What precursor protein is connected with AL amyloid?
Usually a subunit of a light chain of an immunoglobulin.
How can AL amyloid be diagnosed?
24hr urine collection or serum.
Patients must have a biopsy that is positive for amyloid.
What malignancy is associated with AL amyloid?
Multiple myeloma
What is associated with AA amyloid?
Chronic inflammatory condition.
What is the precursor protein associated with AA amyloid?
Serum amyloid A (SAA)
Where is SAA produced?
Liver.
What is necessary for diagnosis of AA amyloid?
Biopsy of organ showing amyloid
SAA immunohistochemistry
Appropriate clinical context
What is the gene most commonly associated with familial amyloid?
Transthyrein (TTR) gene
Where is TTR-derived protein made?
Liver
What complication is commonly associated with TTR-associated familial amyloidosis?
Increased risk of CHF
What is needed for a diagnosis of familial amyloidosis?
Gene sequencing.
Where can amyloids deposit?
Anywhere but the CNS.
What is the most common site of amyloid presence?
Kidney.
Always in AA, usually in AL
Tongue involvement with amyloids is diagnostic of what type of amyloidosis?
AL amyloid
What can amyloids do in the vascular system?
Amyloid can pull factor X from blood. Requires treatment/consideration with recombinant factor VIIa.
How do you treat AA amyloid?
Limit or reduce process that produces SAA (eg treat rheumatoid arthritis, etc.)
What is the treatment for TTR-associated familial amyloid?
Liver transplant.
Amyloidosis takes quite a while to develop-->the removed liver can be transplanted into another patient.
How would you reduce the production of the precursor protein in AL amyloid?
Treatment similar to multiple myeloma: targets plasma cells where immunoglobulin protein is made.
What does eprodisate do?
Eprodisate treats amyloidosis by inhibiting the polymerization of amyloid fibrils.
What is a common treatment for AL amyloid?
Dexamethasone and melphalan.
Also bortezumib.
HOw many years might a person live with AL amyloid?
More than 10 years.
What therapies may be used in treating AA amyloid?
Therapies that block TNF-alpha: etanercept, adalimumab, influximab
What is the age distribution of Hodgkins?
Bimodal distribution: adolescence/young audults and above 60.
What is required for a diagnosis of Hodgkins disease?
Reed-Sternberg cells in the lymph node biopsy.
Fine needle aspiration is NOT sufficient.
What does the immunohistochemistry of Hodgkins disease cells show?
CD15+
CD30+
CD3- (T cells)
CD20- (B cells)
What are the four subtypes of classic Hodgkins' disease? Of those, which are the two most common?
Nodular sclerosing*
Mixed Cellularity*
Lymphocyte rich
Lymphocyte depleted
What is characteristic of nodular sclerosing HD?
More common in females!!!
Typically in young adults
Lymph node pattern: nodular pattern w/bands of fibrosis
What is characteristic of mixed cellularity HD?
Diffuse effacement of lymph node by mixed inflammatory cells
typically in older patients
Presents in more advanced state
Associated w/EBV
What are the two types of HD?
Classic HD
Lymphocyte predominant HD
What is characteristic of lymphocyte predominant HD?
RS cells are not seen
Popcorn (L&H) cells are seen instead.
Behaves similarly to indolent NHL.
Patients are usually in their 40s.
DOES NOT TRACK BETWEEN NODES
What is the immunohistochemistry of lymphocyte predominant HD?
CD25+
CD15-
CD30-
What is the typical presentation of a patient with classic HD?
Painless neck adenopathy and/or anterior mediastinal mass (75% of the time involved left neck)
Contiguous nodal spread is essential!!!
B symptoms may be present, as may anemia, fatigue, pain after EtOH consumption, shortness of breath
Is inguinal or bone marrow disease likely in HD?
Not if the disease is limited to the neck.
What is present in a tissue diagnosis of classical HD?
CD15+
CD30+
RS cells
Must be excisional biopsy!!!
What other tests are indicated in diagnosing HD?
CBC, differential (lymphocyte count), ESR, LDH, albumin
CT of chest, abdomen, pelvic
PET (HD tumors take up glucose)
What is the advantage of PET scans in HD treatment?
PET scans can differentiate between residual tumor and scar tissue post-treatment.
Is a bone marrow biopsy necessary in treatment of HD?
Not if disease is above the diaphragm.
What is the overall survival rate for HD?
75%
What are poor prognostic factors for early-stage HD?
Age>40
ESR>50
Bulky disease
B symptoms
Involvement of >3 nodal sites
What are poor prognostic factors for advanced stage HD?
Male
Age>45-50
Hemoglobin<10.5
Stage III/IV
WBC>15000
Albumin<4.0
Lymphocyte count<600
What staging system is used for HD?
Ann Arbor staging
What is Stage I HD?
Involvement of 1 site.
What is Stage II HD?
Involvement of 2 or more lymph node regions on the same side of the diaphragm.
Localized continuguous involvement of extralymphatic site=IIE
What is Stage III HD?
Involvement on both sides of the diaphragm.
Can involve spleen (IIIS) or be IIIE
What is Stage IV HD?
Involvement (diffuse or disseminated) of 1+ extralymphatic tissues w/ or w/o lymph node involvement
What is modern therapy for HD?
ABVD given on days 1 & 15 of a 28d cycle for 4-6 cycles
May include XRT.
What is ABVD?
Adriamycin
Bleomycin
Vinblastine
Dacarbazine
What was the first/old therapy for HD?
MOPP
Caused sterility.
What is Stanford V?
A more intensive regiment for treating HD.
Includes radiation for masses>5cm
What is BEACOPP?
A very intensive regiment for high risk or advanced stage cases of HD.
Causes sterility.
Increased risk of secondary MD and secondary leukemias.
What is the standard of care for early stage HD with good prognostic factors?
4 cycles of ABVD + involved field XRT
No mantle field XRT in young females
Chemo alone may be acceptable
What is the standard of care for early stage HD with poor prognostic factors?
6 cycles of ABVD + involved field XRT
What is standard of care for advanced stage (III/IV) HD?
6 cycles ABVD + XRT (if disease is bulky)
What is the therapy for relapsed HD if XRT is the only prior treatment?
Chemo.
What is the therapy for relapsed HD in patients who have previously received chemotherapy?
Salvage chemo or high-dose chemo+ autologous stem cell transplant
ESHAP
ICE
GVD
When is an allogeneic stem cell transplant indicated in treatment of HD?
1. Relapse after autologous stem cell transplant.
2. Primary refractory disease (disease returned during treatment)
What is the followup after treatment of HD?
Exam + CBC q3m for 2 years, q6m for years 3-5
CT scans for five years.
Mammograms for women beginning 8y after treatment
TSH annually
What is the consequence of hemoglobin with abnormally high oxygen affinity?
Decreased release of oxygen into tissues.
Increased erythropoiesis
Erythrocytosis
What is the consequence of hemoglobin with abnormally low oxygen affinity?
cyanosis
What is methemoglobin?
Hemoglobin with iron in the oxidized rather than reduced state.
Results in cyanosis.
What is the mutation associated with sickle cell?
6glu->val on the beta-chain gene of hemoglobin
Descibre HbSA
Heterozygous state of sickle cell (one mutated gene, one normal gene)
Screening test can make sickled cells visible/induce sickling.
Describe HbSS.
Homozygous state of sickle cell
Results in sickle cell anemia.
Severe hemolysis, manifests w/in weeks of birth.
Leads to progressive organ damage, beginning w/spleen.
What is used to diagnose sickle cell anemia?
Hb electrophoresis.
Antenatal dx can be made using MstII restriction site.
What are heinz bodies?
Precipitates that collect in cells as the result of unstable hemoglobin. Usually only visible in spleen.
Cells w/heinz bodies are destroyed by splenic macrophages.
How do you diagnose the presence of hemoglobins w/high O2 affinity?
presence of low P50.
How do you diagnose the presence of hemoglobins w/low O2 affinity?
presence of high P50
What are M hemoglobins?
Hemoglobins with an amino acid substitution in either the alpha or beta chain in the heme pocket resulting in an abnormally stable Hb-->forms methemoglobin.
How do you diagnose M hemoglobin?
Absorption spectrum at 450-750nm, gel electrophoresis at pH 7.1
What is Hemoglobin H?
A type of alpha thalassemia: deletion of 3 alpha-chain alleles of hemoglobin.
Results in small amount of HbA formed.
What is the problem with Hemoglobin H?
Excess HbB chains that cannot form a whole molecule with A chains form tetramers of B chains which accumulate.
How do you diagnose HbH?
Electrophoresis: HbH behaves as unstable hemoglobin.
What is hydrops fetalis?
Complete lack of production of HbA due to deletion of 4 alleles of alpha hb.
Only hemoglobin Barts is produced (tetramer of gamma)-->no tissue oxygen delivery
Fatal in utero
What is Hb constant spring?
Behaves like alpha thalassemia
What is characteristic of beta thalassemia minor?
Generally asymptomatic.
May have palpable spleen.
Microcytosis, hypochromia, RBCs with basophilic stippling
HbA2 levels elevated.
What is used to diagnose beta thalassemia major?
Complete lack of beta hemoglobin on electrophoresis.
What is HbE?
A mutated beta hemoglobin that is NOT beta thalassemia resulting in reduced beta hemoglobin.
Common in SE Asian populations.
Manifests as beta-thalassemia
What is CLL?
Malignant, clonal LPD leading to the accumulation of mature-appearing but biologically immature lymphocytes of B-lineage.
What types of cells are involved in CLL?
B-lineage cells!!!
What is the age tendency of CLL?
Median=68y
Very rare in patients<30y
What is the typical clinical presentation of a patient with CLL?
Usually asymptomatic.
Usually incidentally have lymphocytosis and slightly enlarged lymph nodes.
Fatigue complaints are possible.
What are the physical findings of CLL?
Enlarged lymph nodes, spleen, or liver.
What are the laboratory findings of CLL?
WBC elevated
Presence of smudge cells and mature lymphocytes.
Low protein/albumin
LDH is rarely elevated
What are the genetic abnormalities associated w/CLL?
del(17)(p13.1)
del(11)(q22.3)
del(13)(q14)
+12
What are the genetic abnormalities related to CLL with the worst prognosis?
del(17)(p13.1)
del(11)(q22.3)
What are the two basic subtypes of CLL?
-B-cells that have not been through the germinal center (unmutated VH gene)
-B-cells that have been through the germinal center (mutated VH gene)
Which CLL subtype has worse prognosis?
B-cell that have not been through the germinal center due to unmutated VH gene which makes it more resistant to apoptosis.
What is needed for a diagnosis of CLL?
Peripheral abs. lymphocyte count>5x109/L
CLL cells w/monoclonal Ig w/low or moderate staining intensity
CD20+, CD19+ (B cells)
Expression of CD23 on Bcell clone
Simultaneous demonstration CD5 on B-cell antigen+ population
If considering a diagnosis of CLL, what might make you think mantle cell lymphoma instead?
CD23- cells
What differentiates CLL from Waldenstrom's macroglobulinemia?
Elevated IgM in WM
Lymphocytosis is less common in WM
Px has hyperviscosity symptoms in WM
What is lymphoma?
Malignant transformation of mature lymphoid cells in secondary lymphoid organs (B cells, T cells, NK cells)
What is leukemia?
Malignant transformation of immature lymphoid cells in bone marrow.
What are key symptoms of lymphoma?
Lymphadenopathy and splenomegaly.
What is primary nodal lymphoma?
Crises in lymph nodes, spleen, thymus
What is primary extranodal lymphoma?
crises in scattered lymphatic tissue
What is MALT lymphoma?
Mucosal associated lymphoid tissue lymphoma.
B cell lineage
In respiratory & GI lymphoid tissue
What is CTCL?
Cutaneous T cell lymphoma
Common skin lymphoma
What is low-grade NHL?
Well-differentiated malignances w/indolent course. NOT curable. Typically watch and wait strategy.
What is high-grade NHL?
Poorly-differentiated but curable.
Aggressive course.
What is follicular lymphoma?
Most common indolent lymphoma.
Has nodular (follicular) growth pattern.
Origin: germinal center B cells
What is the mechanism of follicular lymphoma?
progressive accumulation due to lack of apoptosis driven by aberrant expression of Bcl-2
What is the genetic abnormality related to follicular lymphoma?
t(14;18)
What is diffuse large B cell lymphoma?
DLBCL
diffusely homogenous carpet of cells w/large, irregular nuclei occupies entire lymph node
Origin: germinal center B cells
High proliferative capacity due to abnormal expressino of Bcl-6
What is the genetic abnormality related to DLBCL?
Problem w/chromosome 3
BCL-6 mutation.
What is the clinical presentation of NHL?
Most px have peripheral lymphadenopathy.
Acute NHL may have bulky abdominal or chest mass.
What is the pattern of bone marrow involvement with NHL?
Not as predictable as HD-->actually, unpredictable and not contiguous.
What are common labs with NHL?
Normochromic, normocytic anemia.
LDH high in acute.
What is smoldering tumor lysis syndrome?
A syndrome that can appear if treatment is "too" good.
Evidenced by increased uric acid, phosphate, LDH, lactate.
Can result in CHF.
How do you prevent smoldering tumor lysis syndrome?
Allopurinol and forced diuresis.
What is needed for staging of NHL?
history, physical, CT of chest & abdomen, bone marrow biopsy, serum LDH.
What are the poor prognostic factors for NHL?
Age>60
Performance status >/= 2
Extranodal sites >/=2
LDH>1xnormal
Stage III or IV
How do you determine the low, intermediate and high risk groups for NHL?
Low: 0-1 prognostic factors
Int: 2-3 prognostic factors
High: 4-5 prognostic factors
What is the treatment of follicular lymphoma?
Watchful waiting until patient becomes clinical.
What is the avg. survival of a px w/FL?
8-10 yrs from diagnosis
What is the treatment for DLBCL?
Aggressive-->Immediate Treatment
Rituximab!!!
What chromosomal abnormalities are associated with AML?
t(8;21)(q22;q22)
t(15;17)(q22;q11-12)
(inv(16)(p13q22)
t(16;16)(p13;q22)
11q23
What chromosomal abnormality is associated with MCL?
t(11;14)
What chromosomal abnormality is associated with FL?
t(14;18)
What chromosomal abnormality is associated with Anaplastic Large Cell Lymphoma (ALCL)?
t(2;5)
What chromosomal abnormality is associated with MALT lymphoma?
t(11;18)
What chromosomal abnormality is associated with Burkitt's lymphoma?
t(8;14)
What does B7 bind to?
CD28 on the single-positive T cell in T-cell activation.
What else is B7 known as?
CD80/CD86
What two signals are needed to activate a T cell?
Signal 1: binding of TCR to peptide:MHC complex on APC & CD4/CD8 binding to MHC.
Signal 2: Co-stimulation via the binding of B7 and CD28
What cytokine are characteristic of TH1 cells?
IFN-gamma
How does an activated CD8+ T cell function?
1. Infiltrates infected tissue
2. Collides with infected cell.
3. TCR binds to peptide:MHC complex on infected cell. Adhesion molecules form tight association.
4. T cell releases lytic granules into infected cell which causes apoptosis of the infected cell.
5. T cell releases infected cell & begins to synthesize new lytic granules.
6. T cell binds to another infected cell and kills it.
What are other functions of CD8+ T cells aside from cytotoxicity?
CD8+ T cells produce IFN-gamma which activates macrophages.
CD8+ T cells also upregulate CTLA-4 which binds B7 extremely strongly-->inhibitory signal to T cells.
What makes memory T cells different from new T cells?
Memory T cells do not have a need for costimulation, so their response is much more rapid than that of regular T cells.
What causes CD4+ T cells to differentiate into TH1 cells?
Presence of IFN-gamma and IL-12.
What causes CD4+ T cells to differentiate into TH2 cells?
Presence of IL-4.
What type of immunity are TH1 cells associated with?
Cellular immunity.
What type of immunity are TH2 cells associated with?
Humoral immunity.
What does TCR signaling do in activation of T cells?
TCR signaling works via CD3 complex, ITAMs and PTKs to induce the expression of both IL-2 and IL-2R.
T cells with high-affinity IL-2Rs respond to IL-2 and proliferate. This is called clonal expansion.
How does TCR signaling activate increased expression of IL-2 and IL-2R?
Induces NF-kB, NFAT, and AT-1 to bind to the promoter of the genes for both products.
Describe the pathway of antigen processing for MHC class I molecules.
Endogenous/cytosolic pathway.
Intracellular proteins are degraded to peptides by proteasomes.
Peptides are transported to the ER by transporter-associated proteins (TAPs)
Peptides are loaded onto empty MHC class I molecules in the ER
Vesicles transport the peptide:MHC complex to the cell surface.
Describe the pathway for antigen process in MHC class II molecules.
Exogenous/endosomal pathway.
Extracellular proteins are endocytosed by phagocytic cells (macrophages and dendritic cells)
Vesicles become acidic & fuse w/lysosomes.
Proteases in lysosomes degrade proteins to peptides.
Peptides are loaded onto empty MHC class II molecules in late endosomes.
Loaded MHC class II molecules are delivered to the cell surface.
What is the consequence of DiGeorge's syndrome?
No T cells are made because there is no developed thymus.
What mediates negative selection of T cells?
Dendritic cells & macrophages in the corticomedullary region of the thymus.
What mediates positive selection of T cells?
Cortical epithelial cells in the thymus.
What type of rearrangement does the alpha chain of the TCR receptor undergo?
VJ rearrangement.
What type of rearrangement does the beta chain of the TCR receptor undergo?
VDJ rearrangement.
What occurs if a T cell with a TCR that is high affinity for self peptide escapes the thymus?
usually rendered anergic in the periphery.
What percentage of thymocytes die by apoptosis due to incomplete/unsuccessful rearrangement in the thymus?
98%
What delivers the first signal forhte thymocytes to proliferate?
Thymic stromal cells (TSCs)
What type of thymocytes are stimulated to proliferate for the first time by TSCs?
Double-negative thymocytes.
What do gamma:delta TCR containing T cells do?
Migrate to skin, reproductive tract, and intestinal tract.
Do not need/have MHC restriction.
What is the first gene rearranged by thymocytes?
The beta, gamma, or delta chain genes. Usually the beta chain.
What happens once VDJ rearrangement of the beta chain in thymocytes is successful?
The beta chain assembles with a surrogate alpha chain (pTalpha), a zeta chain, and CD3 to form the pre-TCR
Define anemia.
Condition characterized by too few RBCs or too little Hb.
Define erythrocytosis.
Condition characterized by too many RBCs.
Define leukocytosis.
Condition characterized by abnormally high WBC count.
Define leukopenia.
Condition characterized by abnormally low WBC count.
Define thrombocytosis.
Condition characterized by abnormally high platelet count.
Define thrombocytopenia.
Condition characterized by abnormally low platelet count.
Define leukemia.
Simply, cancer of white blood cells.
Define lymphoma.
Basic: cancer of the lymphatic system. Typically cancer of lymphocytes.
Define myeloma.
Cancer of plasma cells.
What is a cytokine?
Protein molecule released by a specific immune cell that alters the behavior of a target cell.
Define paracrine.
Acts on another cell located locally.
Define autocrine.
Acts on itself.
What is a chemokine?
Cytokine that acts as a chemoattractant to recruit immune cells to a site of infection
What is the basic function of a Th1 cell?
Secrete IFN-gamma to help a macrophage work better.
What is the basic function of a Th2 cell?
Secrete IL-4 to help a B cell make antibodies.
What are the cells of myeloid lineage?
Monocyte/macrophage
Dendritic cell
Neutrophil
Eosinophil
Basophil
Mast cell
What are the cells of erythroid lineage?
Megakaryocytes
RBCs
What are the cells of lymphoid lineage?
B cells
T cells
NK cells
What are the basic components of an MHC class I molecule?
Beta-2-microglobulin
alpha-chain (H-chain)
What are the basic components of an MHC class II molecule?
Alpha chain
Beta chain
How many domains are in the alpha chain of an MHC class I molecule?
3
How many domains are in the alpha chain of an MHC class II molecule?
2
What are the characteristics of beta-2-microglobulin?
Encoded on separate chromosome from MHC
Not polymorphic
Not membrane bound
Small compared to other molecules involve in MHC.
What are the HLA class I molecules?
HLA-A,-B,-C
What are the HLA class II molecules?
HLA-DP,-DR,-DQ
What are the products of MHC class III genes?
Various secreted proteins associated w/immune fxn
What is the nature of the peptide-binding cleft of an MHC I molecule?
Closed at both ends-->limit to size of peptide.
alpha1/alpha1
What is the nature of the peptide binding cleft of an MHC class II moluecule
Open at both ends.
alpha1/beta1
Where is the peptide anchored in the binding cleft of an MHC class II molecule?
At anchor residues along the entire length of the peptide.
Binding is via Hbonds
Where is the peptide anchored in the binding cleft of an MHC class I molecule?
At anchor residues at each end of the peptide.
Binding is usuall hydrophobic COOH-terminal anchor.
Middle of peptide can arch up away from cleft
What is degenerate binding specificity?
the ability of MHC molecules to bind a variety of molecules.
How are peptides held by MHC molecules?
Noncovalent bonds.
What is intravascular hemolysis?
Lysis of RBCs in general circulation.
What is extravascular hemolysis?
Lysis of RBCs in sinusoids of liver, spleen, and bone marrow.
What occurs to hemoglobin in intravascular hemolysis?
Hemoglobin is released directly into the plasma.
What is haptoglobin?
A plasma protein that binds free hemoglobin.
What happens to haptoglobin-hemoglobin complexes?
Removed by liver parenchymal cells.
What is evidence of intravascular hemolysis?
Decreased in plasma levels of haptoglobin. Once haptoglobin stores are depleted, hemoglobin is left free in the plasma-->pink-red appearance.
Also, plasma hemopexin levels drop as well.
What protects RBCs from oxidative stress?
GSH (glutathione)
What hereditary condition can cause increased oxidative stress to RBCs?
G6PD.
How does G6PD lead to hemolytic anemia?
G6PD inhibits HMP shunt-->inhibits formation of GSH.
Lack of GSH leads to increased oxidative stress-->membrane rigidity-->cell lysis.
What are the hereditary characteristics of G6PD?
X-linked
Particularly common in Mediterranean populations.
What is hereditary spherocytosis?
Gradual progression of spherical shape of RBCs due to memrbane loss leading to lysis in splenic sinusoids.
What is the hereditary nature of hereditary spherocytosis?
Autosomal dominant in 2/3s of patients.
What is used to diagnose hereditary spherocytosis?
Osmotic fragility test to detect spherocyte presence.
Compare sensitivity of normal RBCs to affected RBCs in varying concentrations of NaCl
What are the clinical characteristics of hereditary spherocytosis?
Palpable splenomegaly
What is the treatment for hereditary spherocytosis?
Splenectomy.
What are immune hemolytic anemias?
Shorted RBC survival due to antibodies and/or complement on cell membranes.
Whar are the mechanisms of immune red cell destruction?
Hemolysins
Agglutinins
Coating/"incomplete" antibodies
What are hemolysins?
A type of antibody that can cause RBC destruction.
Can cause complement fixation & activation w/RBC lysis.
Usually IgM antibodies such as blood groups (anti A or anti B)
What are agglutinins?
A type of antibody that can cause RBC destruction.
Have ability to agglutinate red cells in saline or serum.
Usually cold active IgM molecules.
Hemolysis occurs due to capillary sequestration.
Related to cold agglutinin disease & ABO incompatible transfusions.
What are coating/"incomplete" antibodies?
A type of antibody that can cause RBC destruction.
Attach to the RBC but do not produce agglutination or complement-mediated lysis.
Typically IgG (warm-acting abs)
Produce rapid sequestration of RBCs in spleen
Always have a positive Coombs test.
What is the Coombs test?
Test used to detect antibody and/or complement on RBC membranes.
Coombs positive cells agglutinate.
What is the cold agglutination test?
Serum study to determine presence of agglutinating antibodies.
Test is carried out by incubating varying dilutions of pt. serum w/normal RBCs at 40°C.
Assay is reported as highest dilution of serum capable of production agglutination.
What is a cold hemolysis test?
Serum study to determine presence of cold-dependent hemolysin (Donath-Landsteiner ab).
What is hypersplenism?
Syndrome of shortened RBC survival & splenic sequestration due to pathologic enlargement of the spleen w/trapping of normal RBCs.
Causes hemolytic anemia.
What is the path of blood through the spleen
Splenic aa.-->trabecular aa.-->small aa. in white pulp-->arterioles which empty into marginal zone-->red pulp-->splenic cords-->trabecular vv.-->splenic vv.
What are the hematologic findings in hypersplenism?
Anemia: mild-moderate
WBC: low
Platelets: low
Peripheral smear: reticulocytosis & spherocytosis.
What is the treatment for hypersplenism?
Splenectomy or treat the disorder causing the hypersplenism.
What causes microangiopathic hemolytic anemia?
Trauma, such as abnormal blood vessels or heart valves.
What is the normal lifespan of an RBC?
120 days.
What are diagnostic abnormalities of hemolysis?
Reticulocyte count: elevated
Unconjugated bilirubin: elevated
LDH: elevated
Hemopexin: decreased
What proteins are affected in hereditary spherocytosis?
ankryin
spectrin
Usually deficient in these proteins.
How are monoclonal proteins detected?
1. Serum protein electrophoresis
2. Immunoelectrophoresis
3. Immunofixation
What disease is spinal cord infiltration related to?
Multiple myeloma
What are symptoms of multiple myeloma?
Anemia
Bone pain due to infiltration into cortical bone of axial skeleton.
Hypercalcemia/osteoporosis
Renal disease
What are the hematologic effects of multiple myeloma?
Decreased fxn of normal hematopoietic elements resulting in anemia, thrombocytopenia, leukopenia.
Rouleaux formation is visible on peripheral smear
What is the median age of diagnosis of multiple myeloma?
70 years.
Is multiple myeloma curable?
No.
What is multiple myeloma?
Incurable clonal B-cell disorder of differentiated and slowly proliferating plasma cells.
What can preclude the development of multiple myeloma?
MGUS (Monoclonal Gammopathy of Unknown Significance)
What are the biological stages of MM?
Germinal center B cell
MGUS
Smouldering myeloma
Intramedullary myeloma
Extramedullary myeloma
Multiple myeloma
What changes through the biological stages of MM?
Bone marrow stromal cell dependence disappears in progression.
IL-G dependence in CONSTANT.
What is somewhat unique about myeloma cells?
They change their environment to create a favorable environment for their growth.
What cytokines are released by myeloma cells?
IL-6
TNF-alpha
IL-1beta
What is an M protein?
Monoclonal protein.
Monoclonal antibody that is identical to others b/c they are produced by one type of immune cell that is a clone of a single parent cell. Found in MM and MGUS.
How can an M protein be identified?
Serum Protein Electrophoresis (SPEP)
Urine Protein Electrophoresis (UPEP)
Can be detected here. Cut out band on gel and use ELISA (immunofixation) to technically IDENTIFY protein.
What are Bence Jones proteins?
Proteins produced by light chain-only myelomas. Only kappa or lambda chains are found in the urine.
What are gamma globulins?
A class of proteins in the blood identified by electrophoresis.
Most common are antibodies-->found in MM.
What is monoclonal gammopathy?
A peak on SPEP that may be indicative of MM.
What the most common types of immunoglobulin involved in MM?
IgA, IgG, light chain.
What is needed for a diagnosis of MM?
M-protein in serum or urine
Kappa or lambda restricted plasmacytoma or marrow plasma cells
Related organ or tissue impairment (ROTI)
What are the components of ROTI for MM?
Buy CAVIAR
B: Lytic bone lesions (visible of xray)
C: hypercalcemia
A: anemia
V: hyperviscosity
I: infections
A: amyloidosis
R: renal failure
What causes lytic bone lesions in MM?
Osteoclasts are activated w/o activation of osteoblasts so bone is destroyed.
In what type of MM is hyperviscosity a particularly common?
IgM-secreting myeloma
Describe MGUS.
Asymptomatic.
M protein in serum < 3
<10% clonal PCs on BmBx
Avg. dx=70ys
What is smoldering myeloma?
Myeloma bloodwork w/o ROTI
What is non-secretory myeloma?
No M-component is found.
BmBx shows clonal plasma cells>10%
ROTI
What is a plasmacytoma?
Small amt. of M protein
Kappa or lambda plasmacytoma (all have just one)
No clonal plasma cells on BmBx b/c all myeloma is in one mass
No ROTI
Can be removed.
What else might be in the ddx for MM?
AL (primary) amyloidosis
Waldenstrom's macroglobulinemia
other NHLs
What activated NFAT-Pi?
Calcineurin.
What does NFAT cause to be produced?
IL-2.
What is atgam?
Non-specific polyclonal rabbit antibody against human thymocytes that blocks all T cell function.
What is ATG?
Non-specific polyclonal rabbit antibody against human thymocytes that blocks all T cell function.
How must ATG/atgam be administered?
IV
What is ATG/atgam used to treat?
In organ transplant rejection as last resort.
What is muromonab CD3?
Mouse monoclonal antibody directed against CD3. Blocks T cell function.
What is orthoclone OKT3?
Mouse monoclonal antibody directed against CD3. Blocks T cell function.
What is muromonab CD3 used for?
acute renal transplant rejection
What is orthoclone OKT3 used for?
acute renal transplant rejection
What is the first dose effect?
the possibility of an antigenic effect on the first administration of an antibody treatment that causes a strong cytokine release. Symptoms range from flu to shock.
Prevent w/high-dose steroids.
What is alefacept?
A recombinant factor that binds CD2.
Treats psoriasis.
What is efalizumab?
Monoclonal antibody that binds CD11a.
Treats psoriasis.
What is a possible complication of efalizumab?
CD11a is not found just on T cells. It can inhibit other immune system cells.
How does etanercept work?
Directly binds TNF.
What is etanercept used to treat?
RA
What is infliximab?
A monoclonal mouse/chimeric human antibody against TNF.
Used to treat crohns, RA, ulcerative colitis, psoriasis
What is adalimumab?
A monoclonal fully human antibody against TNFalpha.
Used to treat RA.
What is cyclosporine used for?
Transplantation.
Dry eye (restasis)
Psoriasis
How does cyclosporine work?
Cyclosporine binds cyclophilin.
The complex of these two inhibits the activation of calcineurin by calcium.
This blocks the internal activation of T cells.
What is a difficulty in administering cyclosporine?
It is highly lipid soluble, so cannot be injected.
Frequently given as an emulsion.
Neoral (microemulsion) has increased bioavailability.
What are the side effects of cyclosporine?
Hepatotoxicity
Nephrotoxicity
Hypertrichosis (XS hairgrowth)
Gingival hyperplasia (gum enlargement)
Increased cholesterol (dose-related)
Hypertension (dose-related)
What metabolizes cyclosporine?
P450
How does tacrolimus work?
Binds to FKBP-->FKBP:tacrolimus complex blocks activation of calcineurin by calcium.
What are the side effects of tacrolimus?
Nephrotoxicity
Neurotoxicity
Alopecia
Diabetes*
What is the advantage of tacrolimus over CSA?
More potent than CSA.
What metabolizes tacrolimus?
P450
What are glucocorticoids?
Classic immunosuppressants that can activate/inhibit target genes in the nucleus.
Have many side effects.
How does sirolimus work?
Binds FKBP.
sirolimus:FKBP complex inhibits a kinase needed for binding of IL-2-induced TFs to nuclear sites.
Prevents IL-2 mediated activation of T cells.
What is daclizumab?
A humanized (90% human 10% mouse) MAB against IL-2R.
What is basiliximab?
A chimeric MAB against IL-2R.
What is a humanized MAB?
90% human
10% mouse
What is a chimeric MAB?
65% human
35% mouse
What are the benefits of basiliximab vs. daclizumab?
Basiliximab is more effective but has more adverse reactions due to increased mouse component.
What is azathioprine?
A prodrug that is metabolized to 6-mercaptopurine which is needed by stimulated T cells to synthesize guanosine de novo.
Blocks purine synthesis.
What are the side effects of azathioprine?
Bone marrow suppression
How does mycophenolate mofetil work?
Prodrug that is metabolized to mycophenolic acid that very selectively inhibits IMP-DH.
IMP-DH is needed for synthesis of purines.
What is the advantage of mycophenolate mofetil over azathioprine?
Fewer side effects.
How does methotrexate work?
Analog of folic acid that inhibits DHF dehydrogenase.
Inhibits synthesis of THFA.
Overall: inhibits mammalian cell division.
What is leflunomide used to treat?
RA
How does leflunomide work?
A prodrug that inhibits dihydrooretate dehydrogenase, thus inhibiting pyrimidine synthesis.
What is a serious side effect of leflunomide?
Teratogenic effects.
Is leflunomide more effective on B cells or T cells?
B cells.
What three cytokines are on the surface of T cells and active in T cell activation?
CD2, CD3, CD11a
What drugs affect T cell activation externally?
Etanercept
Adalixumab
Infliximab
Efalizumab
Alefacept
Muromonab
What drugs affect internal T cell activation?
cyclosporine (CSA)
Tacrolimus
Sirolimus
What drugs block IL-2R?
Basilixumab
Daclizumab
What drugs inhibit T cell division?
Azathioprine
Mycophenolate mofetil
Methotrexate
Leflunomide
What in the peripheral smear might be indicative of MM?
Rouleaux formation.
What cells are targeted by immunosuppressive agents?
CD4+ T cells
What is Rouleaux formation?
The stacking/aggregation of RBCs.
Can be found sporadically normally, but many Rouleaux formations may be indicative of MM.
What is found in the BmBx in MM?
Eccentric nuclei w/walltowall plasma cells.
What is stage I MM?
beta-2-microglobulin<3.5
albumin>3.5
What is stage II MM?
beta-2-microglobulin<3.5 and albumin>3.5
OR
3.5<beta-2-microglobulin<5.5
What is stage III MM?
beta-2-microglobulin>5.5
What is the OS of stage I MM?
5-10 years
How long might a person with stage III MM be expected to survive?
2-3 years
What staging system is currently used for MM?
Internation Staging System
What are the chances of progression from MGUS to MM?
10%
What increases the chances of progression from MGUS to MM?
Increased M protein.
What are the low risk factors for progression from MGUS to MM?
M protein <1.5
IgG subtype
Normal FLC (free light chain ratio)
What is used to treat MM today?
Induction w/dexamethasone plus: bortezomib, thalidomide, or lenalimode
What was the treatment for MM in 2004?
VAD (cytotoxic) followed by autologus stem cell transplant w/melphalan
What are the aggressive cytogenetics of MM?
t(14;16)
p53 deletion (17p)
How does thalidomide treat MM?
immune modulator that attack NK cells
How does lenalidomide treat MM?
immune modulator that attack NK cells
What is bortezomib?
Proteasome inhibitor.
Is CLL related to radiation exposure?
NO
What is CLL?
accumulative disease of immunologically incompetent lymphocytes.
What is the median age of dx of CLL?
70y
What is the immunohistochemistry of CLL?
Surface Ig: dim
CD19+
CD20dim
CD5+
CD23+
CD10-
t(11;14)-
What is CD5 in CLL?
An aberrant T cell marker appearing on malignant B cells.
What test is necessary to diagnose B-cell CLL?
Flow cytometry
What cells are involved in CLL?
Non-dividing (G0) B cells that have low rate of apoptosis but normal proliferative capacity.
What immunohistochemistry is needed for diagnosis of CLL?
5000 B-CLL cells/microliter
CD5+
Negative for CD2,CD3,CD4,CD8
Positvie for CD19, CD20(dim), CD22(dim)
CD23 positive
SIg weakly positive
What enhances resistance of CLL cells to apoptosis?
Contact w/stromal cells.
What is the typical presentation of a patient w/CLL?
Usually asymptomatic
May present w/fatigue, organ enlargement.
B symptoms are rare.
What are the lab features of CLL?
Lymphocytosis w/smudge cells
Thrombocytopenia
Hypogammaglobulinemia (low protein)
LDH: NL
Ca: NL
Cholesterol: can be low
What bone marrow findings are required for a diagnosis of CLL?
>30% non-RBCs are lymphocytes
Normal or Hypercellularity
What are complications of CLL?
Infections
Autoimmune disease
Transformation
Secondary malignancies
What causes most deaths related to CLL?
infection
Where are the most common CLL-associated infections located?
Mucocuteanous
What can cause autoimmune disease in CLL?
CLL or treatment-->need to determine which one.
What is Richter's transformation?
Transformation from CLL-->other cancer.
Usually large cell NHL.
What are the staging systems for CLL?
Modified Rai
Benet
What is low risk/stage 0 CLL?
lymphocytosis
What is intermediate risk CLL?
Lympadenopathy (1)
Organomegaly (2)
What is high risk CLL?
Hb<11 (3)
Platelets<100k (4)
Is therapy indicated for low risk CLL?
no
Is therapy indicated for intermediate risk CLL?
If systematic.
What is the OS for low risk CLL?
10yrs
What is the OS for int. risk CLL?
6-7 years
What is the OS for high risk CLL?
2 yrs
What is the best cytogenetic marker of disease volume for CLL?
beta-2-microglobulin
What is the worst genetic prognostic group in CLL?
del17p13
deletion of p53 gene!!!
What is a poor genetic prognosis group in CLL?
del11q22-23
loss of ATM tumor suppressor gene-->inactivation of p53
What is indicated by unmutated IgVH in CLL?
Earlier therapy is needed.
Poor prognosis.
What is standard of care prognostic determination in CLL?
Interphase (FISH) cytogenetic analysis.
What treatment is recommended for asymptomatic high risk CLL pts?
only clinical trial
What is the response rate of untreated CLL to fludarabine?
80%
What is rituximab?
anti-CD20 antibody
Does combination therapy improve OS in CLL?
no.
What is improved with combination therapy over fludarabine alone?
OR
CR
PFS
Is rituximab approved for CLL?
NO. but used.
What is bendamustine?
An alkylator used in CLL.
Much safer than chlorambucil.
What is chlorambucil?
An alkylator.
Not as safe as bendamustine.
What is a complication in using lenalidomide for CLL?
Tumor flare.
What particularly lengthens time to relapse in CLL therapy?
Eliminating disease in the bone marrow.
What is the bestish therapy for CLL?
FCR
What is used in relapsed CLL?
Not fludarabine.
Monoclonal antibodies such as alemtuzumab
How long might fludarabine refractory patients live?
<1 year
What is flavopiridol?
Inhibitor of cyclin-dep kinases that downregulates Mcl-1-->induces p53-indep. apoptosis
Experimental in treatment of CLL
What is a serious complication associated w/flavopiridol?
Tumor lysis syndrome
What is flavopiridol particularly promising in?
High risk cases of CLL
Is reduced intensity allogeneic stem cell transplantation indicated for CLL?
It IS the only curative treatment.
High TRM (15-20%)
Used mostly in younger CLL patients.
For which CLL cases is allogeneic SCT indicated?
Fludarabine resistance
Poor prognostic factors
What is Type 1 VWD?
Decreased synthesis of otherwise normal VWF
What is type 3 VWD?
Total lack of synthesis of VWF
What is type 2 VWD?
synthesis of abnormal VWF
often w/loss of high MW multimers.
What is a typical clinical presentation associated w/VWD?
ecchymoses
epistaxis
mucous membrane bleeding
menorrhagia
excessive bleeding w/trauma or surgery
MUCOCUTAENOUS BLEEDING
What are typical labs in type 1 VWD?
Platelet count: NL
PFA: prolonged
PT: NL
PTT: prolonged
Factor VIII: decreased
VWF antigen conc.: decreased
Ristocetin cofactor activity: decreased
Dist. of VWF multimers: NL
What are typical labs in type 2 VWD?
Platelet count: NL
PFA: prolonged
PT: NL
PTT: NL or prolonged
Factor VIII act.: NL or decreased
VWF antigen: NL or decreased
Ristocetin cofactor activity: decreased
VWF multimers: decrease in HMW multimers
What is the treatment for VWD?
Desmopressin
Factor VIII concentrated
Cryoprecipitates
Fibrinolytic inhibitors
Avoid drugs that inhibit platelet fxn
What causes type 1 hemophilia A?
reduced synthesis of otherwise normal factor VIII
What causes type 2 hemophilia A?
synthesis of abnormal factor VIII
What are typical labs in hemophilia A?
Platelet ct.: NL
PFA: NL
PT: NL
PTT: prolonged
Factor VIII act.: v. low (<1% of NL)
VWF antigen: NL
Risocetin cofactor: NL
VWF multimers: NL
How do you treat hemophilia A?
Factor VIII concentrates
Cryoprecipitate
Fibrinolytic inhibitors
Avoid drugs that inhibit platelet fxn
What is hemophilia B?
deficiency of factor IX
What is vitamin K?
fat soluble vitamin needed for synthesis of factors II, VII, IX, X and proteins C and S.
Proteins cannot bind Ca2+
What are the clinical settings for vitamin K deficiency?
malabsorption in GI tract
Dietary insufficiency
Anitbiotics
Biliary tract disease
Oral anticoagulants
Rodenticide
What is the clinical presentation of vitamin K deficiency?
Bleeding from multiple sites
PT: prolonged
PTT: prolonged
(PT is prolonged more than PTT)
What is the treatment for vitamin K deficiency?
Parenteral vitamin K
What is DIC?
Disease process characterized by excessive intravascular activation of thrombin and plasmin.
What is seen in DIC?
microvascular thrombosis & hemorrhage
What is the clinical manifestation of DIC?
Microvascular thrombosis
Hemorrhage
Hypotension & shock
What are the labs of DIC?
Thrombocytopenia
Hypofibrinogenemia
Prolonged PT and PTT
Elevated levels of D-dimers
What is factor V Leiden?
Mutation in factor V (Arg->Gln) that causes thrombophilia.
Factor Va cannot be inactivated by APC.
What is the prothrombin gene mutation and what does it cause?
A G->A mutation in the 3'UTR of prothrombin gene.
Results in increased levels of thrombin.
Causes thrombophilia.
What are hereditary causes of thrombophilia?
Factor V Leiden
Prothrombin gene mutation
Antithrombin deficiency
Protein S deficiency
Protein C deficiency
What is particularly characteristic of thrombi?
Lines of Zahn
What is a white thrombus?
Typically a thrombus in the arterial circulation.
Composed mostly of platelets and fibrin.
What is a red thrombus?
Typically a thrombus formed in the venous circulation.
Composed of platelets, fibrin, and trapped RBCs.
What is a saddle embolus?
A PE that lodges @ bifurcation of the pulmonary a.
What is a PE?
Pulmonary embolus.
Lodges in pulmonary arterial circulation.
Usually from large proximal vv. of legs.
What is a "silent" PE?
A PE that lodges usually in midsized to small pulmonary aa.
What is a paradoxical embolus?
An embolus from the venous circulation that passed to arterial circulation via septal defect.
Where is a a PE that causes a pulmonary infarction?
relatively small pulmonary branches of pulmonary arterial ciruclation.
Where is a PE that causes a pulmonary hemorrhage?
obstruction of mid-sized branches of pulmonary arterial ciruclation.
What commonly causes arterial emboli?
MI or atrial fibrillation due to stasis.
What are tissues commonly affected by arterial emboli?
Brain, extremities, viscera
What is an amniotic fluid embolus?
infusion of amniotic fluid into maternal circulation that lodges in maternal lungs
associated w/acute DIC
What causes a fat embolization?
Typically trauma to skeleton, long bones!
What is the gross appearance of an infarct?
Wedge shaped area whose apex points to site of vascular occlusion.
Demarcation is best at 24-48hours
White infarcts appear yellow after days.
What is the microscopic appearance of an infarct?
Initially, little to no change.
At 5-10 days, macrophages remove the necrotic tissue
2-4 weeks: granulation tissue grows into the infarct
<8 wks: scar formation/fibrosis
What can happen to a thrombus over time?
Propagation: growth
Spontaneous lysis: fibrinolysis!
Embolization: break freee
Organization: replaced by scar tissue & small vessels