Reading...
Play button
Play button
Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
463 Cards in this Set
- Front
- Back
- 3rd side (hint)
|
Where does BM come from embyologically?
|
Mesoderm
|
|
|
|
Embyologic time course of BM production
|
Yolk sac (3wks) --> Liver (6wks) --> Spleen (12wks) --> BM (3rd trimester)
|
|
|
|
Correlation b/w BM and age
|
Age is inverse to cellularity (fat replaces cells as we age)
|
|
|
|
Normal platelet survival
|
8-10 days
|
|
|
|
Primary Lymphoid Tissue & Role in development
|
BM and Thymus
Initial B and T-cell development |
|
|
|
Secondary Lymphoid Tissue & Role in development
|
Spleen and Lymphnodes
Maturation of immature lymphocytes in response to Ag |
|
|
|
Organomegaly (in heme) is due to:
|
1. Infiltration of organ with excess cells (i.e. lymphocytosis)
2. Extramedullary hematopoeisis (i.e. defective BM) |
|
|
|
RBC lifespan
|
120 days
|
|
|
|
When does alpha thalassemia present and why?
|
Fetal life.
All Hb contains alpha (even fetal Hb), therefore can present in utero. |
|
|
|
When does beta thalassemia present and why?
|
6mo after birth.
This is when transition from fetal Hb to adult Hb, which contains B chains, occurs. |
|
|
|
Tx for B-thalassemia and mechanism
|
Hydroxyurea
Increases HbF production |
|
|
|
List the different types of Hb and chains that comprise them
|
HbA - a2beta2
HbA2 - a2delta2 HbF - a2gamma2 |
|
|
|
Where is thrombopoeitin produced?
|
Liver
|
|
|
|
What is the most common site for BM Bx is adults?
|
PSIC
|
|
|
|
List 3 possible blood lab abormalities
|
1. Cold Agglutinins --> IgM Abs causing RBCs to clump
2. EDTA induced pseudothrombocytopenia --> clumping of platelets in vitro 3. Platelet Clumping --> falsely high WBC + falsely low platelet count |
|
|
|
What is pseudothrombocytopenia and what is it caused by?
|
Clumping of platelets caused by EDTA anticoagulant.
Repeat CBC with specimen collected in citrate. |
|
|
|
Perifollicular hemorrhages, Vit C deficiency
|
Scurvy
|
|
|
|
Scurvy - Buzz Words
|
Vit C deficiency
perifollicular hemorrhages bleeding gums easy bruising |
|
|
|
Primary hemostatic response = _____ plug
|
Platelet
|
|
|
|
Secondary hemostatic response = _____ plug
|
Fibrin
|
|
|
|
Venous thrombosis is mostly comprised of:
Tx with: |
Fibrin > Platelets
Coumadin (Warfarin) |
|
|
|
Arterial thrombosis is mostly comprised of:
Tx with: |
Platelets > Fibrin
Aspirin |
|
|
|
List 4 causes of acquired vascular bleeding disorders:
|
1. Scurvy
2. Glucocorticoid excess 3. Amyloidosis 4. Aging |
|
|
|
List the steps in the primary hemostatic response:
|
1. Vascular constriction and exposure of subendothelial collagen
2. Platelets exposed vWF on exposed collagen via GP1b-IX (constituitively active) 3. Platelet Activation -- ADP and TXA2 are released and cause expression of GPIIb-IIIa 4. Platelet aggregation via GPIIb-IIIa using fibrinogen |
|
|
|
List the steps in the secondary hemostatic response:
|
1. Tissue factor activates coagulation system
2. Platelets provide phospholipid surface and Ca2+ for clotting factor activation 3. Fibrin fills space b/w platelets 4. Fibrinolytic system remodels the clot |
|
|
|
Antithrombin's action
|
Inhibits thrombin, 9, 10, 11
|
|
|
|
Protein C and Protein S
Mechanism of action |
Inactivates factor 5 and 8
|
|
|
|
Abnormalities in Primary Hemostasis
|
1. Vascular
2. Platelet Defects 3. Defects in vWF |
|
|
|
Bleeding symptoms in primary hemostatic defects
|
Mucocutaneous bleeds.
Petechiae, purpura, ecchymoses, GI/GU |
|
|
|
Bleeding symptoms in secondary hemostatic defects
|
Soft tissue, joint, intracranial bleeds.
Also have mucocutaneous bleeds. |
|
|
|
Abciximab mechanism
|
GpIIb/IIIa inhibitor
Prevents aggregation |
|
|
|
Clopidogrel mechanism
|
ADP receptor inhibitor
Prevents platelet activation and aggregation |
|
|
|
Aspirin mechanism
|
Blocks COX 2 enzyme and therefore TxA2
Prevents platelet activation |
|
|
|
Mechanism of ITP
|
Autoimmune disease
1. IgG attaches to platelet receptor 2. Macs bind Fc portion of IgG and destroy IgG coated platelets in spleen |
|
|
|
ITP Symptoms
|
Very low platelet counts
Mucocutaneous bleeds |
|
|
|
ITP Tx
|
Glucocorticoids
IVIG Splenectomy Rituximab Give platelets only if bleeding |
|
|
|
Differential Dx for Thrombocytopenia
|
1. Low production
2. Accelerated destruction 3. Abnormal sequestration (splenomegaly) |
|
|
|
Bernard-Soulier
|
GpIb-IX receptor abnormality
No platelet adhesion Large platelets No ristocetin aggregation, otherwise normal aggregation |
|
|
|
Glanzman's thrombasthenia
|
GpIIb/IIIa receptor abnormality
Aggregate only in ristocetin |
|
|
|
Reactive thrombocytosis - sequelae
|
No clinical sequelae
|
|
|
|
Clonal thrombocytosis - sequelae
|
Thrombosis
Ex: Essential thrombocythemia Polycythemia rubivera CML |
|
|
|
Most common congential bleeding disorder
|
vWD
|
|
|
|
Functions of vWF
|
1. platelet adhesion
2. Factor 8 carrier |
|
|
|
ADAMSTS13
|
Cleaves ULvWF into smaller subunits
Absence --> inherited TTP |
|
|
|
Name the types of vWF deficiencies
|
Type 1: mild quantitative defect
Type 2: qualitative defect Type 3: severe quantitative defect |
|
|
|
Which type of vWD can be mistaken for Hemophilia A?
|
Type 2N
Decreased affinity for Factor 8 |
|
|
|
That factors can physiologically increase vWF?
|
Steroids
Stress Acute inflammation Estrogens/pregnancy |
|
|
|
What factor can exhibit decreased levels of vWF?
|
Blood type O
|
|
|
|
Tx for type 1 vWD?
|
Desmopressin (ADH analogue)
|
|
|
|
Tx for type 2 vWD?
|
vWF concentrates
|
|
|
|
Extrinsic pathway factors
|
Factor 7
|
|
|
|
Intrinsic pathway factors
|
8, 9, 11, 12
|
|
|
|
Common pathway factors
|
2, 5, 10, fibrinogen
|
|
|
|
Vitamin K-dependent factors
|
2, 7, 9, 10
|
|
|
|
PT measures:
|
Extrinsic pathway
|
|
|
|
PTT measures:
|
Intrinsic pathway
|
|
|
|
Describe a mixing study
|
Mix patient's plasma with normal plasma and repeat PT and PTT
|
|
|
|
Mixing study results: PT or aPTT normalizes
|
Clotting factor deficiency
|
|
|
|
Mixing study results: PT or aPTT does not normalize
|
Specific factor inhibitor is present
(i.e. lupus anticoagulant, etc.) |
|
|
|
Site of production of most clotting factors:
|
Liver
|
|
|
|
Sites of production of vWF
|
Endothelium and platelets
|
|
|
|
Hemophilia A and B - what factors are deficient?
|
A - factor 8
B- factor 9 Clinically indistinguishable |
|
|
|
Factor 12 deficiency, HMWK, Pre-kallikrein
|
Marked prolongation of aPTT
NEVER results in bleeding symptoms |
|
|
|
Thrombomodulin
|
Anchored on endothelium
Converts thrombin to anticoagulant Activates Protein C |
|
|
|
Virchow's triad
|
Thrombosis
1. Blood flow stasis 2. Hypercoaguable state 3. Endothelial injury |
|
|
|
Red Clot
|
Venous/fibrin/RBC clot
|
|
|
|
White Clot
|
Arterial/platelet clot
|
|
|
|
Endogenous inhibitors of platelet aggregation (2)
|
Prostacyclin
NO |
|
|
|
Endogenous inhibitors of coagulation (4)
|
Thrombomodulin
Heparin sulfate Protein C/S Tissue factor pathway inhibitor |
|
|
|
Prevents deposition of fibrin
|
Plasminogen activators
|
|
|
|
Name hereditary risk factors of venous thrombosis (5)
|
1. Factor V Leiden (APC resistance)
2. Prothrombin 2010 mutations (increased prothrombin) 3. Antithrombin deficiency 4. Protein C/S deficiency 5. Homocystinuria |
|
|
|
Where are venous thrombi more likely to form?
|
Promixal leg veins > distal
|
|
|
|
Heparin mechanism
|
Indirect thrombin inhibitor
Unfractionated: accelerates action of antithrombin LMWH: Factor Xa inhibitor |
|
|
|
Advantages and disadvantages of Unfractionated Heparin
|
ADV: can use in renal failure, reversible with protamine, shorter half-life
DISADV: need aPTT monitoring, greater risk of HIT |
|
|
|
Advantages and disadvantages LMWH
|
ADV: SubQ dosage, don't need aPTT monitoring, HIT is rarer
DISADV: C/I in renal failure, longer half-life, not reversible with heparin |
|
|
|
UFH heparin prolongs what?
|
aPTT
|
|
|
|
How is LMWH dosed and monitored?
|
Based on body weight. Don't need to monitor.
|
|
|
|
HIT
|
Immune-mediated
Ab develops 5-10 days Thrombocytopenia with/without thrombosis |
|
|
|
Tx for HIT
|
1. Stop heparin
2. Start direct heparin inhibitors (Argatroban and Lepirudin) |
|
|
|
Why bridge Warfarin with heparin?
|
Causes a transient decrease in Protein C --> hypercoaguable
|
|
|
|
With Warfarin therapy, how long do you have to wait until you can discontinue heparin?
|
Until INR is in the therapeutic range (2-3)
|
|
|
|
Warfarin mechanism
|
Vitamin K antagonist
Inhibits conversion of Vit K epoxide to Vit K |
|
|
|
Warfarin complications
|
Bleeding
Teratogenic (can cross placenta) Osteoporosis Drug interactions (CYP2C9) |
|
|
|
Factor V Leiden
|
APC resistance --> Hypercoaguability
|
|
|
|
Factor V
|
Cofactor for Factor X, which converts prothrombin --> thrombin, which converts fibrinogen --> fibrin
|
|
|
|
Most common inherited risk factor for venous thrombosis
|
Factor V Leiden
|
|
|
|
Prothombrin 20210A mutation
|
Mutation in 3'UTR leading to increased Prothrombin translation
|
|
|
|
Fibrinolytic system
|
Plasminogen converted to plasmin by t-PA
Plasmin breaks down fibrin into fibrin degradation products (D-dimers) PAI prevents conversion of plasminogen --> plasmin |
|
|
|
Antiphospholipid Antibody Syndrome
|
Abs (IgG and/or IgM) interfere with phospholipid dependent reactions
Presents with venous thrombosis and recurrent spontaneous abortions |
|
|
|
Name Antiphospholipid Antibody Syndrome Ab/Inhibitors (3)
|
Lupus Anticoagulant
Anti-Cardiolipin Ab Lupus inhibitors |
|
|
|
Recurrent spontaneous abortions
|
Antiphospholipid Syndrome
|
|
|
|
What labs should you order if you suspect Antiphospholipid Syndrome?
|
1. Coagulation based tests (Mixing Study)
2. Immunologic Tests: cardiolipin, B2-glycoprotein |
|
|
|
Thrombolytic therapy
|
t-PA
activates plasmin --> lyse fibrin clot significant risk of hemorrhage |
|
|
|
Indications for thrombolytic therapy
|
acute MI
massive PE peripheral artery thrombosis |
|
|
|
Pregnancy is a temporary risk factor for:
|
Venous thrombosis. Most clots occur post-partum.
|
|
|
|
Describe DIC/ICF (intravascular Coagulation and Fibrinolysis)
|
Activation of intravascular coagulation with simultaneous activation of fibrinolysis
Usually bleeding (use up platelets and factors) and thrombosis |
|
|
|
What lab results do you see in DIC?
|
Increased: PT, PTT, D-dimers
Decreased: fibrinogen, platelets See shistiocytes |
|
|
|
Most common cause of DIC
|
Sepsis
|
|
|
|
Causes of acute DIC
|
STOP Making New Thrombi
S - Sepsis T - Trauma O - Obstetric-amniotic fluid emboli P - Acute Pancreatitis M - Malignancy (APL-M3) N - Nephrotic Syndrome T - Transfusion |
|
|
|
If you see circulating PMN bands, suspect:
|
Infection
|
|
|
|
If you see hypersegmented PMN, suspect:
|
B12/Folate deficiency
|
|
|
|
If you see hyposegmented PMN, suspect:
|
MDS (Myelodysplastic Syndrome)
|
|
|
|
Selectins
|
mediate rolling in PMNs (bind Sialyl Lewis proteins on endothelium)
|
|
|
|
Integrins
|
mediate adherence and vascular transmigration (bind to ICAM/VCAM/PECAM on endothelium)
|
|
|
|
Leukocyte Adhesion Deficiency
|
Defective Selectins (no rolling) or Integrins (no vascular transmigration).
Impair PMNs ability to leave vessel and reach infected site. |
|
|
|
CGD (Chronic Granulomatous Disease)
|
X-linked NADPH Oxidase defect.
Unable to convert O2 --> O2 radicals --> H2O2 to cause bacterial killing. Negative NBT test. Susceptible to infections, esp. catalase+ organisms (s. aureus) |
|
|
|
Myeloperoxidase
|
PMNs, convert H2O2 to HOCl (bleach) --> kill bacteria
|
|
|
|
Chediak-Higashi
|
Microtubule Defect --> impaired chemotaxis and degranulation --> decreased phagocytosis
|
|
|
|
Negative NBT (Nitrobluetetrazolium) test
|
CGD
|
|
|
|
ANC Calculation
|
WBC x % (Neutrophils + Bands)
|
|
|
|
Spurious causes of neutrophilia
|
Platelet Clumping
Cyoglobulinemia |
|
|
|
What MUST you rule out whenever WBC is elevated?
How do you differentiate? |
CML vs Leukemoid rxn
Use LAP (Leukocyte Alkaline Phosphatase) - elevated in Leukemoid, but not in CML |
|
|
|
Causes of neonatal neutropenia
|
Preterm infants: physiologic
Alloimmune: Maternal Ab to fWBC Kostmann's Syndrome Cyclical Neutropenia |
|
|
|
Kostmann's syndrome
|
Severe neutropenia at birth --> severe infxns
BM maturation arrest at promyelocyte stage |
|
|
|
Most common cause of neutropenia in adults
|
Post-chemo aplasia
|
|
|
|
Pelger Huet Anomaly
|
Biloped neutrophil
Can be bengin Psuedo - due to MDS, Myelofibrosis, AML |
|
|
|
Pseudo Pelger Huet Cell
|
Biloped PMN --> MDS
|
|
|
|
Basophilia in CML could be a sign of:
|
upcoming terminal blast crisis --> poor prognosis
|
|
|
|
Wiskott-Aldrich Syndrome
|
Triad of:
Eczema Thrombocytopenia Immunodeficiency |
|
|
|
Classic PBS findings for IDA
|
Anisocytosis
Poikilocytosis Hypochromia Pencil/cigar cells Microcytes |
|
|
|
Necessities for Erythropoiesis
|
DNA synthesis: Folate and B12
Hgb: Fe and Globin |
|
|
|
Erythropoiesis is controlled by
|
Oxygen tension
Low O2 tensoin stimultes Epo production in kidney |
|
|
|
Which factors increase RBC mass?
|
Testosterone
Hypoxia Dehydration Pregnancy (if Fe/folate is ok) |
|
|
|
Classification of anemia based on MCV
|
Microcytic - inadequate Hb synthesis
Normocytic - hemolysis, hemorrhage, hypoproliferative processes Macrocytic - inadequate DNA synthesis |
|
|
|
Physical exam findings in IDA
|
Conjunctival Pallor
Palmar Pallor Fatigue, HAs, dyspnea Hypovolemia Tachycardia, flow murmur Koilonichya - spoon nails Pica - pacophagia (ice chewing) |
|
|
|
DDx for Microcytic Anemia
|
TAILS
Thalassemia ACD IDA Lead Poisoning Sideroblastic Anemia |
|
|
|
Ferritin
|
form in which Fe is stored
marker of total body Fe |
|
|
|
Ferroportin
|
channel that allows release of Fe
|
|
|
|
Hepcidin
|
inhibits Ferroportin (therefore decreases Fe release)
|
|
|
|
Transferrin
|
carrier of free Fe in serum
|
|
|
|
IDA: acute or chronic loss?
|
ALWAYS chronic
|
|
|
|
Anisocytosis
|
Different size RBCs --> Increased RDW
|
|
|
|
Poikilocytosis
|
Different shape RBCs
|
|
|
|
Hypochromic RBC
|
Central pallor > 1/3
|
|
|
|
IDA Lab Findings
|
Decreased:
Ferritin Serum Fe Hepcidin Transferrin Saturation (TIBC increases) Increased: TIBC |
|
|
|
Transferrin Saturation
|
Serum Fe/TIBC
|
|
|
|
Plummer-Vinson Syndrome
|
Microcytic Anemia (IDA)
Esophageal Webs Atrophic glossitis |
|
|
|
Side effects of Fe replacement therapy?
|
Constipation
Black stools |
|
|
|
Causes of IDA
|
inadequate dietary intake (vegeter.)
increased requirement (pregnancy) decreased absorption (malabs. dis) increased loss (bleeding, CRC) |
|
|
|
Beta synthesis in early life
|
starts in fetal life, but ramps up at 6mo
Beta thalassemias and sickle cell anemia does not present until after 6mo |
|
|
|
B-thalassemia trait is protective against:
|
Malaria
|
|
|
|
PBS results in B-thal
|
Microcytes
Hypochromia TARGET CELLS BASOPHILIC STIPLING |
|
|
|
Fe study results in B-thal
|
Fe studies are normal
|
|
|
|
B-thal symptoms
|
skeletal disfiguration - BM expansion
hepatosplenomegaly high output CHF |
|
|
|
How to Dx B-thal?
|
Hb electrophoresis
Decreased HbA Increased HbF, A2 |
|
|
|
How many genes present for B-thal?
|
2
|
|
|
|
How many genes present for alpha chain?
|
4 genes
|
|
|
|
Alpha thalassemia types
|
1 gene missing = ASx
2 genes = Alpha-thal trait 4 genes = Hb Barts (hydrops fetalis) |
|
|
|
Sideroblastic anemia
|
most commonly related to alcoholism
Failure to create heme molecules, so Fe deposits in mitochondria --> ringed sideroblasts around nucleus Congenital --> microcytic anemia Acquired --> macrocytic, MDS type |
|
|
|
Most common anemia of hospitalized patients
|
Anemia of chronic disease
|
|
|
|
Anemia of chronic disease - mechanism
|
Chronic inflammation causes increased hepcidin --> increased ferritin --> decreased serum Fe --> Fe remains stuck in Macs and can't be utilized
|
|
|
|
Anemia of Chronic Disease - PBS results
|
Microcytic (often normocytic!)
Hypochromatic Rouleaux |
|
|
|
Mechanism of rouleaux in ACD
|
excess inflammatory factors coat RBC, causing loss in negative charge and repulsion --> aggregation
|
|
|
|
Lab results in ACD
|
Increased: Hepcidin, Ferritin
Decreased: Serum Fe, TIBC (less transferrin production), Epo Normal: Transferrin saturation (both serum Fe and TIBC decrease) |
|
|
|
Causes of ACD
|
Chronic infxn (osteomyelitis)
Chronic immune disorders (SLE, RA) Chronic neoplastic disorders |
|
|
|
How does IDA present with thombocytosis and increased thrombosis risk?
|
Epo is high in IDA, which cross reacts with thrombopoietin, which stimulates platelet production
|
|
|
|
Causes of normocytic anemia without reticulocytosis
|
Inadequate BM response to the anemia
Aplastic anemia Renal failure Myelophystia (Stem cells replaced by non-RBC producing cells, i.e. malignancy, infection, fibrosis) |
|
|
|
Causes of normocytic anemia with reticulocytosis
|
Implies adequate BM response
Acute hemorrhage Hemolysis |
|
|
|
Which is more common, extravascular or intravascular hemolysis?
|
Extravascular (95%)
|
|
|
|
Extravascular hemolysis is always mediated by what immune molecule?
|
IgG
|
|
|
|
Intravascular hemolysis is always mediated by what immune molecules?
|
Complement
|
|
|
|
In what ways can you categorize hemolysis?
|
Intravascular vs. Extravascular
Extrinsic vs. Intrinsic |
|
|
|
Three general types of intrinsic hemolysis and examples of each
|
Membrane - Hereditary Spherocytosis, Eliptocytosis, PNH
Enzyme - G6PD deficiency, pyruvate kinase deficiency Hb - Sickle cell anemia, Thalassemia |
|
|
|
3 causes of spherocytosis
|
1. Hereditary Spherocytosis
2. AIHA 3. Post transfusion |
|
|
|
Hereditary spherocytosis
|
Extravascular hemolysis
100% spherocytes (affects all RBCs) Splenomegaly + aplastic crisis Pigment gallstones |
|
|
|
What can infection can commonly cause aplastic crisis?
|
Parvovirus B19 (decreases Epo)
|
|
|
|
Family Hx of premature cholecystectomy and normocytic anemia
|
Hereditary spherocytosis
|
|
|
|
Tx for hereditary spherocytosis?
|
Splenectomy
|
|
|
|
Howell-Jolly bodies
|
Hyposplenism or Splenectomy
|
|
|
|
Paroxysmal Nocturnal Hemoglobinuria
|
Intravascular hemolysis
Acquired stem cell defect-increased sensitivity of RBCs to complement Hemolysis at night High risk thrombotic complications |
|
|
|
Normocytic anemia + reticulocytosis might look like:
|
Macrocytosis, due to reticulocytes which are larger
|
|
|
|
Hemolysis results in:
|
accumulation of Hb catabolism products
marked compensatory increase in erythropoiesis in BM |
|
|
|
G6PD Deficiency
|
X-linked recessive
Lack of G6PD makes pts more prone to oxidative stress induced hemolysis |
|
|
|
What factors can cause oxidative stress and excerbate hemolysis in G6PD?
|
Fava beans
Oxidative drugs (anti-malarials, sulfonamides, etc.) Infxn (Parvo B19) |
|
|
|
PBS results in G6PD
|
Heinz bodies
Bite cells (bit by Macs) |
|
|
|
Heinz bodies
|
denatured, precipitated Hb
seen in G6PD |
|
|
|
Autosplenectomy
|
Sickle cell
|
|
|
|
Sickle cell anemia - inheritance and mutation
|
AR inheritance
aa point mutation: Glu --> Val |
|
|
|
Sickle cell trait
|
1 defective allele
1/2 Hb is HbA 1/2 Hb is HbS |
|
|
|
Sickle Cell Disease
|
Homozygous --> 100% HbS
|
|
|
|
At what age does sickle cell disease present
|
6 mo, when B chain production ramps up
|
|
|
|
Sickle Cell Disease
|
Homozygous --> 100% HbS
|
|
|
|
At what age does sickle cell disease present
|
6 mo, when B chain production ramps up
|
|
|
|
What induces Hb polymeration and sickling in Sickle Cell Disease?
|
LOW O2 STATES
Dehydration Low pH |
|
|
|
1st generation Cephalospornis?
Clinical Use? |
Cephalexin Cephazolin (Flexn and Zolin)
Gram positive cocci, Proteus M, E. coli, Klebsiella |
(Flexn and Zolin)
PEcK |
|
|
Therapy for Sickle Cell Disease
|
Hydroxyurea
Prevent infxns, sickling Tx acute crisis (100% O2) |
|
|
|
Clinical presentations in sickle cell disease
|
1. Chronic Hemolytic Anemia (RBC span is 20 days)
2. Occlusion of small vessels 3. Autosplenectomy by age 12 4. Acute pulmonary crisis (blockage of pulmonary capillaries) |
|
|
|
Hemolysis is a risk factor for what type of deficiency?
|
Folate
Not recycled like Fe |
|
|
|
Time it takes to become Fe, folate, B12 deficient
|
Fe - weeks
Folate - months B12 - years |
|
|
|
Where are Fe, folate and B12 absorbed?
|
Fe - stomach
Folate - duodenum B12 - terminal ileum |
|
|
|
AIHA
|
AutoAb attaches to RBC --> Macs bind Fc portion of Ig --> hemolysis
Warm and Cold AIHA |
|
|
|
PBS results for AIHA
|
Spherocytes
Macs take bite out of RBC --> reshapes into a sphere |
|
|
|
Warm AIHA
1. mediated by: 2. etiology: |
1. IgG (extravascular)
2. Primary - idiopathic Secondary - Lymphomas/CLL, SLE/Autoimmune |
|
|
|
Cold AIHA
1. mediated by: 2. etiology: |
1. IgM binds and fixes complement (intravascular) --> clumping at cold temps --> peripheral/cool body parts
2. EBV, Mycoplasma (Lymphomas and CLL also) |
|
|
|
AIHA test
|
Coomb's test
+ result: agglutination Direct - antihuman Abs added directly to patient's RBCs Indirect - patients serum is added to RBCs |
|
|
|
Microangiopathic Hemolytic Anemia causes (5)
|
Intravascular
Heart valves TTP HUS DIC Drugs |
|
|
|
PBS results in microangiopathic hemolytic anemia
|
Shistocytes (shear cells)
Reticulocytes |
|
|
|
TTP - most common etiology
|
Thrombotic thrombocytopenic purpura
ADAMTS13 deficiency --> increased ultra molecular weight vWF |
|
|
|
HUS etiology
|
E.coli O157:H7
Shigella |
|
|
|
Causes of extrinsic, non-immune hemolytic anemia
|
1. Mechanical - microangiopathic hemolytic anemias (heart valves, DIC, etc.)
2. Infxn (Malaria, babesiosis, clostridium) 3. Toxic Damage (Snake venom, brown recluse spider, Wilson's disease, drugs) |
|
|
|
Shistocytes indicate
|
Microangiopathic Intravascular Hemolysis
|
|
|
|
Burr cells
|
Seen in HUS
contain spiculations |
|
|
|
Coomb's positive hemolysis
|
usually Warm AIHA, not cold
|
|
|
|
Tx for Hemolysis
|
Tx secondary cause
Replenish Fe, folate Transfusions |
|
|
|
Tx for AIHA
|
Immunosuppresion
Splenectomy |
|
|
|
Extravascular hemolysis labs:
|
Increased:
Indirect Bilirubin LDH (cell turnover) Normal: Haptoglobin Urine hemosiderin Urine Hb |
|
|
|
Haptoglobin
|
protein that binds free Hb in the blood
|
|
|
|
Intravascular hemolysis lab results
|
Increased:
Indirect bilirubin LDH Urine hemosiderin Urine hemoglobin Decreased: Haptoglobin (due to all the spilled free Hb) |
|
|
|
What accounts for some of the normal lab values in extravascular hemolysis?
|
RBCs are lysed by macs in spleen.
RBC contents are taken up by Macs (hemosiderin, Hb) and are not spilled into circulation |
|
|
|
What accounts for the abnormal lab values in intravascular hemolysis
|
RBC contents are spilled into circulation
|
|
|
|
How do you evaluate normocytic anemia?
|
1. Retic count
2. High --> Hemolysis labs 3. Low --> BM Bx |
|
|
|
How do you differentiate TTP from HUS and DIC?
|
Decreased ADAMST13 --> ULVWF --> binds platelets, forms clots, blocks vessels
CNS changes!! Normal Coag studies |
|
|
|
How do you differentiate HUS from TTP and DIC?
|
E.coli/shigella etiology (no ADAMST13 involvement)
Renal problems!! Normal Coag studies |
|
|
|
How do you differentiate DIC from TTP and HUS?
|
Prolonged PT/aPTT (uses up clotting factors)
D-dimer + Low fibrinogen Always secondary to something...no such thing as idiopathic DIC |
|
|
|
How do you approach macrocytosis?
|
Check retic count!
High: hemolysis or hemorrage Low: Problem with DNA synthesis or phospholipid membrane |
|
|
|
What type of macrocytes do you see with DNA synthesis problems?
|
Oval macrocytes
|
|
|
|
What type of macrocytes do you see with a phospholipid membrane problem?
|
Round macrocytes
|
|
|
|
Etiologies of macrocytic megaloblastic anemia
|
Oval macrocytes
1. B12/folate deficiency 2. Drugs (DNA inhibitors), MDS |
|
|
|
Etiologies of macrocytic, non-megaloblastic anemia
|
Round macrocytes
1. Reticulocytosis - hemolysis, hemorrhage 2. W/o retic. - EtOH, Liver disease, hypothyroidism |
|
|
|
Causes of macrocytic, non-megaloblastic anemia without reticulocytosis
|
Liver disease
EtOH Hypothyroidism |
|
|
|
Source of B12
|
animal protein
|
|
|
|
Storage of B12
|
liver
|
|
|
|
Describe absorption of B12
|
1. acids in stomach release B12 from proteins
2. binds R-factor in the stomach 3. trypsin from pancreas releases R-factor from B12 in the duodenum 4. IF from stomach parietal cells binds B12 5. B12-IF is absorbed in the terminal ileaum |
|
|
|
Causes of B12 deficiency
|
1. Lack of absorption
Achlorhydria/gasterctomy Pernicious anemia Gastric by-pass Pancreatic insufficiency TI abnormality (malabsorption, bacterial overgrowth, resection, D. latum) 2. Insufficient intake (strict vegans) |
|
|
|
Diphyllobothrum latum can cause:
|
B12 deficiency
|
|
|
|
Most common cause of B12 deficiency in elderly
|
Pernicious anemia
Abs to IF or stomach parietal cells |
|
|
|
B12 Deficiency - Clinical Manifestation
|
Subacute combined degeneration (posterior and lateral columns)
Vibration/position loss Ataxia Weakness/paresthesia Psychosis Hypo/hyperpigmentation Atrophic glossitis |
|
|
|
PBS results in B12 deficiency
|
Oval macrocytes
Hypersegmented PMNs Megaloblasts |
|
|
|
Lab results in B12 deficiency
|
Increased:
MMA - Methylmalonic acid Coa Homocysteine LDH Indirect bilirubin |
|
|
|
How do you test for pernicious anemia?
|
Schilling test
Radiolabeled B12 |
|
|
|
How are the lab results different in B12 vs folate deficiency?
|
B12 causes increased MMA, folate does not
both increase homocysteine |
|
|
|
Therapy for B12 deficiency
|
PARENTERAL B12
reversible if not too late |
|
|
|
Which is more common - B12 or folate deficiency?
|
Folate
|
|
|
|
Folate sources
|
greens, fruits, veggies
|
|
|
|
Where is folate absorbed?
|
Proximal Small Bowel
|
|
|
|
Causes of folate deficiency
|
Insufficient intake (i.e. alchol abuse)
Increased need (hemolysis) Decreased absorption (Celiac) Impaired use (folate antagonist drugs) |
|
|
|
Clinical manifestations of folate deficiency
|
Same as B12, but NO neuro manifestations
atrophic glossitis hypo/hyperpigmentation |
|
|
|
Folate vs. B12 deficiency
|
Both increase homocyteine
B12 - neuro + MMA |
|
|
|
Hyperhomocysteinemia
|
Increased thrombosis
|
|
|
|
Therapy for folate deficiency
|
Oral folate
Do not replace folate before checking if B12 is deficient --> worsen neuro manifestations |
|
|
|
Megaloblastoid anemias - etiologies
|
Drugs - inhibit DNA synthesis
Methotrexte Zidovudine Anticonvulsants, OCPs, EtOH (folate) 6-MP 5-fluorouracil Defects in HSCs MDS |
|
|
|
PBS results in Liver disease
|
Target cells
Acanthocytes (spiculated cells) Round Macrocytes |
|
|
|
Porphyria
|
Disorder of heme synthesis
|
|
|
|
Hemoglobinopathies
|
Qualitative hemoglobin disorder
|
|
|
|
Thalassemias
|
Quantitative hemoglobin disorder
|
|
|
|
Geographic distribution of thalassmia
|
India
Mediterranean |
|
|
|
Geographic distribution of sickle cell disease
|
Africa
SE Asia |
|
|
|
Porphyria manifestations
|
CNS or skin problems
abdominal pain fever nausea/vomitting constipation peripheral neuropathy paralysis psych symptoms |
|
|
|
Osmotic fragility test
|
Hereditary spherocytosis
|
|
|
|
Which ethnicity is sickle cell most prevalent in?
|
African American
|
|
|
|
Why does low O2 tension precipitate sickling?
|
Deoxygenated HbS is less soluble than oxygenated
|
|
|
|
What occurs in a sickle cell pain crisis?
|
Sickled cells cause vaso-occlusion
|
|
|
|
What test do you use for sickle cell?
|
Sickle Solubility test --> indicates presence of HbS, but not type
HbS electrophoresis to determine trait vs disease |
|
|
|
Sickle cell disease clinical manifestations
|
Pain crises at 6mo
Vaso-occlusive pain crises Splenic sequestration crisis Autosplenectomy Aplastic crisis Salmonella Osteomyelitis Hematuria Retinopathy |
|
|
|
Management of sickle cell disease
|
Prophylactic Abx
HYDROXYUREA |
|
|
|
HbC Disease
|
Codon 6 on beta chain: Glu --> Lysine
Less severe than HbS |
|
|
|
Mutations that decrease chances of pain crisis in sickle cell disease
|
1. Hereditary persistence of HbF
2. Hereditary Sickle/B-thal trait (decreased production protects against vaso-occlusion) |
|
|
|
Beta-thal minor
|
usually Asx
one abnormal allele microcytosis Hb Electrophoresis: increased HbA2, HbF |
|
|
|
Beta-thal major: Pathophysiology
|
Unpaired alpha chains (due to decreased beta chains) --> hemolysis in spleen and decreased erythropoiesis in BM --> profound anemia
|
|
|
|
Beta-thal major: Clinical
|
Asx until 6 mo
Pallor, irritability Fe overload (from increased eryropoiesis due to profound anemia) Extramedullary hematopoiesis HEPATOSPLENOMEGALY SKELETAL DEFORMITIES |
|
|
|
Beta-thal major: moderators of severity
|
1. Co-inheritance of alpha thalassemia (decrease alpha chains, reduce severity)
2. HbF expression |
|
|
|
Beta-thal major: therapy
|
transfusion
Fe chelation Infxn prophylaxis BM transplant |
|
|
|
Alpha-thal trait
|
1-2 genes deleted, Asx
|
|
|
|
HbH Disease
|
Alpha thalassemia, 3 genes deleted
Moderate/severe anemia Splenomegaly, hemolysis, skeletal changes |
|
|
|
Hb Barts
|
Alpha thalassemia, 4 genes deleted
Hydrops fetalis --> CHF and generalized edema Fetal loss or still birth |
|
|
|
Which M-proteins are seen in Multiple Myeloma?
|
IgG (50%)
IgA (25%) Light chains only (25%) |
|
|
|
Multiple Myeloma
|
Monoclonal M-spike + CRAB
|
|
|
|
Approach to Multiple Myeloma
|
SPEP
UPEP BM Bx with kappa/lambda stain(> 10% Plasma Cells) also SIFE |
|
|
|
Formal Dx of multiple myeloma
|
Evidence of Monoclonal Plasma Disorder + one or more CRAB
|
|
|
|
CRAB - MM
|
hyperCalcemia
Renal failure Anemia Bone lytic lesions/pain also see infxns |
|
|
|
High risk prognostic factors in multiple myeloma
|
Chr 13 deletion
17p deletion stage amount of M protein |
|
|
|
Multiple Myeloma Tx:
|
No cure
Autologous SC transplant Melphalan-Prednisone Lenalidomide Supportive care - bisphosphonates, prophylactic Abx |
|
|
|
Bence-Jones proteins
|
light chains in urine
|
|
|
|
Histology findings in multiple myeloma
|
PBS: rouleaux (M-proteins coat RBC surface)
BM: >10% Plasma Cells, sheets of plasma cells, increased kappa:lambda ratio |
|
|
|
DDx for plasma cell disorders
|
No Sx: MGUS, SMM
Paraprotein: Amyloid, neuropathy, Light Chain Deposition Disease, Cryoglobulinemia Tumor Bulk: MM, Waldenstroms, Plasmacytoma |
|
|
|
Smoldering Multiple Myeloma
|
>10% PC in BM and/or M-protein >3
No signs of end organ damage |
|
|
|
MGUS
|
<10% PC in BM and M-protein <3
No signs of end organ damage |
|
|
|
Risk of progression from MGUS --> MM
|
1% per year
increases with higher M-spike |
|
|
|
Risk of progression from SMM --> MM
|
10% per year
|
|
|
|
Solitary Plasmacytoma
|
Single bony, extramedullary lesion
BM is not involved M-protein may be present Bone pain at site if osseus Osseus has greater risk of becoming MM than extra-osseus/soft tissue |
|
|
|
Waldenstrom's Macroglobulinemia/
Lymphoplasmacytic Lymphoma |
IgM producing B or Plasma cells
Lymphoplasmacytoid appearance |
|
|
|
Waldenstrom's Sx
|
Hyperviscosity (HA, epistaxis, vision changes)
NO LYTIC BONE LESIONS Anemia Infxns Lymphadenopathy Hepatosplenomegaly |
|
|
|
Why do you get hyperviscosity syndromes in Waldenstrom's?
|
IgM forms large pentamers
|
|
|
|
What findings in Waldenstrom's make it also a lymphoma?
|
Lymphadenopathy
Hepatosplenomegaly |
|
|
|
What differ Waldenstrom's from MM?
|
IgM
B or Plasma Cell Malignancy Lymphadenopathy Hepatosplenomegaly Hyperviscosity Sx |
|
|
|
Dx of Waldenstrom's
|
IgM M-protein
End-organ damage BM > 10% Lymphoplasmacytoid cells |
|
|
|
Waldenstrom's Tx
|
Rituximab
Purine analogues/Alkylators Plasmapheresis if hyperviscosity is present |
|
|
|
Most common type of Amyloidosis
|
AL (Primary)
Amyloid Light Chain |
|
|
|
Amyloid - AL
|
Primary, Amyloid Light Chain
Only amyloid with proliferative plasma cell disorder Cardiomyopathy, nephropathy, macroglossia |
|
|
|
AL Sx's
|
Heart - RCM, CHF, arrhythmias
Kidneys - nephrotic syndrome Nerves - peripheral neuropathy Tongue - macroglossia |
|
|
|
AL Tx
|
Melphalan-Dexamethasone
Auto-transplant |
|
|
|
What constitutes an acute leukemia?
|
>20% blasts
|
|
|
|
Chronic leukemias - general presentation
|
Indolent/prolonged course
mature cells with low proliferative rate |
|
|
|
Acute leukemias - general presentation
|
Fulminant clinical course
immature cells with high proliferative rate |
|
|
|
Blast morphology
|
large nucleus
open cytoplasm pale open chromatin |
|
|
|
Auer rod
|
AML
Crystallized myeloperoxidase enzyme in blasts |
|
|
|
Blast markers
|
CD34
TdT (more common in lymphoid) |
|
|
|
CD45
|
Hematpoietic SC marker
|
|
|
|
CD19, 20, 10
|
Lymphoid B-cell maker
|
|
|
|
CD 3
|
T-cell Lymphoid marker
|
|
|
|
Cytochemistry - use
|
only really good for myeloid, since detects enzyme activity and lymphocytes dont make many enzymes
|
|
|
|
Myeloid cytochemistry markers
|
myeloperoxidase
Sudan D Black Butyrate esterase (monocytes) |
|
|
|
Acute lymphoblastic leukemia (ALL)
|
most common malignancy in pts <15
varying leukocytosis marrow suppression LN, spleen, testis, CNS involvement |
|
|
|
Which involves CNS more, ALL or AML?
|
ALL, bad prognostic sign
|
|
|
|
ALL morphology
|
Blasts with cytoplasmic vacuoles
|
|
|
|
What is critically important for classification of ALL?
|
Immunophenotyping
|
|
|
|
Which is more common, B-ALL or T-ALL and which has better prognosis?
|
B-ALL
|
|
|
|
What is critically important for prognosis/outcome determination of ALL?
|
Cytogenetics, predicts disease outocmes
|
|
|
|
Poor prognostic findings in ALL
|
increased WBC
>2yo hypodiploidy any translocation CNS involvement Males T-ALL |
|
|
|
AML
|
80% of adult acute leukemia
Cytopenias Increased Uric acid (tumor lysis) Splenomegaly Gingival infiltration |
|
|
|
AML Lab Dx
|
Auer rods
Cytochemistry - myeloperoxidase, butyrate esterase (monocytes) |
|
|
|
AML-M3 (APL)
|
Acute Promyelocytic leukemia
Young patients Favorable prognosis Presents with DIC Tx with ATRA |
|
|
|
APL Cytogenetics
|
t(15;17) --> retinoic acid receptor homodimers
|
|
|
|
Young patient with splinter hemorrhages, increased D-dimer
|
DIC --> AML-M3
|
|
|
|
How do you treat APL?
|
ATRA
|
|
|
|
APL Histology
|
Faggot cells (creased cells)
Auer rods Often CD34- |
|
|
|
When are translocations a bad prognosis?
|
ALL
|
|
|
|
When are translocations a good prognostic sign?
|
AML
|
|
|
|
MDS
|
Chronic myeloid disorder, <20% blasts (otherwise AML)
|
|
|
|
Cardinal features of MDS
|
Age 65-70
Prior chemo/radiation Cytopenia (cells die in BM) Hypercellular BM - dysplastic cells Abnormal chromosomes |
|
|
|
MDS sequelae
|
Pre-leukemia
25% develop AML 50% die of complications of cytopenia |
|
|
|
Lab results in MDS
|
Megaloblastic Macrocytic Anemia
r/o folate deficiency |
|
|
|
Clinical presentation of MDS
|
Anemia
Neutropenia Thrombocytopenia |
|
|
|
5q syndrome
|
5q deletion, better prognosis in MDS
responds well to Lenalidomide |
|
|
|
What are good prognostic factors in MDS?
|
5q- deletion, responds well to thalidomide
|
|
|
|
Poor prognostic signs in MDS
|
% blasts
# of cytopenias complex karyotypes |
|
|
|
MDS Tx
|
Transfusion
Supportive (Abx, Epom Hematopoietic growth factors: G-CSF) Lenalidomide Allogeneic stem cell transplant Hypomethylation agents |
|
|
|
MDS Histology
|
Hyperplastic BM
Dysplastic features in all lineages Megaloblastoid RBC (oval macrocytes) Dacrocytes (tear drop cells) hyposegmented neutrophils Pseudo-Pelger-Huet cells (bilobed PMNs) |
|
|
|
Dacrocytes
|
tear drop cells - MDS
|
|
|
|
Pseudo Pelger-Huet Cells
|
MDS
|
|
|
|
Hyposegmented PMNs
|
MDS
|
|
|
|
Name the four Myeloproliferative Disorders.
|
1. CML
2. Polycythemia rubivera 3. Essential thrombocythemia 4. Myelofibrosis |
|
|
|
Which MPDs are JAK2 + ?
|
PV, Essential thrombocythemia, Myelofibrosis
|
|
|
|
Which MPD has the best prognosis?
|
Essential thrombocythemia
|
|
|
|
MPN can evolve into?
|
AML (Blast crisis, >20% blasts)
|
|
|
|
Clinical features of CML
|
Organomegaly
Hypercellular bone marrow Left shifted leukocytosis-myelocyte bulge Basophilia/eosinophilia |
|
|
|
CML genetics
|
t(9;22) - Philadelphia chr - bcr-abl1
constituitively active tyrosine kinase CML - p210 |
|
|
|
CML Tx
|
Gleevec/Imatinib
competively inhibits bcr-abl kinase |
|
|
|
Essential thrombocythemia
|
Large platelets, thrombocytosis
erythromelalgia thrombotic/hemorrhagic complications |
|
|
|
DDx for essential thrombocythemia
|
Reactive thrombocytosis (inflammation, splenectomy, IDA)
Another MPD |
|
|
|
Tx for essential thrombocythemia
|
Low risk: aspirin
High risk: Cytoreduction (hydroxyurea) and aspirin |
|
|
|
Polycythemia vera
|
Increase in RBC mass --> increase Hct
BM problem |
|
|
|
True vs Apparent polycythemia
|
True: PV, 2ary - Epo doping, ectopic Epo tumor, chronic hypoxia
Apparent: dehydration (decrease plasma volume), high normal values |
|
|
|
Distinguish Polycythemia vera from other polycythemias
|
Plasma volume increases in PV but is normal in other polycythemias
|
|
|
|
Polycythemia Clinical Features
|
Post-Bath Pruritus
Budd-chiari syndrome Erythromelalgia Portal Vein thrombosis Splenomegaly Increased WBC, platelets |
|
|
|
4H's
|
Polycythemia vera Sx's
Hyperviscosity Histamine (post bath pruritus) Hypervolemia Hyperuricemia |
|
|
|
Polycythemia vera genetics
|
JAK2+
|
|
|
|
Lab results in PCV
|
Hgb >17.5
Low/nL Epo Increased RBC, WBC, platelets |
|
|
|
PCV Tx
|
PHLEBOTOMY
Cytoreduction (Hydroxyurea) Aspirin |
|
|
|
Pathogenesis of Primary Myelofibrosis
|
Clonal megakaryocyte proliferation --> secrete cytokines --> sclerosis --> ineffective erythropoiesis --> huge splenomegaly
|
|
|
|
Dacrocytes
|
Myelofibrosis and MDS
|
|
|
|
Clinical Features of Myelofibrosis
|
HUGE splenomegaly
Constitutional Sx's |
|
|
|
Histology - Myelofibrosis
|
Dacrocytes
Hypercellular marrow with fibrosis Reticulin stain Megakaryocyte proliferation |
|
|
|
Lymph path through LN
|
Subcapsular sinus --> cortex --> medulla --> hilum --> efferent vessel
|
|
|
|
LN Cortex
|
B-cells
|
|
|
|
Primary LN follicle
|
resting state, B-cells not yet exposed to Ag
|
|
|
|
Secondary LN follicle
|
active state, B-cells proliferate after exposure to Ag
|
|
|
|
Germinal Centers
|
pale central region of a 2ary follicle, lots of mitotic activity --> B-cell proliferation
|
|
|
|
LN Paracortex
|
T-cells
increased size during cellular response help control which B-cells proliferate |
|
|
|
LN Medulla
|
Cords - Plasma Cells
Sinuses - Macs |
|
|
|
Reactive LN hyperplasia
|
Non-malignant
Localized lymphadenopathy |
|
|
|
Tender lymphadenopathy
|
Acute lymphadenitis
|
|
|
|
General histology of reactive LN hyperplasia?
|
LN architecture is preserved
|
|
|
|
3 types of reactive LN hyperplasia
|
Follicular lymphoid hyperplasia (B)
Paracortical lymphoid hyperplasia (T) Sinus histiocytosis (Mac) |
|
|
|
Causes of follicular lymphoid hyperplasia
|
Bacterial infxn
Toxoplasma gondii CMV HIV Auto-immune disease (RA) |
|
|
|
Histology of Follicular lymphoid hyperplasia caused by toxoplasma
|
follicular lymphoid hyperplasia
monocytoid B-cell hyperplasia Epithelioid mac clusters abutting germinal ctr |
|
|
|
HIV - follicular lymphoid hyperplasia
|
follicles have irregular shapes
|
|
|
|
Causes of paracortical lymphoid hyperplasia
|
EBV (infects B-cells, but increases T-cells in response)
Drug rxn (dilantin/phenytoin) SLE Granulomatous lymphadenitis (mycobacteria, fungal inxns, sarcoid) |
|
|
|
Features of Hodgkin's Lymphoma
|
Germinal center B-cell malignancy
Reed-Sterneberg cells Bimodal age distribution Contiguous LN spread Preferentially involves Cervical LN |
|
|
|
HL - Clinical Sx
|
B-Sx
PRURITUS Alcohol induced pain in LN SVC syndrome (mass compression) Painless cervical lymphadenopathy |
|
|
|
3 key histologic features of HL
|
1. Effacement of LN architecture
2. Reactive cell background 3. Neoplastic RS Cells |
|
|
|
Reed-Sternberg Cells
|
Bilobed nucleus
prominent nucleoli HL |
|
|
|
How do you Dx HL?
|
Excisional LN Bx
|
|
|
|
Lacunar cells
|
RS variant
Nodular sclerosing HL subtype |
|
|
|
L&H/Popcorn cells
|
RS variant
Lymphocyte predominant HL subtype (non-classical HL) |
|
|
|
Classical HL - Nodular Sclerosis
|
Most common
young adults mediastinum/cervical LN good prognosis Lacunar cells |
|
|
|
Classical HL - Mixed Cellularity
|
Strong association wiht EBV
|
|
|
|
Classical HL - Lymphocyte depleted
|
Middle aged men, HIV+
disseminated disease Poor diagnosis |
|
|
|
Non-classical HL - Lymphocyte predominant
|
Young males
No B-sx's RELAPSES Excellent prognosis L&H/Popcorn Cells |
|
|
|
What is the most important determinant of prognosis in HL?
|
Staging! Ann-Arbor System
|
|
|
|
Describe HL Ann-Arbors stages.
|
1- single LN region
2- 2 or more LN on same side of diaphragm 3- LN regions on either side of diaphragm 4- Involvement of extra-lymphatic sites (BM, liver) A/B Symptoms |
|
|
|
What are good prognostic factors in HL?
|
Lower stage
Younger age Absence of B-sx Fewer RS cells |
|
|
|
Tx of HL
|
Early: radiation+/-chemo
Late: ABVD |
|
|
|
ABVD
|
Tx for HL
|
|
|
|
Complications of HL therapy
|
Hypothyroidism
Solid tumor post radiation increased leukemia risk with chemo |
|
|
|
Age of HL pts
|
Bimodal: Young adults and elderly
|
|
|
|
Disseminated painless lymphadenopathy
|
think NHL
|
|
|
|
Localized painless lympadenopathy
|
think HL
|
|
|
|
Extranodal involvement is common in this malignancy
|
NHL
|
|
|
|
Reactive cells outnumber neoplastic cells
|
HL
|
|
|
|
Neoplastic cells outnumber reactive cells
|
NHL
|
|
|
|
RCHOP
|
NHL
|
|
|
|
NHL Tx
|
RCHOP
|
|
|
|
Which is more curable, HL or NHL
|
HL
|
|
|
|
Which one has a prognosis that correlates with stage of disease, HL or NHL?
|
HL
|
|
|
|
NHL
|
malignant proliferation of lymphoid, heterogenous, T-cell or B-cell
more often B-cell |
|
|
|
Which is more common, HL or NHL?
|
NHL
|
|
|
|
T-cell markers
|
CD3, any CD< 9
|
|
|
|
B-cell markers
|
CD20, CDs >9
|
|
|
|
Tx of clinical grades of NHL
|
Low: palliatively, chronic disease
Intermediate: aggresively Tx, cure High: Intensive Tx, CNS prophylaxis |
|
|
|
CD5
|
Normal T-cell circulating marker, but used by B-cells as they proliferate, so use for B-cell lymphomas
|
|
|
|
CD5+ NHL
|
Pre-Germinal Cell
CLL/SLL Mantle Cell |
|
|
|
CD10+ NHL
|
Germinal Cell
Follicular DLBCL Burkitt's |
|
|
|
CD5-, CD10- NHL
|
Post-germinal center
Marginal Cell Hairy Cell |
|
|
|
Follicular Lymphoma
|
common NHL in adults
generalized painless adenopathy small cell (centrocytes), nodular bcl2+ t(14;18)--> activates bcl-2 |
|
|
|
follicular lymphoma grading is based on:
|
centrocytes (small) vs centroblasts (large)
|
|
|
|
what can follicular lymphoma transform to?
|
DLBCL (centroblasts)
lose nodularity |
|
|
|
activated bcl-2 NHL
|
Follicular lymphoma
t(14;18) |
|
|
|
t(14;18)
|
activates bcl-2 in follicular lymphoma (inhibits apoptosis)
|
|
|
|
DLBCL
|
most common NHL
Rapidly enlarging Can present in extranodal sites (GI) EBV related Aggressive but curable |
|
|
|
Prognosis of DLBCL
|
aggressive but curable
|
|
|
|
CLL/SLL
|
CLL-BM/PB based
SLL-LN based CD5+ Proliferation centers --> cloudy sky pattern |
|
|
|
Proliferation centers/cloudy sky on histology
|
CLL/SLL
|
|
|
|
Marginal Zone Lymphoma
|
MALT Lymphomas
Indolent Gastric - H.pylori --> B-MALT |
|
|
|
H. pylori can cause what type of malignancy?
|
MALT Lymphoma (marginal cell lymphoma)
|
|
|
|
Mantle Cell lymphoma
|
Worst NHL prognosis --> aggressive but incurable
Elderly CD5+ Extranodal sites - GI (lymphomatous polyposis) t(11;14) |
|
|
|
Lymphomatous GI polyposis
|
Mantle cell lymphoma
|
|
|
|
t(11;14)
|
Mantle Cell Lymphoma
|
|
|
|
Burkitt's Lymphoma
|
Endemic: rapid growing jaw mass in african child, EBV
Sporadic: terminal ileum/pelvic mass in child Immundeficiency-assoc: HIV, dismal prognosis c-myc oncogene t(8;14) |
|
|
|
Rapid growing mass on jaw in african child
|
EBV --> Burkitt's Lymphoma
highly aggressive, but potentially curable |
|
|
|
Burkitt's Lymphoma histology
|
Starry sky pattern --> tingible body Macs amongst sheets of homogenous B-cells
|
|
|
|
Starry sky pattern --> tingible body Macs
|
Burkitt's Lymphoma histology
|
|
|
|
Terminal ileum/pelvic mass in child
|
Sporadic Burkitt's lymphoma
|
|
|
|
C-myc oncogene
|
Burkitt's Lymphoma t(8;14)
drives cells into cell cycle |
|
|
|
t(8;14)
|
Burkitt's Lymphoma
c-myc oncogene |
|
|
|
Precursor T-Lymphoblastic Lymphoma/Leukemia (T-LBL/ALL)
|
Precursor T Lymphoblast
large mediastinal mass |
|
|
|
Mycoides Fungoides
|
Most common T-cell (CD-4) lymphoma of the skin (early)
Late presentation: Sezary, blood involvement |
|
|
|
Sezary syndrome
|
Late presentation of mycoides fungoides in blood
|
|
|
|
CD4+ T-cell lymphoma
|
Mycoides fungoides/Sezary
|
|
|
|
NHL Staging
|
Same as HL Staging
|
|
|
|
t(11;14)
|
Mantle cell
Cyclin-d |
|
|
|
cyclin-d
|
Mantle cell lymphoma
t(11;14) |
|
|
|
Indolent, not curable NHL
|
Follicular lymphoma
|
|
|
|
Aggressive, curable NHL
|
DLBCL
|
|
|
|
Highly aggressive, curable NHL
|
Burkitt's
|
|
|
|
Aggressive, not curable NHL
|
Mantle cell
|
|
|
|
Tx for DLBCL
|
R-CHOP
|
|
|
|
Reactive Lymphocytosis Differential
|
Viral infxns (EBV, CMV)
Bordatella pertussis Toxoplasmosis, mycobacterium Acute infxious lymphocytosis Hypersensitivity rxn (phenytoin) Autoimmune thyrotoxicosis Hyposplenism |
|
|
|
CLL presentation
|
Persistent absolute lymphocytosis
variable lymphadenopathy hepatosplenomegaly Hypogammaglobulinemia (infxns) Warm AIHA Increased bilirubin |
|
|
|
CLL immunophenotyping
|
CD19, 20, 5
|
|
|
|
CLL cytogenetics
|
17p- is bad prognosis (loss of p53 gene)
|
|
|
|
17p-
|
p53 gene is lost
bad prognosis in CLL |
|
|
|
CLL prognostic factors
|
RAI Clinical stage
17p- IgVH mutational status (mutation is better --> exposed to Ag) |
|
|
|
CLL prognosis
|
1/3 have indolent course
1/3 progress to aggressive course 1/3 present in aggresive phase |
|
|
|
Hairy cell leukemia
|
elderly man with:
Pancytopenia, MONOCYTOPENIA, splenomegaly, dry tap BM Bx, TRAP+, red pulp--blood lakes in spleen |
|
|
|
Hairy cell leukemia Tx
|
Responds well to purine analogues
|
|
|
|
T-Cell LGL
|
Neutropenia
Indolent course, long survival assoc. with RA CD8+ |
|
|
|
Adult T-cell leukemia/Lymphoma
|
assoc. with HTLV-1 (reovirus)
CD4+ floret cells Japan, Carribean, Central Africa |
|
|
|
T-cell leukemias
|
Mycoides fungoides/Sezary
T-LGL Leukemia Adult T-cell leukemia/lymphoma |
|
|
|
CD8+ T-cell malignancy
|
T-Cell large granular lymphocyte leukemia
|
|
|
|
Cyclophosphamide toxicities
|
Hemorrhagic cystitis (bladder)
MDS/leukemia |
|
|
|
Doxorubicin toxicity
|
Cardiac (Dilated cardiomyopathy)
|
|
|
|
Vincristine toxicity
|
neuropathy
|
|
|
|
cyclophosphamide MOA
|
DNA cross-links
|
|
|
|
Doxorubicin MOA
|
topoII/helicase inhibitor
|
|
|
|
Vincristine MOA
|
binds tubulin, inhibits MT necessary for mitosis, arrests cells
|
|
|
|
Cytarabine toxicity
|
cerbellar (ataxia, nystagmus)
|
|
|
|
idarubicin toxicity
|
cardiac
|
|
|
|
bleomycin
|
pulmonary fibrosis
|
|
|
|
cytarabine MOA
|
DNA synthesis inhibitor
|
|
|
|
Idarubicin MOA
|
topoII, helicase inhibitor
|
|
|
|
Bleomycin MOA
|
DNA synthesis inhibitor
|
|
|
|
Methotrexate MOA
|
Dihydrofolate reductase inhibitor --> blocks DNA synthesis
|
|
