BCR-ABL fusion

9:22 translocation

Philadelphia chromosome

JAK2 mutation (50%)

MPL mutation (10%)

AML--> see >20% blasts in the bone marrow

MPN-->see hypercellular bone marrow with mature cells

MDS-->see hypercellular bone marrow but maturation is abnormal and final products are reduced (pancytopenia)

CML Chronic Phase Diagnosis

(what about Neutrophil Alkaline Phosphatase?)

• Granulocytosis
• Basophilia or Eosinophilia
• High platelets
• Hypercellular bone marrow with more myeloids than lymphoid cells...less than 5% blasts
• Neutrophil alkaline phosphatase is decreased (this is increased in regular leukomoid rxn)

• Progressive splenomegaly
• Blasts>5% (if greater than 20%...it's AML)
• Fibrosis in bone marrow

High NAP/LAP in Leukemoid Reaction

Low NAP/LAP in CML

Cytogenetics show positive Ph Chrom in CML

• Hgb>18.5 in men or >16.5 in women
• Low EPO (negative feedback)
• JAK2 or exon 12 mutation

Hyperviscosity symptoms

Thrombocytosis

Death from hemorrhage or thrombosis

Treatment: phlebotomies, hydroxurea (for sickle cell too), low-dose aspirin

• Lots of platelets (>450,000)
• Multi-lobed many megakaryoctyes in bone marrow
• No sign of reactive thrombocytosis
• Hemorrhage
• Trauma
• Malignancy
• Hemolytic anemia

Alkylating agents

Topoisomerase II inhibitors

Ionizing radiation

• Pancytopenia
• Elderly or history of chemotherapy
• Dysplasia in the bone marrow
• No splenomegaly
• No lymphadenopathy
• Apoptosis and dysplasia in at least 1 cell line (in BM and blood)

Myelodysplastic Syndrome Genetic Abnormality

(therapy-related)

TH2? 

TH17?

CD40L?

TH2: produced by CD4s, important in eosinophil activations and IgE

TH17: activate neutrophils and monocytes

CD40L: bind to B cells and activate them

Features of Inflammatory or Infectious Lymphadenopathy

(Acute)

• Tender lymph nodes
• Large, reactive germinal centers (B cells being activated there)...not seen in tumors
• Macrophages eat debris in lymph node (starry sky)
• Neutrophils present in lymph node
• Cervical and axillary lymphadenopathy

Features of Inflammatory or Infectious Lymphadenopathy

(Chronic)

(SLE, cat scratch, mycobacterium, HIV)

• Nontender nodes (tender in acute infection)
• Enlarged axillary and inguinal nodes
• Follicular hyperplasia
• Paracortical if T cells are activated (viruses)
• Expanded sinuses (in smokers especially)

• Tuberculosis
• Lymphoma
• Metastatic malignancy

Physical Exam for Lymphadenopathy

Localization

Size

Consistency

Moveability

Tenderness

Location: generalized LAD is systemic disease

Size: bigger they are, more likely to be cancer

Consistency: cancers are hard from fibrosis; firm, rubber in chronic leukemias and lymphomas...soft in acute leukemias

Moveability: immovable by inflammation or cancer

Tenderness: tenderness usually indicates inflammation; nontender may be a sign of cancer/lymphoma

Supraclavicular

Right?

Left?

Right: thoracic malignancy

Left: abdominal malignancy

Open Biopsy

Fine needle aspirate has a lot of false negatives and doesn't show lymph node architecture

*Generalized lymphadenopathy: do a CBC and a CXray...then maybe HIV antibody, ANA, heterophile antibody, PPD

*Localized lymphadenopathy should be monitored for 3-4 weeks if no sign of malignancy (don't just give antibiotics)...if no improvement-->biopsy

WARM=IgG (cells are phagocytosed/hemolyzed in spleen)

COLD= IgM (activate compliment-->intravasc. hemolysis)

PIGA gene

Normally synthesizes GPI anchors used for surface protein attachment-->disorder makes RBC more likely to lyse

1. TTP
2. HUS
3. Malignancy
4. Malignant hypertension
5. SLE (rarely)

G6PD Deficiency

Enzyme deficiency reduces RBC ability to prevent oxidative injury. Heinz bodies are denatured Hgb that precipiates inside of RBC and splenic phagocytes bite them out-->bite cells.

For B12 and Folate deficiencies, which ones will have high methylmalonate and/or high homocysteine levels?

What do the coenzymes synthesize?

B12: high homocysteine and high methylmalonate

Folate: high homocysteine

They lead to the synthesis of thymidine. Deficiencies lead to defective DNA synthesis.

Demyelination of dorsal and lateral columns

Ataxia

Hyperreflexia

Decreased position and vibration sensation

(the case 3 patient had most of these)

Alcoholism

Cirrhosis of the liver traps folate in the liver and causes excessive urinary loss.

(methotrexate can also-->deficiency)

(pregnancy, infancy, and cancer increases folate demand)

What is the most sensitive test for iron deficiency anemia?

What will other iron markers show?

Ferritin (low)

• TIBC will be high (low in chronic disease)
• Serum Fe is low
• Microcytic, hypochromic anemia

What is the main pathogenesis of anemia of chronic disease?

What is hepcidin (hint: not part of main pathogenesis)?

IL-6/inflammation or kidney disease leads to decreased EPO production

Hepcidin is upregulated to decrease iron absorption and to store more iron

The bad HbS aggregates when deoxygenated. This can happen under stress or increased workload. Sickling can occur in times of hypoxia or low pH or dehydration.

The spleen destroys sickled cells.

Sickle-cell anemia

Beta Thalassemia

• Vaso-occlusion-->swelling of hands and feet
• Vaso-occlusion-->painful sickle cell crises
• Splenic infarct-->autosplenectomy-->increased risk for encaspulated bacteria infection
• Aplastic anemia if B19 infection

Fetal Hgb is increased (but it's not adequate)

HbA alpha-chains will also be high and aggregate. This causes decreased RBC lifespan and apoptosis of precursor cells.

Describe the alpha-thalassemias in severity.

1 alpha-globulin affected?

2 alpha-globulins affected?

3 alpha-globulins affected?

4 alpha-globulins affected?

1. Asymptomatic
2. Minimal anemia
3. HbH forms which has a high O2 affinity; severe anemia even with good amount of Hgb
4. Hydrops fetalis/intrauterine death!

• Haptoglobin (decreased in intravascular)
• Hemoglobinuria (increased in intrasvascular) once there is not more haptoglobin capacity
• Hemosiderinuria (increased in recent intravascular) when tubules reabsorb free hemoglobin and convert it to hemosiderin...when tubules are shed, they maintain some hemosiderin
• LDH (really high in MAHA)
• Indirect bilirubin (high in both) and cause jaundice if it overwhelms the liver

Beta thalassemia

Ineffective RBC production-->increased iron absorption and extramedullary erythropoeisis-->splenomegaly

What factor deficiencies will only give you a long PTT?

Differential diagnosis for only a long PTT?

12, 11, 9, 8

Factor 8, 9, or 11 deficiency (hemophilias)

Factor 13 deficiency

Von Willebrand Factor deficiency

Acquired factor inhibitor

Lupus anticoagulant (affecting in vitro test)

Heparin use

What factors are Vitamin K dependent?

What drug affects these factors?

2, 7, 9, 10

Protein C and Protein S

Warfarin

If protein C deficiency, there is a higher likelihood of warfarin skin necrosis because of protein C's short half-life.

That there's a factor deficiency and not a factor inhibitor.

(FEIBA bypasses a Factor 8 inhibitor)

• Von Willebrand disease
• Carrier of factor VIII or IX deficiency (symptoms but normal PTT)
• Mild factor XI deficiency
• Qualitative platelet disorders (e.g. Bernard Soulier or Glanzmann)

(BS=poor adhesion w/ defect in Gp Ib)

(Glanz=poor aggregation w/ defect in Gp IIb/IIIa)

Type 1: Less likely to have joint bleeds, more common to have GI bleeds, mucous membrane bleeding, autosomal dominant, decrease in vWF quantity

Type 2: qualitative defect in vWF; autosomal dominant

Type 3: autosomal recessive; similar to type 1 but more severe

vWF binds to factor VIII in circulation to keep it from getting degraded.

Without vWF, factor VIII may not work.

1. Immune destruction (ITP, drugs)
2. Non-immune causes (HUS/TTP)
3. Hypersplenism
4. Leukemia
5. Aplastic anemia

What is treatment for ITP?

Immune destruction of platelets with lots of megakaryocytes in bone marrow

Epidemiology: common in ages 2-6

• Platelet transfusion (if platelets under 10,000)
• IVIg
• Anti-D Ig (Rhogam) for Rh+ patients to distract macrophages from eating platelets
• Steroids

Antithrombin III Deficiency

Heparin works on ATIII, but in deficiency, it won't have anything to work on

Protein C inhibits factors Va and VIIIa (anticoag)

Protein S is a cofactor for Protein C

Cleaved factor V actually stimulates more Protein C action (+ feedback...really specific detail)

STOP Making New Thromboses

Sepsis, Trauma, Obstetric complication, Pancreatitis, Malignancy (including AML), Nephrotic syndrome, Transfusion reaction

Chronic ITP pathogenesis?

(treatment)?

IgG autoantibodies to gp IIb-IIIa or Ib-X

OR...

Antibodies to platelets 2^o to SLE, HIV, or B-cell neoplasm

Then...phagocytes recognize IgG on platelets and eat platelets

Treat with steroids and splenectomy

1. Megakaryoctyes express CD4 & CXCR4 so they get infected w/ HIV

   ---

2. B-Cell dysregulation-->autoantibody production-->ITP

1. DIC
2. Vitamin K deficiency
3. Liver disease

What is a more common finding in T Cell ALL that can distinguish it frmo B Cell ALL?

[other than cell markers]

Thymic hyperplasia

Others

<25% blasts in the bone marrow (overlap)

Higher incidence in adolescence

ALL: more condensed chromatin, smaller nucleoli, less cytoplasm, lacks granules, does not stain for myeloperoxidase

B-cell ALL: CD 10, CD19, CD20, PAX5, IgM chain

T-cell ALL: CD1, CD2, CD5, CD7...later on, they may show CD3, CD4, and CD8

"Loss of function"

-Balanced t(12:21) translocation involving TEL & AML1

-Mutation on PAX5, E2A, or EBF gene

-Mutations on tyrosine-kinase CRFL2, IKAROS, & JAK are associated with poor prognosis (possibly therapy at JAK)

Fatigue from normocytic anemia

Infection secondary to neutropenia (possible fever)

Bleeding from thrombocytopenia

LAD, hepatospenomegaly, testicular enlargement

CNS symptoms (more in ALL than AML); headache, vomiting, nerve palsies

"Gain of Function"

NOTCH 1 gene mutation

Good prognosis: age 2-10, WBC<10,000, CD10 positive, hyperploidy (only B-cell), trisomy of 4 7 or 10, t(12:21) mutation (only B-cell?)

Bad prognosis: age<2 or >10, WBC>50,000, major organ involvement, CD10 negative, t(9:22) mutation, male

Monocytes

Myeloblastic form of AML will have Auer rods

t(15;17)-->APL

inv(16)

t(8;21)

If following a therapy-associated myelodysplastic syndrome, the abnormality is usually a 5 or 7 deletion

High: leukemoid reaction, polycythemia vera, essential thrombocytosis, primary myelofibrosis

Low: CML, AML