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Genetics > Lecture 5: CML & Hemophilia > Flashcards

Lecture 5: CML & Hemophilia Flashcards

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Biology 101 flashcards
1
Q

Leukemia

A
  1. cancer of hemopoietic tissue that usually produces and extraordinary high number of leukocytes and their precursors
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2
Q

Myeloid Leukemia

A

AML/CML

uncontrolled granulocyte production

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3
Q

Lymphoid Leukemia

A

ALL/CLL

uncontrolled lymphocyte production

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4
Q

Chronic Myelogenous Leukemia (3)

A
  1. Myeloproliferative d/o of granulocytic cells
  2. abnormal cell line is increased in number, but cells produces are functionally inert
  3. the greater the tumor burden of these abnormal cells, the less marrow space and resources exist for other cells such as healthy white blood cells, red blood cells, and platelets
    - results in infections, anemia, and bleeding

OVERVIEW

  1. uncontrolled production of mature and maturing granulocytes
  2. predominately neutrophils, but also basophils and eosinophils
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5
Q

Neutrophils

A

Phagocytic: bateria and fungi

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6
Q

Eosinophil

A

Parasites, allergy, inflammation response

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7
Q

Basophil

A

release histamine

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8
Q

Epidemiology CML

4 rx factors

A
  1. 1.5 cases per 100,000 in the US
    - 4000 cases annually
  2. rx factors
    a. prior high dose radiation exposure (WWII/Chernobyl/Fuskashima)
    b. exposure to certain organic solvents (benzene)
    c. age: median age at presentation is 55 years
    d. Male >female
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9
Q

CML Clinical Presentation (5)

A
  1. 30% asymptomatic
    -elevated WBC >25,000/L
    discovered incidentally
  2. fatigue, night sweats, weight loss, fever
  3. abdominal fullness, pain and/or early satiety due to splenomegaly
  4. easy bruising and purpura
  5. sternal tenderness-may be a sign go marrow over expansion
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10
Q

Genetics CML

final result

final product

A
  1. Fusion of 2 genes:
    a. BCR (chromosome 22)
    b. ABL 1 (chromosome 9)
    =fusion BCR-ABL 1 gene
  2. final result: abnormal chromosome 22 called philadelphia (Ph) chromosome
  3. Final product: BCR-ABL 1 fushion protein, dysregulated tyrosine kinase
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11
Q

Cml and Ph chromosome

A
  1. detected chromosome abnormalities via FISH
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12
Q

Pathophysiology CML and Ph chromosome (4)

A
  1. the BCR (breakpoint cluster region) gene is located on chromosome 22 and is constitutively active
  2. proto-oncogene ABL on chromosme 9 codes for tyrosine kinase involved in growth regulation and has a well-regulated expression pattern
  3. translocation t(9;22) results in a fushion gene with loss of expression and regulation, leasing to increased tyrosine kinase activity and increased cell proliferation
  4. a philadelphia chromosome occurs in more than 90% of CML (classic CML)
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13
Q

BCR-ABL fusion protein and its role in CML pathogenesis (3)

A
  1. promotes cellular proliferation via tyrosine kinase activity
  2. oligomerazation of bcr/abl is crucial for oncogenicity
  3. tumor proliferation
    - speed up cell divion
    - inhibit DNA repair
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14
Q

Diagnostic Studies CML (4)

A
  1. Demonstrating the presence of the t(9:22) or its gene product is aboluletly essential in diagnosing a patient with CML*
  2. Cytogenetic analysis (karyotype) of bone marrow is needed in all cases at diagnosis
    - ID Philadelphia chromosome and other chromosomal abnormalities
  3. FISH
    - can ID bcr/abl rearrangement even if philadelphia chromosome cannot be identifies by cytogenetic analysis
  4. Quantitative polymperase chain reaction (PCR)
    - baseline measure of bcr/abl transcript levels prior to the start of therapy
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15
Q

Phases CML based on 2 factors

A
  1. number of immature cells in the blood and bone marrow biopsy
  2. severity of patient’s symptoms
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16
Q

Early Stage CML

A

<10% blast cells in blood and bone marrow samples

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17
Q

Accelerated stage CML

A

10-20% blasts, platelet counts decline

-usually within 6-8 months

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18
Q

Final/blastic phase CML (3)

A
  1. 20% or more blasts
  2. Bastic Crisis: cellular criteria of blast phase accompanies by fatigue, fever, splenomegaly
    - resembles acute leukemia
  3. median survival point is less than 4 months oftentimes
19
Q

Treatment CML (3)

A
  1. Tyrosine Kinase Inhibitors
  2. Allogenic bone marrow transplantation
  3. Cemotherapeutic agents
20
Q

Tyrosine Kinase Inhibitors

A
  1. treatment for CML
  2. Imatinib Mesylate
    a. inducing apoptosis in cells with bcr/abl gene
    b. 70% patients on TKI will have a complete cryogenic response (no philadelphia chromosome detected)
    c. used in high doses for blast phase
    d. effective for shorter durations, requires higher doses id advanced stages
21
Q

Allogenic Bone marrow transplantation for CML

A
  1. rarely used to patients in chronic phase
  2. good option for younger, otherwise healthy patients in accelerated or blast phases
    - less successful for the blast phase
22
Q

chemotherapeutic agents for CML

A
  1. hydroxyurea

- induces rapid disease control often necessary to prior treatment

23
Q

Prognosis CML

factors affected chance of recovery (5)

A
  1. 80% are alive and without disease progression at 6 years with the use of imatinib mesylate and other molecular targeted agents
  2. factors affecting chance of recovery
    a. patient age
    b. phase CML
    c. amount of blasts in blood or bone marrow
    d. size of spleen at diagnosis
    e. general health of patient
24
Q

Hemophillias (2)

A

Hereditary clotting d/o

  1. Factor VIII deficiency (Hemophilia A)
  2. Factor IX deficiency (hemophilia B)
25
Q

3 Pathways that makeup the classical blood coagulation pathway

A
  1. Intrinsic
  2. Extrinsic
  3. common
26
Q

Epidemiology Hemophilia (2)

A
  1. Hemophila A most frequent of the severe coagulation d/os
  2. Men 1 in 10,000 for A
    - 1 in 30,000 for hemophilia B
27
Q

Genetics of Hemophilia A (classic hemophilia) (5)

A
  1. x-linked gene factor VIII
  2. predominantly in males
  3. Mild, moderate, severe forms depend on specific mutation
    - Large gene: many different mutations, new mutations common due to large size
    - clinical manifestations proportional to the amount of normal f8 protein present
  4. lack of factor VIII, normally part of activation of factor X at start of common pathway
  5. decreased fibrin production
28
Q

Genetics of Hemophilia A

A
  1. F8 gene responsible for making coagulation factor VIII
  2. the F8 gene for factor VIII is located close to the ends of the long arm of the X chromosome (Xq28)
  3. 5% have deletions in f8 gene that have also been assoc. with severe hemophilia
  4. homozygous hemophilia A in women is extremely rare.
    - if a woman proved to be hemophiliac, Turner Syndrome should be rules out
    - alternate explanations are skewed, X inactivation, a translocation of the f8 gene or antibodies against clotting factors
29
Q

Genetics of Hemophilia B (7)

A
  1. Defect in factor IX gene on X-chromosome
    - x-linked
  2. seen in males
  3. “christmas disease” first identified in stephen Christmas
  4. results in production of functionally impaired factor IX proteins
  5. clinical manifestations proportional to the amount of normal F9 protein present
  6. similar to A, but much less common
  7. mutation seen in european royals is in hemophilia B
30
Q

Variable Expressivity

A
  1. means that the expression of the disease is variable among those who are affected
  2. severity of symptoms is variable
31
Q

Severe Hemophilia

A

<1%

spontaneous joint and muscle bleeding; post-trauma and postoperative bleeding

32
Q

Moderate Hemophilia

A

1%-5%

bleeding in joints and muscles due to minor trauma, postoperative bleeding

33
Q

Mild Hemophilia

A

5-40% postoperative and mild trauma bleeding

34
Q

Dx Hemophilia (4)

A
  1. prolonged bleeding after injury, surgery, or tooth extortion
  2. Menorrhagia, hematochezia, or melena
  3. 75% may have family history of bleeding d/o while 25% may not have a family hx (de novo mutation)
  4. hemarthroses
35
Q

Testing and counseling hemophilia

A
  1. screen all bleeding d/o by APTT measurement, PT measurement, and bleeding time measurement and a platelet count
  2. order specific coagulation factor assays based on results from screening
36
Q

APTT

A

good measure of intrinsic pathway

37
Q

PT

A

evaluates extrinsic pathway

38
Q

Management & treatment hemophilia

A
  1. estrogens, orgal contraceptives, epinephrine, desmopressin acetate, and vigorous exercise can be used to increase the levels of factors VIII and IX
  2. specific factor deficiencies can be corrected through infusion of synthetic factors
  3. referral to hemophilia treatment centers
    a. federally funded hospitals
    b. team approach to treatment -> comprehensive care
    c. lower mortality rates
39
Q

Syndromes Assoc with hemophilia (4)

A
  1. Von Willebrand’s disease
  2. Factor XI deficiency
  3. Hemophilia B Leyden
  4. Acquired Hemophilia
40
Q

Normal Functions vWF (2)

A
  1. forms complex with factor VIII
    - protects it from inactivation and clearance
  2. vWF interacts with platelets and collagen during clotting to form the platelet plug
41
Q

Von Willebrand’s disease

A

bleeding d/o assoc. with low factor VIII activity in which von willebrand factor is missing or does not function properly

*can be assoc. with hemophilia

42
Q

Acquired Hemophilia

A

similar to inherited hemophilia, but due to autoantibodies and usually first appears in adulthood

  • can be assoc. with hemophilia
43
Q

Hemophilia B Leyden

A

rare variant of hemophilia B inherited in x-linked pattern

  1. altered developmental expression of factor IX
  2. assoc. with several point mutations in the gene for factor IX
  3. episodes of excessive bleeding in childhood that resolves after puberty
44
Q

Factor XI Deficiency

A
  1. AKA Plasma thromboplastin antecedent (PTA deficiency) /Hemophilia C
    - deficient of factor IX and is second only to vWF disease among bleeding d/o women
    - autosomal recessive
    - mild, most don’t require treatment

Genetics (14 decks)

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