4. HDS Multisystem > Stem Cell Disorders > Flashcards

Stem Cell Disorders Flashcards

(41 cards)

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1
Q

Aplastic Anemia

Overview

A
  • A relatively uncommon disease
  • Due to injury/destruction of the pluripotent stem cell
  • Affects all subsequent cell populations ⇒ pancytopenia
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2
Q

Aplastic Anemia

Etiologies

A
  • 50% of cases have no identifiable cause
  • Congenital
    • Fanconi’s anemia
  • Immune
    • Ab that ⊗ hematopoiesis
  • Drugs/Toxins
    • Predictable dose-related → idiosyncratic (unpredictable)
    • Usu. improves w/ withdrawal of the agent
    • Ex: chemotherapy, immunosuppressant drugs, XRT acute exposure – industrial accident benzene, gold, NSAIDS, neuroleptics
    • Chloramphenicol ⇒ both reversible dose-related and idiosyncratic rxns
      • Idiosyncratic rxn is irreversible and fatal
      • Occurs in 1 in 50K people who take the drug
  • Viral
    • Hepatitis ⇒ usu. hep C; EBV
  • Thymoma
  • Pregnancy
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3
Q

Fanconi’s Anemia

A

AR trait

Associated with:

  • Hypoplasia or other abnormalities of the kidneys
  • Hyperpigmentation of the skin
  • Hypoplastic or absent thumbs and radii
  • High risk of developing acute leukemia
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4
Q

Aplastic Anemia

Clinical Manifestations

A
  • Weakness, fatigue, high output failure
  • Infection
  • Bleeding
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5
Q

Aplastic Anemia

Diagnosis

A
  • Ultimately rests in the bone marrow interpretation
    • Must distinguish from hypoplastic myelodysplasia
  • Peripheral blood – pancytopenia
  • Bone marrow –aplasia; replaced w/ fat
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6
Q

Aplastic Anemia

Treatment

A
  • Supportive care
  • Transfusions
  • Abx
  • Immunosuppressant agents
    • ATG; cyclosporine
    • 50% of pts respond
  • Bone marrow transplant
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7
Q

Pure Red Cell Aplasia

A
  • Selective failure of the red cell precursors
  • Other cellular elements are normal
  • Associated w/ Parvo B19 infection
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8
Q

Myelophthisic Anemia

A
  • Infiltration of the bone marrow by tumor, fibrosis, granuloma
    • Most common malignancies ⇒ breast, prostate, lung, thyroid
  • Thrombopoiesis is impaired but usu. not neutrophil production
    • Often see a left shift
  • Severe normochromic, normocytic anemia w/ teardrop cells and nucleated red blood cells
  • Bone marrow biopsy is diagnostic
  • Treat the underlying disorder
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9
Q

Myelodysplastic Syndromes (MDS)

Overview

A
  • Clonal disorder in which the exact mechanism remains undefined
  • Ineffective hematopoiesis ⇒ peripheral cytopenias and hypercellular marrow
  • Chromosomal abnormalities seen in 50-60% of cases
  • Complex cytogenetics
  • Associated w/ rapid progression to acute leukemia
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10
Q

Myelodysplastic Syndromes (MDS)

Secondary Causes

A
  • Alkylating agents:
    • Cytoxan
    • Mustine
    • Nitrosureas
    • Procarbazine
    • Melphalan
    • Benzene
    • Insecticides
    • Pesticides
  • Typically occur 2-3 years after exposure
  • If d/t chemotherapy, can be up to 5-7 years
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11
Q

Myelodysplastic Syndromes (MDS)

Clinical Manifestations

A
  • Anemia: Pallor
  • Thrombocytopenia: Bleeding
    • 60% of pts have thrombocytopenia
  • Leukopenia: Fever, infection
    • 60% of pts neutropenic and cannot mount an inflammatory response to infection
    • Qualitative abnormality in neutrophils
  • 10% of pts present initially w/ infection
  • Cause of death in 21% of pts
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12
Q

Myelodysplastic Syndromes (MDS)

Pathology

A
  • Peripheral Blood ⇒ Macrocytic anemia (↑MCV)
    • Multinucleated primitive RBCs
    • Abnormal neutrophils
    • Hypolobulated PMNs ⇒ Pelger-Huet anomaly
    • Agranular PMNs
    • Abnormally large platelets
  • Bone Marrow ⇒ Hypercellular
    • ↑ Cells in intermediate stages of maturation: ringed sideroblasts, micromegakaryocytes, multinucleated normoblasts
    • ↑ Iron stores
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13
Q

Myelodysplastic Syndromes (MDS)

FAB Classification

A
  • Refractory Anemia (RA) ⇒ < 5% blasts in marrow
  • Refractory Anemia w/ Ringed Sideroblasts (RARS) ⇒ 15% sideroblasts in iron stains of the marrow
  • Refractory Anemia w/ Excessive Blasts (RAEB) ⇒ Blasts of 5% to < 20%
  • Refractory Anemia w/ Excessive Blasts in Transformation (RAEB-T) ⇒ > 20% blasts (now defined as acute leukemia)
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14
Q

Chronic Myelomonocytic Leukemia (CMML)

A
  • Peripheral monocytosis > 1,000/ul accompanied by other lineage cytopenia
  • Peripheral blasts < 5%
  • Dysplastic ∆ in the marrow
  • Often see pleural/pericardial effusions from 3rd spacing of fluids
  • ± Hepatosplenomegaly
  • Some feel that it belongs to the myeloproliferative disorders
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15
Q

Myelodysplastic Syndromes (MDS)

Chromosomal Abnormalities

A

Most common:

  • Trisomy 8, 5q
  • Monosomy 7
  • Complex (> 3)
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16
Q

Myelodysplastic Syndromes (MDS)

Treatment

A
  • Supportive Care
  • Aggressive Chemotherapy ⇒ anti-leukemia drugs
  • Experimental ⇒ monoclonal Ab, Arsenic
  • Hypomethylating agents ⇒ help ∆ of marrow and ⊕ nl hematopoiesis
  • Bone Marrow Transplant
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17
Q

Myeloproliferative Neoplasms

(MPN)

Study These Flashcards
A
  • Neoplasms of the multipotent stem cell
  • Diseases share features and overlap
  • Often have cytogenetic abnormalities ⇒ can progress to acute leukemia
  • Except CML, diseases run a chronic course over many years
  • 4 main types are:
    • Polycythemia Vera
    • Essential thrombocytosis
    • Agnogenic Myeloid Metaplasia
      (also known as Primary Myelofibrosis)
    • Chronic Myelogenous Leukemia (CML)
18
Q

Polycythemia Vera

Study These Flashcards
A
  • Clonal disorder involving the hematopoietic stem cell
  • Leads to autonomous proliferation of erythroid, myeloid, and megakaryocytic cell lines w/ red cells predominating
  • Males > females
  • Occurs in middle life
    • Average age @ dx is 60-65 years
  • Must be distinguished from secondary polycythemia
19
Q

Secondary Polycythemia

Study These Flashcards
A

Caused by ↑ erythropoietin

  • Physiologic Secondary Polycythemia
    • High altitude
    • Right to left shunts
    • Chronic lung disease
    • Hemoglobin – oxygen dissociation abnormalities
  • Pathologic Secondary Polycythemia
    • Kidney cysts or renal transplant
    • Neoplasms ⇒ renal cell, hepatoma, pheochromocytoma
    • Adrenal cortical hypersecretion
    • Exogenous androgens
20
Q

Polycythemia Vera

Criteria

Study These Flashcards
A
  • Category A:
    • Total RBC mass > 36 mg/kg (Male) / > 32 mg/kg (Female)
    • Arterial oxygen saturation > 92%
    • Splenomegaly
  • Category B:
    • Thrombocytosis (> 400K)
    • Leukocytosis (> 12K)
    • ↑ LAP (leukocyte alkaline phosphatase) score
    • Serum B12 > 900 pg/ml or B12 binding capacity > 2200pg/ml
    • Polycythemia Vera dx is established by presence of certain combinations of these criteria
21
Q

Polycythemia Vera

Clinical Manifestations

Study These Flashcards
A
  • Ineffective hematopoiesis ⇒ anemia:
    • Fatigue
    • Pruritus (likely from hyper-catabolism)
    • Night sweats
    • Bone pain
    • Fever
    • Weight loss
  • Sx that reflect ↑ plasma viscosity:
    • Headaches
    • Dizziness
    • Blurred vision
    • Chest pain
    • Thrombosis
    • Bleeding
  • Extramedullary hematopoiesis ⇒ splenomegaly
  • Consider PV in people who develop unprovoked thrombo-embolic event and in unusual sites such as dural sinuses
22
Q

Polycythemia Vera

Prognosis

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A
  • Without therapy, median survival is 2 years
  • W/ phlebotomy alone, survival is 10-12 years
  • 10% have progressive fibrosis and anemia ⇒ spent phase
23
Q

Polycythemia Vera

Complications

Study These Flashcards
A
  • Clonal Evolution
    • Can transform to MDS and/or AML
    • 10% risk w/ PV at 10 years of follow-up
    • Highest w/ CML (90%)
    • Lowest w/ Essential Thrombocytosis (5%)
  • Bleeding
    • Usu. mild and occurs at high platelet counts
  • Thrombosis
    • Arterial and venous thrombosis
    • Microcirculatory d/o like erythromelagia (episodes of pain, redness, and swelling in various parts of the body)
24
Q

Polycythemia Vera

Treatment

Study These Flashcards
A
  • Mild symptoms ⇒ phlebotomy
  • More significant sx ⇒ myelo-suppressant agents (Busulfan)
  • Goal of tx is to achieve a nl HCT
25
Essential Thrombocytosis Overview
* Clonal disorder of the hematpoietic stem cell * **Leads to autonomous proliferation of all cell lines w/ platelets predominating** * Platelet count can be as high as 3 to 4 million * An overproduction of platelets in the absence of stimulus * Must rule out reactive thrombocytosis which can be caused by: * Inflammation, Bleeding, Iron deficiency, Hemolysis, Malignancy, Post-splenectomy * **Usu. occurs in age \> 60 years**
26
Essential Thrombocytosis Clinical Manifestations
Sx are linked to platelet dysfunction and aggregation in the microvasculature: * **Thrombosis** * **Bleeding** * **Headaches** * **Amaurosis fugax** (blindness due to a lack of blood flow) * **Pruritis** * **Claudication** * **Early satiety** 2/2 hepatomegaly and/or splenomegaly
27
Essential Thrombocytosis Laboratory Findings
* Laboratory Findings * **Sustained platelet count \> 450K** * Peripheral blood: **platelets of different morphologies** * Large platelets * Hypogranular platelets * **Abnormal platelet aggregation studies**
28
Essential Thrombocytosis Course and Prognosis
* Median survival better than PV * \< 10% transform to acute leukemia * Death due to hemorrhage or fatal thrombosis
29
Essential Thrombocytosis Treatment
* **Plateletpheresis** ⇒ used to emergently drop the platelet count * More significant sx ⇒ **add myelosuppressant agent** * Busulfan, Hydroxyurea, Agrylin * Goal platelet count 300K – 400K
30
Agnogenic Myeloid Metaplasia Overview
**“Primary Myelofibrosis”** Characterized by: * **Progressive fibrosis of the bone marrow** * **↑ Proliferation of granulocytes and platelets** * Development of **extramedullary hematopoiesis** * Usu. occurs in **age \> 60 years**
31
Agnogenic Myeloid Metaplasia “Primary Myelofibrosis” Differential Diagnosis
* Metastatic cancer to the bone * Infections and granulomas * Hairy cell leukemia
32
Agnogenic Myeloid Metaplasia “Primary Myelofibrosis” Clinical Manifestations
* Early satiety and weight loss * Massive spleen * Abdominal pain * Anemia * Bone pain
33
Agnogenic Myeloid Metaplasia “Primary Myelofibrosis” Pathology
* _Peripheral Blood:_ * **Anemia w/ pancytopenia** * **Tear drop cells** * Abnormal large platelets * Presence of precursor WBCs and nucleated RBCs * _Bone Marrow:_ * **“Dry tap”** ⇒ difficult to aspirate * ↑ megakaryocytes * **\> ⅓ myelofibrosis w/ ↑ reticulin + collagen** * **Extramedullary hematopoiesis** ⇒ spleen, kidneys, liver, lungs, adrenal glands
34
Agnogenic Myeloid Metaplasia “Primary Myelofibrosis” Diagnosis
**Via bone marrow biopsy ⇒ see fibrosis and osteosclerosis** Megakaryocytes release platelet derived growth factor (PDGF) ⇒ ⊕ fibroblasts ⇒ fibrosis
35
Agnogenic Myeloid Metaplasia “Primary Myelofibrosis” Course and Prognosis
* **Usu. asymptomatic for the first 1- 2 years** * Median survival 5 years * Some may live up to 15 years * Those w/ platelet counts \< 100K and hemoglobin \< 10 g have a worse prognosis * **Death due to infection, CHF, bleeding, portal HTN**
36
Agnogenic Myeloid Metaplasia “Primary Myelofibrosis” Treatment
* **Supportive care** * **Chemotherapy** * **Splenectomy** ⇒ for severe cytopenias or severe sx * **Bone Marrow Transplant** ⇒ may reverse fibrosis
37
Chronic Myelogenous Leukemia (CML) Overview
* **Myeloproliferative disorder** * **↑ proliferation of granulocytes w/o loss of their capacity to differentiate** * Dx is often made incidentally on routine CBC * CML encompasses **15-20% of adult leukemias** * Seen mainly in **ages 25-60 years** * Usu. there are no predisposing factors in pts presenting w/ the disease * ↑ incidence seen in persons exposed to atomic bombs in Hiroshima and Nagasaki * ↑ incidence seen in pts who had radiation for Ankylosing Spondylitis or cervical cancer
38
Chronic Myelogenous Leukemia (CML) Chromosomal Abnormalities
* **The Philadelphia Chromosome** * Translocation b/t chromosomes 9 and 22 * c-abl oncogene from chromosome 9 → bcr breakpoint on chromosome 22 * Aberrant **bcr/abl** transcript ⇒ **tyrosine kinase gene product w/ enhanced activity** * ⊕ Cell division much greater than normal c-abl gene product * ⊗ Apoptosis * Unregulated myeloproliferation * **JAK2** * Located on short arm of chromosome 9 * Mutations ⇒ constitutive tyrosine kinase phosphorylation activity ⇒ **hypersensitivity to cytokines** * **Most abundant in RBCs and myeloid cells** * Dysregulated TK activity ⇒ possible tx approaches such as in CML
39
Chronic Myelogenous Leukemia (CML) Pathology
* _Peripheral Blood:_ * **↑ in granulocytes** w/ presence of immature or intermediate stage cells of myeloid series * **± ↑ Basophils** * **↑ Platelets** * **↓ (zero) in LAP score** * _Bone Marrow:_ * **Hypercellular w/ ↑ in myeloid elements**
40
Chronic Myelogenous Leukemia (CML) Clinical Course
* **_Chronic Phase_** * Most pts are asymptomatic * **Peripheral blood leukocytosis \> 25K**, can be up to 300K * Mild splenomegaly and anemia * Thrombocytosis * Lasts 2-3 years * **_Accelerated Phase_** * Usu. 3-4 years after presentation * **↑ Resistance to therapy** * **↑ Marrow and peripheral blasts** * Splenomegaly despite therapy * ± Extramedullary disease * Cytogenetic evolution * Median survival 8-18 months * **_Blast Crisis (Acute leukemia)_** * Develops in 75-85% of pts * **Can be AML or ALL** * Survival 3-6 months * **20% blasts or blasts + promyelocytes in blood/marrow** * Constitutional sx (fever, sweats) * Infection * Anemia * Thrombocytopenia * Extramedullary disease
41
Chronic Myelogenous Leukemia (CML) Treatment
* **Hydroxyurea** * Still occassionally used until dx established ⇒ ↓WBCs while awaiting genetics * **Interferon-α** * Hematologic control in 70-80% * **Imatimib (Gleevac) STI571** * ⊗ ATP receptor preventing phosphorylation * Tyrosine kinase gene product cannot be made * **Bone Marrow Transplant** should be performed within one year of dx for best results
4. HDS Multisystem
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