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4. HDS Multisystem > Stem Cell Disorders > Flashcards

Stem Cell Disorders Flashcards

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)

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

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

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

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

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

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

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

A
  • Mild symptoms ⇒ phlebotomy
  • More significant sx ⇒ myelo-suppressant agents (Busulfan)
  • Goal of tx is to achieve a nl HCT
25
Q

Essential Thrombocytosis

Overview

A
  • 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
Q

Essential Thrombocytosis

Clinical Manifestations

A

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
Q

Essential Thrombocytosis

Laboratory Findings

A
  • Laboratory Findings
  • Sustained platelet count > 450K
  • Peripheral blood: platelets of different morphologies
    • Large platelets
    • Hypogranular platelets
  • Abnormal platelet aggregation studies
28
Q

Essential Thrombocytosis

Course and Prognosis

A
  • Median survival better than PV
  • < 10% transform to acute leukemia
  • Death due to hemorrhage or fatal thrombosis
29
Q

Essential Thrombocytosis

Treatment

A
  • Plateletpheresis ⇒ used to emergently drop the platelet count
  • More significant sx ⇒ add myelosuppressant agent
    • Busulfan, Hydroxyurea, Agrylin
  • Goal platelet count 300K – 400K
30
Q

Agnogenic Myeloid Metaplasia

Overview

A

“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
Q

Agnogenic Myeloid Metaplasia

“Primary Myelofibrosis”

Differential Diagnosis

A
  • Metastatic cancer to the bone
  • Infections and granulomas
  • Hairy cell leukemia
32
Q

Agnogenic Myeloid Metaplasia

“Primary Myelofibrosis”

Clinical Manifestations

A
  • Early satiety and weight loss
  • Massive spleen
  • Abdominal pain
  • Anemia
  • Bone pain
33
Q

Agnogenic Myeloid Metaplasia

“Primary Myelofibrosis”

Pathology

A
  • 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
Q

Agnogenic Myeloid Metaplasia

“Primary Myelofibrosis”

Diagnosis

A

Via bone marrow biopsy ⇒ see fibrosis and osteosclerosis

Megakaryocytes release platelet derived growth factor (PDGF) ⇒ ⊕ fibroblasts ⇒ fibrosis

35
Q

Agnogenic Myeloid Metaplasia

“Primary Myelofibrosis”

Course and Prognosis

A
  • 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
Q

Agnogenic Myeloid Metaplasia

“Primary Myelofibrosis”

Treatment

A
  • Supportive care
  • Chemotherapy
  • Splenectomy ⇒ for severe cytopenias or severe sx
  • Bone Marrow Transplant ⇒ may reverse fibrosis
37
Q

Chronic Myelogenous Leukemia (CML)

Overview

A
  • 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
Q

Chronic Myelogenous Leukemia (CML)

Chromosomal Abnormalities

A
  • 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
Q

Chronic Myelogenous Leukemia (CML)

Pathology

A
  • 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
Q

Chronic Myelogenous Leukemia (CML)

Clinical Course

A
  • 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
Q

Chronic Myelogenous Leukemia (CML)

Treatment

A
  • 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 (43 decks)

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