Petchrod,Thanat 1

Agents used in anemia

Anemia (ภาวะโลหิตจาง)
เป็ นภาวะที่มีการลดลงของเม็ดเลือดแดง หรื อ hemoglobin ส่งผลให้ มีการขนส่ง O2 ไปสูเ่ นื ้อเยื่อต่างๆของร่างกายลดลง
Causes of anemia
 increased RBCs loss (e.g. acute or chronic blood loss)
 decreased production of RBCs (e.g. iron, folic acid or vitamin B12 deficiency)
 increased destruction of RBCs (e.g. hemolysis)

Classification of anemia
 Microcytic, hypochromic anemia e.g. iron deficiency anemia
 Normochromic, normocytic anemia e.g. recent blood loss
 Macrocytic anemia e.g. folic acid deficiency, vitamin B12 deficiency

Iron deficiency anemia (Microcytic, hypochromic anemia)

- most common cause of anemia
- a state of negative iron balance
Etiology

 blood loss, increased iron requirements,

 decreased iron absorption, poor diet

Treatment
 Petchrod,Thanat 2

 รักษาตามสาเหตุ และ/หรื อ iron supplement

Megaloblastic anemias
Etiology
- deficiency of vitamin B12 or folate (cofactors required for the normal maturation of red blood cells)
Treatment
- รักษาตามสาเหตุ เช่น vitamin B12 or folic acid supplement
Agents used in anemias
• Iron
• Vitamin B12
• Folic acid

Role of iron
- essential metallic component of heme
- heme combined with appropriate globin chains forms hemoglobin (Hb)
Pharmacokinetics: Absorption
 Iron is best absorbed in ferrous form (Fe2+)
 Absorption is maximum in duodenum because acid medium of stomach and mucopolysaccharide
chelator substances that prevent iron from precipitating maintain iron in soluble form
 Food interferes with iron absorption therefore it should be administered 1 hr or more before meal
 Iron must be taken with food if patients experience nuasea and diarrhea when taking on empty
stomach
 At alkaline pH, iron tend to form insoluble complex (unavailable for absorption)
 Antacid or medication that reduce stomach acid production impairs iron absorption

Clinical use
 Treatment or prevention of iron deficiency anemia

Oral iron products Ferrous sulfate ----60-65 mg/300- or 325-mg tablet

Parenteral formulation: iron dextran

Adverse effect
 oral iron therapy: GI tract upsets (e.g. nausea, epigastric discomfort, abdominal cramps, constipation,
diarrhea, feces discoloration)
 parenteral iron therapy: immediate hypersensitivity reaction (a small test dose of iron dextran should
always be given)
 Petchrod,Thanat 3

ferro
us
sulfat
eferro
300
mgus
fumar
ferrou
ate
s
200
gluco
mg
nate
300
mg
Iron toxicity
Acute toxicity
- most common in children & usually occurs as a result of accidental ingestion of iron therapy
- urgent treatment is necessary lavage with carbonate solutions, desferoxamine, deferiprone
(licensed in UK)

Chronic iron toxicity (iron overload)

- occurs most often in patients who must receive frequent transfusions, and in those with hemochromatosis (a
disorder characterized by excessive iron absorption)
Iron toxicity
 2 categories: corrosive and cellular toxicities
 Iron is extremely corrosive in GI system manifested as hematemesis or diarrhea
 Severe overdose causes impaired oxidative phosphorylation and mitochondria dysfunction, which can
result in cellular death
 The most affected organ is liver and others including heart, kidneys, lungs and hematologic systems
Desferoxamine
Used to prevent and treat iron overload

Adverse effect

Tinnitus “Not related to deferoxamine dosage”

Reversible transient hearing loss

Less common: decresed night vision

 Petchrod,Thanat 4

 iv infusion > 15 mg/kg/hr may induce hypotension and shock

 Allergic reaction including anaphylaxis (not common)
 Hydrocortisone can be mixed with desferoxamine to reduce allergic reaction
 Diluting desferoxamine reduces irritation at the site of administration
 Excessive iron chelation will cause growth disturbance in children and mineral deficiency

Vitamin B12 (cyanocobalamin)

is a cofactor in the transfer of one-carbon units (step necessary for DNA synthesis)

essential nutrient for hematopoiesis, maintenance of myelin in the nervous system, and production of
epithelial cell

Absorption requires “intrinsic factor” from parietal cell of stomach

Frequent cause of Vit.B12 deficiency is atrophic gastritis leading to lack of intrinsic factor

Besides megaloblastic anemia, damage to mucosal linings and degeneration of myelin sheats with
neurologic sequelae will occur (pernicious anemia)

Vit. B12 is essential in 2 reactions:

1.conversion of homocysteine to methionine (is essential for normal production of RBCs)

2.conversion of methylmalonyl-CoA to succinyl-CoA (essential for lipid metabolism)

 Petchrod,Thanat 5

Clinical use

- available as hydroxocobalamin & cyanocobalamin (have equivalent effects)

- oral cyanocobalamin is well absorbed (peak serum conc.being reached 8-12 hr after ingestion)

- caused by inadequate absorption therapy should be parenteral

Folic acid
 is necessary for synthesis of purines & for the formation of thymidylic acid
 body store is very low, so a decrease in dietary intake is followed by anemia within a few months
 Folates are found in fresh foods but rapidly destroyed by heating during food preparation
Cause of deficient
 Insufficient intake
 Malabsorption in GI diseases
 Increased requirement during pregnancy
 Antiepileptis drugs (phenytoin, primidone, phenobarbital) may decrease FA absorption

Clinical use

Megaloblastic anemias

Folic acid deficiency due to malabsorption syndrome and due to continuous use of anticonvulsants,
particular primidone and phenytoin

Administration of FA can mask Vit.B12 deficiency.

Inhibition due to B12 deficiency is compensated by increased FA intake.

The anemia is readily corrected but nerve degeneration progresses unchecked.

Therefore, indiscriminate use of FA-containing multivitamin preparations can be harmful.

Haemopoietic Growth Factors

 Erythropoietin

 Colony-stimulating factors

 Thrombopoietin
 Petchrod,Thanat 6

Blood cell development

Erythropoietin
 Regulates red cell production
 2 forms of recombinant human erythropoietin: epoetin alfa and epoetin beta (similar activity)
 Given iv.,sc. or ip.
 Greatest response with sc.injection
 Fastest response with iv.injection
Clinical uses
 Anemia of chronic renal failure
 Petchrod,Thanat 7

 Anemia during chemotherapy for cancer

 Prevention of anemia that occurs in premature infants
 To increase yield of autologous blood before donation
 Anemia of AIDS (which is exacerbated by zidovudine treatment)
 Anemia of chronic inflammatory conditions such as rheumatoid arthritis
Adverse effects
 Transeint influenza-like symptoms
 Hypertension
 Encephalopathy with headache, disorientation and sometimes convulsions
 Iron deficiency due to more iron is required for the enhanced erythropoiesis

Colony-stimulating factors
 Stimulate committed progenitor cells and cause irreversible differentiation
 GM-CSF: granulocyte-macrophage colony-stimulating factors
 G-CSF: granulocyte colony-stimulating factors
 Given sc. or iv.
Clinical uses of CSFs
 To reduce severity and duration of neutropenia induced by cytotoxic drugs during
 To stimulate release into circulation of progenitor cells
 To expand the number of harvested cells ex vivo before re-infusing them
 For persistent neutropenia in advanced HIV infection
 Aplastic anemia
Adverse effects
GM-CSF can cause:fever, skin rashes, muscle pain, hypotension, GI symptoms, and arterial oxygen desaturation

Thrombopoietin
 Stimulate proliferation of progenitor cells of platelets
 Recombinant thrombopoietin is being tested clinically
 Petchrod,Thanat 8

LYMPHOID NEOPLASMS

• Lymphoma
• Hodgkin lymphoma
• Acute leukemia
• Acute lymphoblastic leukemia
• Acute myeloid leukemia
• Chronic leukemia
• Chronic lymphocytic leukemia
• Chronic myeloid leukemia

HEMATOPOIETIC AND LYMPHOID NEOPLASMS

WHO classification
Neoplasms of Hematopoietic and lymphoid tissue 2001

 Chronic myeloproliferative diseases

 Myelodysplastic/Myeloproliferative diseases
 Myelodysplastic syndrome
 Petchrod,Thanat 9

 Acute myeloid leukemia

 B-lymphoid cell neoplasms
 T-lymphoid and NK-lymphoid cell neoplasms
 Histiocytic and dendritic-cell neoplasms
 Mastocytosis and mast cells neoplasms

 Chronic myeloproliferative diseases

 Myelodysplastic syndrome
 Acute myeloid leukemia

Chronic myeloproliferative diseases

• Chronic myelogenous leukemia
• Essential thrombocythemia
• Polycythemia vera
• Chronic idiopathic myelofibrosis

Lymphoid Neoplasms
B-cell neoplasms
• Precursor B-cell neoplasms
• Mature B-cell neoplasms
T-cell and NK-cell neoplasms
• Precursor T-cell and NK-cell neoplasms
• Mature T-cell and NK-cell neoplasms

Lymphoma

 Lymphoid (lymphocytic) leukemia

 Plasma cell myeloma (Multiple myeloma)
 Hodgkin lymphoma
 Petchrod,Thanat 10

NON-HODGKIN LYMPHOMAS

Proliferation of neoplastic lymphoid cells without definite Reed-Sternburg cells

Clinical Features

Nodal Extranodal
 Painless lymphadenopathy  Upper respiratory tract : nasal cavity
 B-symptoms  Gastrointestinal tract
o Fever > 38 °C  Skin
o Night sweat
o Weight loss > 10% of body
weight

Classification

 Rappaport classification
 Lukes and Collins classification
 Keil/Lennert classification
 Working formulation
 REAL classification
 WHO classification

Working formulation
 Petchrod,Thanat 11

• Depend on clinicopathologic features

 Cellular morphology
 Arrangement
 Clinical course
 Low grade
• Intermediate grade
• High grade
• Miscellaneous

• Low grade • High grade

• ML, Small lymphocytic • ML, Immunoblastic
• ML, Follicular, small cleaved cell • ML, Lymphoblastic
• ML, Small non-cleaved cell
• ML, Follicular, mixed small cleaved
• Miscellaneous
and large cell • Composite
• Intermediate grade • Mycosis fungoides
• ML, Follicular, large cell • Histiocytic
• ML, Diffuse, small cleaved cell • Extramedullary plasmacytoma
• ML, Diffuse, mixed small and large cell • Unclassifiable
• ML, Diffuse, large cell

WHO classification
à Morphology
à Immunophenotype
à Genetics
à Clinical informations
Precursor cells : immature cells
Peripheral cells : mature cells
 Petchrod,Thanat 12

B-cells
T-cells and NK-cells
• Precursor B-cell neoplasms
Acute lymphoblastic leukemia/lymphoma
• Precursor T-cell neoplasms
Acute lymphoblastic leukemia/lymphoma

• Peripheral B-cell neoplasms • Peripheral T-cell neoplasm

o Chronic lymphocytic leukemia/Small lymphocytic o Adult T-cell leukemia/lymphoma

lymphoma
o Lymphoplasmacytic lympoma
o Splenic marginal zone lymphoma
o Extranodal marginal zone lymphoma
o Nodal marginal zone lymphoma
o Hairy cell leukemia
o Plasma cell myeloma
o Follicular lymphoma
o Mantle cell lymphoma
o Diffuse large B-call lymphoma
o Burkitt lymphoma/Burkitt cell leukemia
o Extranodal NK/T-cell lymphoma, nasal type
o Mycosis fungoides/Sézary syndrome
o Anaplastic large cell lymphoma, primary
cutaneous
o Anaplastic large cell lymphoma, primary systemic
o Angioimmunoblastic T-cell lymphoma
o Peripheral T-cell lymphoma, unspesified
o Angioimmunoblastic T-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL)

 Petchrod,Thanat 13

Follicular lymphoma

Marginal zone B-cell lymphoma

o Extranodal marginal zone lymphoma

o Nodal marginal zone lymphoma
o Splenic marginal zone lymphoma
 Petchrod,Thanat 14

Anaplastic large cell lymphoma

LYMPHOID NEOPLASMS PRESENTING WITH LEUKEMIA OR LYMPHOMA/LEUKEMIA

Acute lymphoblastic leukemia/lymphoma

 Acute lymphoblastic leukemia (ALL)

 Lymphoblastic lymphoma (LBL)

Burkitt lymphoma/leukemia
 Petchrod,Thanat 15

Chronic lymphocytic leukemia (CLL)/ Small lymphocytic lymphoma (SLL)

HODGKIN LYMPHOMAS
Clinical Features
Nodal
Painless lymphadenopathy : cervical region
B-symptoms (25%)
Extranodal
Rare
Splenomegaly

• Reed sternberg cells (RS cells)

• Classic RS cells
• Mononuclear variant
• Lacunar variant
• Lymphocytic and histiocytic (L&H) variant
• Pleomorphic variant
• Other inflammatory cells
 Petchrod,Thanat 16

• Lymphocytes
• Eosinophils
• Plasma cells
• Neutrophils

WHO classification
• Nodular lymphocyte predominance Hodgkin lymphoma (nLPHL)

• Classical Hodgkin lymphoma (CHL)

• Nodular sclerosis
• Mixed cellularity
• Lymphocyte-rich
• Lymphocyte depleted
 Petchrod,Thanat 17

PLASMA CELL
NEOPLASMS
• Immunosecretory disorders
• Expansion of single clone of immuno-secreting B-cells
• Secrete single homogeneous immunoglobulin à M-component or monoclonal component
Classification
WHO classification of Plasma cell neoplasm
• Plasma cell myeloma (multiple myeloma : MM)
• Plasmacytoma
• Immunoglobulin deposition disease
• Osteosclerotic myeloma (POEMS syndrome)
• Heavy chain disease

Plasma cell myeloma

• Bone marrow-base multifocal plasma cell neoplasms
Clinical & Laboratory features
• Anemia
• Bone disease
• Bone pain
• Osteolytic lesion
 Petchrod,Thanat 18

• Monoclonal protein (M-component)

• Intact immunoglobulin or fragments of immunoglobulin (free light chain)
à IgG 52%
à IgA 20%
à IgD 2%
à Free light chain (Bence Jones protein) 16%
• 99% of myeloma patients
à 93% of pt : serum
à 70% of pt : urine

• Alpha-globulin
Alpha1-globulin : Alpha1-antitrpsin
Alpha2-globulin : Haptoglobin
• Beta-globulin
Lipoprotein, Transferrin, Plasminogen and complement
• Gamma-globulin
Immunoglobulin
 Petchrod,Thanat 19

• Hypercalcemia
• Renal insufficiency
M-component (IgD, Bence Jones protein)
Hypercalcemia
Dehydration
Hyperuricemia
Nephrotoxic dugs
• Infection

Pathology of Lymph node

 Petchrod,Thanat 20

LYMPHADENOPATHIES
Lymph nodes enlargement
• Reactive lymphadenopathy
• Reactive hyperplasia
• Atypical hyperplasia
• Lymphadenopathy associated with clinical syndrome
• Infection
• Neoplasm : lymphoma, leukemia, metastatic tumor

REACTIVE LYMPHADENOPATHY
Reactive lymphoid hyperplasia (reactive hyperplasia
• Increased cellularity of lymph nodes
• Palpable mass ~ 1 cm.
• Axilla, inguinal, cervical and supratrochlear
Atypical lymphoid hyperplasia (atypical hyperplasia)
• Condition between benign and malignant condition
à Reactive condition
à Malignant lymphoma
 Petchrod,Thanat 21

Lymphadenopathy associated with clinical syndrome

SLE lymphadenopathy
• SLE à increased risk of lymphoma and infection
Lymph node biopsy à Exclude these conditions

Dermatopathic lymphadenopathy
• Associated with chronic skin lesion
 Petchrod,Thanat 22

Kimura lymphadenopathy
• Asian
• Female > male, 27-40 yrs
• Slowly lymph node enlergement
• Head and neck à auricular area
• Eosinophilia
• Increased serum level of IgE

Kikuchi-Fugimoto lymphadenopathy
• Asian, female
• Painless cervical lymphadenopahty with fever and myalgia
 Petchrod,Thanat 23

Castleman disease (angiofollicular hyperplasia)

• Idiopathic
• Multiple lymph node enlargement

INFECTIOUS LYMPHADENITIS
• Bacterial lymphadenitis
• Ordinary bacterial lymphadenitis
• Mycobacterium lymphadenitis
• Mycobacterium avium-intracellulare lymphadenitis
• Cat-scratch disease
• Fungal lymphadenitis
• Viral lymphadenitis
• HIV lymphadenitis
• Infectious mononucleosis lymphadenitis
• Protozoal lymphadenitis

HIV lymphadenitis
 Petchrod,Thanat 24

Infectious mononucleosis lymphadenitis

• Ebstein-Barr virus
• Fever, pharyngitis, lymphadenopathy
• Teenagers and young adults
• Peripheral blood à atypical lymphocytes (monocytoid lymphocytes, Downey cells)

Cat-scratch disease
• Rochalimaea hensalae
• Incubation period ~ 3 weeks
• Self-limited lymphadenopathy
 Petchrod,Thanat 25

METASTATIC CARCINOMA IN LYMPH NODES

• Adjacent to or distant foci from primary site
• Movable of fixed to soft tissue
• Soft to firm consistency