The Hematopoietic and
lymphoid systems
Normal Anatomy and Physiology
• Fluid
- plasma
• Cells
- white blood cells (leukocytes)
- red blood cells (erythrocytes)
- platelets (thrombocytes)
Hematopoiesis
Overview of Major Diseases
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Anemia
Leukemia
Lymphoma
Bleeding disorders
Hematopoietic system
• Erythrocytes are ideally suited for their
primary function: transport of oxygen
from the lungs into the peripheral
tissues
• Hemoglobin is a complex molecule that
consists of four heme groups and four
globins
Hematopoietic system
• Hemoglobin synthesis requires iron,
vitamin B12, vitamin B6, and folic acid
• Red blood cells live in the circulation 120
days
Hematopoietic system
• Objective measurements of red blood
cell parameters are done with
instruments that estimate the mean
size of red blood cells and their
hemoglobin content
– Mean corpuscular volume (MCV)
– Mean corpuscular hemoglobin (MCH)
– Mean corpuscular hemoglobin
concentration (MCHC)
Red blood parameters
• Hematocrit, RBC count, hemoglobin
conc.
• MCV 76-100 um
• MCH 27-33 pg
• MCHC 33-37 gm/dl
• Reticulocyte count (normal=1.5%)
Anemia
• Decreased red cell mass and hemoglobin
– Hemoglobin
– Hematocrit
– Erythrocyte count
• Classified on the basis of RBC morphology
or etiology and pathogenesis
• May be isolated or part of other diseases
Etiology and Pathogenesis
Anemia may be a consequence of
• decreased hematopoiesis
• abnormal hematopoiesis
• increased loss or destruction of red
blood cells
Decreased hematopoiesis
• Bone marrow failure
– Aplastic anemia
– Mylophthisic anemia
• Deficiencies of nutrients
– Deficiency of vitamin B12 and folic acid
(magaloblastic anemia)
– Protein deficiency
Abnormal hematopoiesis
• Usually consequence of genetic
abnormalities
• Sickle cell anemia
Increased Loss and Destruction
of Red Blood Cells
• Bleeding
• Intrasplenic sequestration
• Immune hemolysis
• Infections (malaria)
Morphology of Red Blood
Cells
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Anisocytosis - variation in size
Poikolocytosis - variation in shape
Target cell
Sickle cell
Schistocyte, helmet cells, spur cells
Spherocytes
Tear drop cells
Morphologic Classification of
Anemia
• Microcytic hypochromic
– Iron deficiency, thalassemia
• Normocytic, normochromic
– Anemia of chronic disease, hemolytic anemia
• Macrocytic
– Megaloblastic (B-12 and folate deficiency)
• Anemias characterized by abnormal red
blood shapes
– elliptocytosis, spherocytosis, sickle cell anemia
Major Forms of Anemia
• Anemia of blood loss
– Acute or chronic bleeding
• Hemolytic anemia
– Intrinsic (corpuscular defect)
– Extrinsic (antibody or mechanical)
• Anemia due to impaired RBC
production
– Stem cell defect (aplastic anemia)
– Defective DNA, hemoglobin synthesis etc
Hemolytic anemia
• Increased red blood cell destruction
(hemolysis)
• Intracorpuscular defects
• Extracorpuscular defects
Hemolytic anemia
• Intracorpuscular
defects
– structural
abnormalities
– sickle cell anemia,
thalassemia, or
hereditary
spherocytosis
• Extracorpuscular
defects
– antibodies, infectious
agents, or mechanical
factors
– autoimmune hemolytic
anemia, hemolytic
disease of the newborn,
transfusion reactions,
malaria, hemolytic
anemia caused by
cardiac valve prosthesis,
DIC
Hemolytic anemia
• anemia (i.e., low erythrocyte count)
• compensatory erythroid hyperplasia of
the bone marrow
• hyperbilirubinemia and jaundice
Hereditary spherocytosis
• The primary defect in the genes encoding
either ankyrin, or α or β chain of spectrin
• The most common hereditary disease of red
blood cells in whites
• Autosomal dominant disease
• Peipheral blood: spherocytes, anisocytosis
• Hemolytic or aplastic crises - splenomegaly
and jaundice
• Splenectomy
Sickle cell anemia
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Substitution of glutamic acid by valine
Synthesis of an abnormal beta chain
Most prevalent among blacks
Multiple infarcts in various organs
– neurologic defects, sharp pain in the
bones, spleen (autosplenectomy), and
extremities, retinal infarcts
• Hyperbilirubinemia and jaundice (bile
stones)
Sickle cell anemia
• Retarded intellectual development and
neurologic deficits
• Cardiopulmonary insufficiency
• Recurrent infections
Thalassemia
• Genetic defect in the synthesis of HbA that reduces
the rate of globin chain synthesis
• No abnormal hemoglobin is produced
• Thalassemia beta - reduced synthesis of the beta
chain
• Thalassemia alpha - reduced synthesis of the alpha
chain of globin
• Thalassemia minor or thalassemia trait
– heterozygotes
– mild and nonspecific symptoms
• Thalassemia major
– Homozygotes
– severe and serious disease
Thalassemia
• Hypochromic anemia
• Splenomegaly, hemosiderosis, and
hepatomegaly
• Bone marrow - compensatory hyperplasia
• Calvarium - “crew-cut” hair on radiographic
study
• Hyperbilirubinemia and jaundice
• Chronic anemia retards the growth of children
• Impairment of normal intellectual development
• Cardiorespiratory insufficiency
Immune hemolytic anemias
• Mediated by antibodies that destroy red
blood cells
– Autoantigen
– Alloantigen
– Neoantigens
• Mismatched blood transfusion
• Hemolytic disease of the newborn
• Autoimmune hemolytic anemias
Autoimmune Hemolytic
Anemia
• Warm antibody (37 C)
– Primary (idiopathic)
– Secondary (lymphoma, drugs)
• Cold antibody ( >30 C)
– Acute (self limited-infectious disease)
– Chronic (idiopathic or lymphoma related)
Intravascular hemolysis with
complement
Iron deficiency anemia
• The most common form of anemia
• Hypochromic microcytic anemia
• Etiology
– increased loss of iron
• chronic bleeding - peptic ulcer, GI bleeding, menstruation
– inadequate iron intake or absorption
• children, pregnancy
• celiac sprue, gastrectomy
– increased iron requirements
Megaloblastic anemia
• Caused by a deficiency of vitamin B12 or
folic acid
• Vitamin B12 deficiency
– pernicious anemia
– lack of the gastric intrinsic factor
– atrophic gastritis
• Folic acid deficiency
– inadequate intake in the diet or because of
malabsorption caused by intestinal disease
Megaloblastic anemia
• Bone marrow
– hypercellular, numerous megaloblasts
• Peripheral blood
– macrocytic anemia
– hypersegmentation of neutrophils
• Low reticulocytes count
Megaloblastic anemia
• Fatigue, shortness of breath, weakness
• Destruction of posterior and lateral
columns in the spinal cord results in a
loss of the senses of vibration and
proprioception, as well as loss of the
deep tendon reflexes
Aplastic Anemia
• Anemia, leukopenia, thrombocytopenia
• Aplastic hypocellular bone marrow
Causes:
• Idiopathic (65%)
• Acquired (secondary)
– Cytotoxic drugs
– Chemicals (benzene)
– Infection (HIV, EB virus)
• Inherited (Fanconi anemia)
Aplastic anemia
• Uncontrollable infections, bleeding
tendency, chronic fatigue, sleepiness,
and weakness
Polycythemia
• Erythrocytosis
• Increased number of red blood cells
• Primary polycythemia or polycythemia vera
• Secondary polycythemia
Polycythemia
• Primary polycythemia - p. vera
– Proliferation of myeloid stem cells
– myeloprolipherative disorder
– Susceptibility to EPO receptor
• Secondary polycythemia
– Increased EPO due to
Compensatory (high altitude, lung disease)
Abnormal secretion (kidney tumors)
Polycythemia
• Hypertension
• Patients appear dark red or flushed in
the face
• Headaches, visual problems, and
neurologic symptoms
• Splenomegaly
• Hypercellular bone marrow
Leukocytic Disorders
Leukopenia
Leukocytosis
Leukemia
Lymphoma
White Blood Cell Disorders
• Leukopenia
– neutropenia (agranulocytosis)
• Leukocytosis
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neutrophilia - bacterial infection
eosinophilia - allergies, parasitic infect., drugs
basophilia - myeloproliferative disorders
monocytosis - chronic infection, autoimmune
• Lymphocytosis
– viral infections
• Lymphopenia
– bacterial, viral, fungal, and parasitic infections
Enlarged Lymph Node
• lymphadenitis
• lymphadenopathy
– follicular hyperplasia
– sinus histiocytosis
– paracortical hyperplasia
• lymphoma
Malignant Diseases of White
Blood Cells
• Leukemias - malignant disease involving
white blood cells in the bone marrow and
peripheral blood (acute and chronic)
– Myeloid
– Lymphoid
• Lymphomas - lymphoid cell malignant
diseases predominantly involve the lymph
nodes
– non-Hodgkin lymphoma
– Hodgkin’s lymphoma)
• Multiple myeloma - malignant disease of
plasma cells
Etiology and Pathogenesis
• The causes of most lymphomas and
leukemias, like the causes of most other
malignant tumors, are unknown
• Viruses
– HTLV-1
– EBV
• Endogenous oncogenes
– t(8,14) - Burkitt’s lymphoma
– t(9,22) - chronic myelogenous leukemia
(Philadelphia chromosome)
Leukemia
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Acute myelogenous
Acute lymphoblastic
Chronic myelogenous
Chronic lymphocytic
Leukemia
• Bone marrow is infiltrated with
malignant cells
• Peripheral blood contains an increased
number of immature blood cells
• Complications: anemia, recurrent
infections, and uncontrollable bleeding
Lymphoma
• Any age group
• Malignant cells often infiltrate the
lymph nodes, spleen, thymus, or bone
marrow, but they may also involve any
other organ in the body
– extranodal spread of lymphoma
• Two large categories
– non-Hodgkin’s lymphoma (NHL)
– Hodgkin’s lymphoma
Non-Hodgkin’s Lymphomas
• There are no benign lymphomas
• Most lymphomas have a B-cell
phenotype
• Lymphomas can spill over into the
blood and present as leukemia
• The most common site of extranodal
lymphomas are stomach and intestines
Klasifikacija SZO (WHO)
• Morphology
• Immunophenotype
• Genetic characteristics
• Clinical data
Lymphomas
HODGKIN
classical type
NLPHL
NON HODGKIN
IMMATURE
MATURE
B lymphomas
nodular sclerosis
lymphocyte rich
mixed cellularity
lymphocyte depletion
T lymphomas
Classification - NHL
1. Precursor B
neoplasms
2. Mature B
neoplasms
3. Precursor T
neoplasms
4. Mature T-cell and
NK-cell neoplasms
Non-Hodgkin’s Lymphomas
• light microscopy
• ancillary techniques
– immunohistochemistry
– flow cytometry
– cytogenetic analysis
• clinical Features
– lymph node enlargement
– systemic constitutional symptoms
– extranodal tumor spread
ALL/LBL
• peak incidence under 15 years, but can
occur in adults also
• the most common form of leukemia in
children
• abrupt onset (fever, fatigue, bleeding)
• generalized lymphadenopathy
• CNS involvement common
• good response to chemotherapy
ALL/LBL
• massive infiltration of the bone marrow
and peripheral blood with immature
lymphoid cells (blasts)
• recurrent infections, generalized
weakness, and bleeding into the skin
and major internal organs
• with modern chemotherapy, remission
can be induced in essentially all
patients
CLL/SLL
• The most common form of leukemia
(30%)
• M:F=2:1; peak age 60 years
• Expansion of mature B-lymphocytes
• Lymphadenopathy = small lymphocytic
lymphoma
• Involves bone marrow, LN, spleen
• Most patients survive 7 to 9 years from
the time of diagnosis
Follicular Lymphoma
• The most common form of lymphoma in the
United States
• Mostly in older people
• Slow-growing tumor
• Most patients present with long-standing
enlargement of the lymph nodes and only
mild constitutional symptoms
• Most patients survive 7 to 9 years after the
onset of the disease
Follicular Lymphoma
Diffuse Large B-Cell Lymphomas
• The most common aggressive form of
NHL
• Tissue is infiltrated with large lymphoid
cells that have irregular nuclear
outlines and prominent nucleoli
• Complete remission can be induced by
chemotherapy in 75 percent of patients
Burkitt Lymphoma
• Highly malignant tumor composed of small
B-cells
• B cell lymphoma with c-myc gene, t(8;14) and
Epstein Barr virus (EBV)
– Endemic in Subsaharan Africa
– Sporadic in US
– HIV infected persons-very aggressive
• Extranodal involvement common (eg. jaw)
• Extranodal masses are often more prominent
than enlarged lymph nodes
Burkitt’s lymphoma
• Endemic variant
– sub-Saharan Africa
– children infected with EBV
– mandible and facial soft tissue
• Sporadic variant
– children and young adults
– abdominal mass (e.g., ovarian or intestinal mass)
• Most children and young adults can be cured
Plasma Cell Neoplasms
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Multiple myeloma
Waldenstrom macroglobulinemia
Heavy-chain disease
Primary amyloidosis
Monoclonal gammopathy of
undetermined significance
Multiple myeloma
• malignant disease of plasma cells
• most patients older than 45 years of age
• the malignant plasma cells typically
proliferate in the bone marrow, and destroy
the surrounding bone (bone fractures)
• punched out holes in the calvaria and the
vertebrae
• hypercalcemia
• renal failure
• anemia and leukopenia
Multiple myeloma
• X-ray studies
• serum
electrophoresis
(monoclonal spike)
• bone marrow biopsy
Multiple myeloma
Multiple Myeloma
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multiple plasma cells tumors (>males 50 y)
bone marrow - skull, ribs, vertebrae, pelvic
infiltrates or >30% plasma cells in BM
monoclonal gammopathy by serum
electrophoresis
• IgG (60%), IgA (20%), others less common
• most patients die within 3 to 4 years,
primarily of kidney failure or infection
• amyloidosis, anemia
Mature Peripheral T- cell
Lymphomas
• Indolent malignancy
of CD4+
lymphocytes
• Mycosis fungoides skin involvement
• Sezary syndrome leukemic form
• Survival 8-9 years
Hodgkin’s Lymphoma
• Age distribution curve is bimodal, with one
peak at 25 years and another at 55 years
• Two types of Hodgkin’s disease
– Nodular lymphocyte predominance Hodgkin
lymphoma
– Classical Hodgkin lymphoma
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nodular sclerosis
lymphocyte rich
mixed cellularity
lymphocyte depletion
Hodgkin’s Lymphoma
• Lymph node enlargement (neck and
mediastinum)
• Extranodal involvement and leukemic
spread are rare
• Reed-Sternberg cells
– bilobed or multilobed nucleus and
prominent nucleoli surrounded by a clear
halo
mononuclear
popcorn
classical RS
mummy
lacunar
anaplastic
Hodgkin’s Lymphoma
• Prognosis of the disease depends
primarily on the clinical stage
– Stage I and II tumors are associated with
an excellent prognosis and a high rate of
cure (over 90 per cent), achieved with
chemotherapy
– Advanced disease has a less favorable
prognosis
Hodgkin’s Lymphoma