• On this day, Buddhists
commemoration of the birth
of Gautama Buddha, the
founder of Buddhism,
thought to have lived in India
from 563 B.C. to 483 B.C.
Actually, the Buddhist
tradition that celebrates his
birthday on April 8 originally
placed his birth in the 11th
century B.C., and it was not
until the modern era that
scholars determined that he
was more likely born in the
sixth century B.C., and
possibly in May rather than
Red Blood & Platelet Cell Deficiencies
Anemia is present when the RBC count is less than 4.5 X 10↑5cells/ l in
males (4.1in females) or hemoglobin (Hgb) is less than 13.5g/dl in
males (11.5 in females).
General features: result from inadequate supply of oxygen reaching the
tissues (pallor, shortness of breath, fatigability).
Classically categorized by microscopic examination of peripheral blood
• Normocytic-normochromic –normal size & color of RBCs
• Microcytic-hypochromic – small and less Hgb than normal
• Macrocytic-hyperchromic – larger and more Hgb (no hole in the
• Mechanisms of anemia
1. Decreased production
2. Increased destruction
3. Blood loss (hemorrhage)
Thrombocytopenia is a reduction in the number of functional platelets,
although normally in the range of ~150,000-300,000/mm3 the
number must dip below 10,000-20,000 before bleeding is clinically
Red Blood Cell & Platelet Excesses
Increased RBCs are associated with hypercellularity of the marrow
• Polycythemia: ↑ RBC number/unit volume
1. Myeloid neoplasia involving hematopoietic precursor cells
2. Polycythemia vera – increased RBC precursor proliferation
independent of erythropoietin (EPO levels are low). Anemia
develops late due to marrow replacement by non-functional
1. Due to increased erythropoietin: chronic hypoxia (altitude, smoking,
lung disease, cyanotic heart disease). Tumors producing
erythropoietin – renal cell, hepatocellular carcinoma
2. Due to loss of plasma (dehydration)
• Increased coagulability requires platelet counts >~400,000,
(>1,000,000 are common) often when the result of
myeolproliferative disorders, the platelets are dysfunctional. The
marrow has markedly increased numbers of megakaryocytes.
Anemias caused by Decreased RBC
1. Bone marrow failure
2. Inadequate supplies of components
Aplastic anemia: Replacement of bone marrow by fats cells or
metastatic disease resulting in anemia, neutropenia &
thrombocytopenia; due to the failure or suppression of multipotent
myeloid stem cells.
• Cause: In 65% the cause is unknown. Drugs may cause anemia in a
predictable, dose dependent and reversible fashion (chemotherapy
agents, benzene, non-neoplastic drugs) or an idiosyncratic fashion
• The onset is usually insidious and symptoms are due to impaired
oxygenation or defects in platelets or WBCs.
• Treatment involves removing the offending agent and/or bone
Iron deficiency anemia: this is the most common cause of anemia
Causes: A negative iron balance
1. Inadequate iron intake or absorption: 20% in ingested heme iron
(animal products) and only 1-2% of non-heme iron is absorbed in
the duodenum, deficiency may result from inadequate intake of an
iron source or inadequate absorption (duodenal disease,
achlorohydria* (acidic environment needed to convert iron to
2. Excess iron loss: chronic blood loss GI, menstrual
3. Increased demand: pregnancy, lactation, infancy
1. Microcytic-hypochromic RBCs
2. Low marrow iron stores
3. Low iron levels in plasma (serum iron, ferritin and transferrin).
Vitamin B12 & folate deficiency
• These adversely affect DNA synthesis in hematopoietic cells and
hinder maturation of precursors. This results in gigantic RBC
precursors (megaloblasts) because granulocytes and platelets
are also affected this often results in pancytopenia. B12 deficiency
anemia is called pernicious anemia (megaloblastic anemia)
1. Malabsorption of B12: B12 is normally found in animal products and
is absorbed in the distal ileum when combined with intrinsic factor
which is produced by the gastric parietal cells. Gastritis, Crohn’s
disease or parasitic infections of the small intestine can result in
malabsorption. Achlohydria is associated with B12 malabsorption.
Antibodies to intrinsic factor may be found. Autoimmune
destruction of gastric parietal cells results in classic pernicious
2. Inadequate folate or B12 as a result of inadequate intake, this
requires chronic malnutrition because of large reserves of both
1.Increased demand for folate during pregnancy
2.Drug treatments may interfere with folate function,
1. RBCs are macrocytic & hypersegmented (immature forms). PMNs
2. Marrow shows megaloblasts
3. Decreased platelet counts
4. B12 & folate levels are decreased.
5. B12 deficiency is associated with demyelination of the dorsal & lateral
spinal cord tracts which results in a spastic paresis and sensory
ataxia. This is absent in anemia due to folate deficiency.
• Bone marrow biopsy from
patient with megaloblastic
anemia. Arrowheads point
to megaloblasts and arrow
to RBC undergoing
Anemias caused by Increased RBC Destruction
• Hemolytic Anemias: characterized by premature RBC destruction,
accumulation of Hgb metabolites (bilirubin) and increased
Intracorpuscular: Hemolysis results from intrinsic RBC abnormalities
such as those affecting RBC structural proteins (spectrin, ankyrin),
the globin portion of Hgb or RBC enzymes (glucose-6-phosphate
• Hereditary spherocytosis is an autosomal dominant
condition most often related to spectrin deficiency.
RBCs lacking spectrin are less deformable resulting in
increased fragility which results in fragmentation and
subsequent phagocytosis by splenic components.
Thalassemia is a term describing a set of anemias due to defective
synthesis of Hgb (a tetramer composed of 2 α chains & 2 β chains).
The α-chain is coded for by 2 separate genes on chromosome 16
the β chain is coded for by 1 gene on chromosome 11.
Two factors account for the anemia seen in thalassemia
• 1. Decreased concentration of normal hemoglobin
• 2. Accumulations of Hgb chains due to the defective production of
the other Hgb chain result in increased RBC destruction.
Types of Thalassemia:
• β- Thalassemias: the most common form, related to a mutation in
one or both β-globin genes resulting in decreased β globin
production. The excess α globin forms unstable aggregates that
damage RBC membranes resulting in destruction in the marrow or
by splenic phagocytes.
1. Thalassemia major - individuals homozygous
for the defective β-globin gene develop
hemolysis, splenomegaly bone marrow hyperplasia
and bony deformities. Without transfusions these people die
early. The failure of transition of fetal α2γ2 to α2β2results in
persistent fetal hemoglobin.
2. Thalassemia minor – individuals have 1 defective gene and
have mild symptoms.
α-Thalassemia: related to the depletion of α-globin, free β-
globin forms tetramers that damage RBC membranes.
There are 4 types depending on the number of
defective genes an individual possess.
1. One defective gene- silent carrier
2. Two defective genes - α-Thalassemia trait, minor
3. Three defective genes Hemoglobin H disease –
increased production of β-globin tetramers that damage
RBCs and result in destruction.
4. Four defective genes – hydrops fetalis, a complete lack
of α-globin, excess fetal Hgb (γ globin) forms tetramers
which do not release bound oxygen easily leading to
Sickle Cell Anemia
Sickle Cell Anemia, a hemoglobinopathy affecting 8% of
African-Americans, is a defect in β-globin resulting in the
formation of HgbS which results in sickling of RBCs under
low oxygen conditions. The presentation depends on the
amount of HgbS; 40% in heterozygotes to 100% in
homozygotes. Symptoms are due to chronic hemolysis, the
average lifespan of an RBC is reduced from 120 to 20 days,
and bilirubin is elevated. Microvascular occlusion results in
tissue hypoxia, mico-infarcts in bones, lungs, liver and brain.
Aplastic crisis may be induced by viral infection on a stressed
Extracorpuscular hemolytic anemia: abnormality outside the RBC
(usually involving antibodies or splenomegaly)
Autoimmune hemolytic anemias – anti RBC antibodies, 2 types
1. Warm antibody type: The most common form is related to the
deposition of IgG antibodies on the RBC surface resulting in
opsonization without complement activation. This type of hemolytic
anemia associated with SLE. Drug induced hemolytic anemias
result from the formation of novel antigens when certain drugs bind
to the RBC surface (common with penicillins).
2. Cold antibody type: This is mediated by IgM antibodies; these
antibodies activate complement in addition to opsonization. They
are especially effective in colder regions of the body (extremities)
and can result in small vessel thrombotic events. This may occur as
an acute process after viral mononucleosis or chronically in
lymphoma patients. These antibodies have their optimal activity at
~30Cº. Hemolytic episodes are associated with cold exposure and
occur in the extremities.
Pathologic findings in hemolytic anemia include compensatory marrow
hyperplasia, reticulocytosis and hemosiderin deposits (due to RBC
Clinical features include jaundice, splenomegaly and hepatomegaly.
• Anemia of renal failure: due to inadequate production of
erythropoietin by the kidney, treatment with EPO improves RBC
• Anemia of chronic disease: Increased chronic inflammatory
mediators causes a sequestration of iron stores from the erythroid
organs (mainly bone marrow) so serum iron is low but total iron
binding capacity (TIBC) is low while ferritin levels are high (there’s
lots of iron it’s just not available for RBC synthesis. Also
erythropoietin production is reduced.
TIBC measures the available binding sites on transferrin
• These disorders may be congenital or acquired and result from
abnormalities in vessel walls, platelets or clotting factors.
• The anemia of acute blood loss results in a compensatory
reticulocytosis in 4-5 days following the hemorrhage.
Thrombocytopenia is defined as a platelet count of <100,000
platelets/microliter. Spontaneous bleeding does not occur until
counts reach <20,000, this presents as petechial bleeding of the
skin and mucous membranes.
1. Decreased production as a result of marrow failure
2. Decreased survival by to sequestration (hypersplenism) or
destruction: due to drugs (heparin, quinidine, alpha-methyldopa)
or viral infection related immune-mediated destruction
3. HIV infection
4. Dilution: In patients receiving transfusions without platelet
supplementation; storage of blood at 4°C fro 24 hours results in
rapid hepatic sequestration of platelets.
A Model of Immune mediated
IgG antibodies form a complex
with heparin and PF4 in the
bloodstream. The tail of the
antibody then binds to an Fc
receptor on the surface of the
platelet. This results in platelet
activation and the formation of
which initiate the formation of
clots; the platelet count falls as
a result (hypercoaguable with
Idiopathic thrombocytopenia purpura
(ITP) is an autoimmune disorders
caused by antibodies to platelets,
megakaryocytes or both.
Opsonized platelets are
sequestered by the spleen & liver.
1. Acute ITP is a self-limited disease
usually related to a viral infection
mononucleosis) affecting children.
2. Chronic ITP affects women 20-40
years of age; platelet depletion is
mediated by antibodies to
particular platelet surface
antigens. It may be treated (75-
80% success) with splenectomy
Thrombotic Microangiopathic Purpura is a term used to
describe several conditions characterized by the
formation of platelet-fibrin thrombi in small vessels
leading to small vessel occlusion and a consumptive-
1. Thrombotic thrombocytopenic purpura (TTP) typically
affects women; features include renal failure, fever,
neurologic symptoms, hemolytic anemia and
2. Hemolytic-uremic Syndrome is similar to TTP but
occurs in children and lacks neurologic symptoms. It is
caused by an infection with an enterhemorrhagic E. coli,
this bacteria produces a toxin that injuries endothelial
cells which promotes platelet activation & aggregation.
Clotting Factor Deficiencies
These may be acquired (liver
disease, vitamin K
deficiency, DIC) or
congenital (hemophilia, von
Willebrand disease). These
disorders present with
prolonged bleeding after
laceration, GI & GU
hemearthrosis in weight
Acquired defects result from
vitamin K deficiency which
results in deficiencies in
factors II, VII, IX, X and
protein C production (all
produced by the liver). This
may also be acquired
through liver failure or a
1. Hemophilia A is due to a decreased amount and activity of factor
VIII, levels of <1% of normal are required for spontaneous bleeding
to occur. This is a classic X-linked disorder.
2. Hemophilia B (Christmas disease) is due to an X-linked defect in
factor IX activity. Its presentation is identical to type A, only clotting
studies can differentiate them.
3. Von Willebrand disease is characterized by a deficiency of von
Willebrand factor which stabilizes factor VIII and participates in
platelet adhesion to endothelial surfaces. This is the most common
hereditary bleeding disorder, it usually results from an autosomal
dominant but some recessive disorders have been identified. It
presents with menorrhagia, excessive bleeding from minor wounds
or spontaneous bleeding from the gums and mucous membranes.
Lab evaluation reveals abnormal platelet function and coagulation.
There are three basic types:
1. Type 1: low level of vWF ± decreased Factor VIII levels (most common,
least severe, autosomal dominant).
2. Type 2: Defective vWF (4 sub-types, autosomal dominant)
3. Type 3: vWF absent & decreased Factor VIII (most severe, recessive)
Mechanisms of bone marrow neoplasia
• Blast cells (malignant) overpopulate the bone marrow and replace
the normal cells causing bony destruction and/or blood or lymphoid
• Malignant cells or their descendents may appear in the peripheral
blood (leukemia), in extramedullary sites such as the spleen and
liver (hepatosplenomegaly) and in lymph nodes (lymphadenopathy).
• Bone marrow malignancy may be accompanied by myelofibrosis
(the extensive deposition of collagen by non-neoplastic fibroblasts).
• Types of bone marrow neoplasia: Malignant transformation of
hematopoietic and lymphoid cell precursors may occur at any point
in their maturation. Malignant cells are classified as myeloid,
lymphoid, or plasmacytic. The characteristic behavior of particular
malignant stem cells determines the presentation of the disease.
There are four major groups:
Types of bone marrow neoplasia
1. Myeloproliferative disorders: Characterized by the malignant
transformation of developmentally pluripotent myeloid stem cells
and their linage-restricted descendants.
2. Myelodysplastic syndromes: Characterized by ineffective
hematopoiesis and pancytopenia.
3. Leukemia: Characterized by the appearance of neoplastic WBCs
in the peripheral circulation.
4. Plasma cell disorders: Characterized by the monoclonal
proliferation of neoplastic plasma cells and plasmacytoid
lymphocytes usually in the bone marrow
These disorders include polycythemia rubra vera
(proliferation of RBC precursors), essential
thrombocytemia (proliferation of platelet precursors)
chronic myelocytic leukemia (proliferation of neutrophil
precursors) and myelofibrosis (proliferation of
fibroblasts). These entities are interrelated and may
transform one into another or into acute myeloblastic
leukemia (AML). Features common to all
1. Peak incidence in 40-70 years of age
2. Marrow hypercellularity, except myelofibrosis which is
dominated by fibrosis
3. Splenomegaly due to extramedullary hematopoiesis
4. Peripheral blood abnormalities and hyperviscosity,
except for myelofibrosis
• Myelodysplastic syndromes (MDS, formerly known as "preleukemia") are
a diverse collection of hematological conditions united by ineffective
production of blood cells and varying risks of transformation to acute
myelogenous leukemia (AML). Anemia requiring chronic blood transfusion is
• Myelodysplastic syndromes (MDS) are bone marrow stem cell disorders
resulting in disorderly and ineffective hematopoiesis manifested by
irreversible quantitative and qualitative defects in hematopoietic cells. In a
majority of cases, the course of disease is chronic with gradually worsening
cytopenias due to progressive bone marrow failure.
• Approximately one-third of patients with MDS progress to AML within
months to a few years.
• The median age at diagnosis of a MDS is between 60 and 75 years; a few
patients are less than 50; MDS are rare in children. Males are slightly more
commonly affected than females. Signs and symptoms are nonspecific and
generally related to the blood cytopenias (anemia, neutropenia,
• A significant proportion of the morbidity and mortality attributable to MDS
results not from transformation to AML but rather from the cytopenias seen
in all MDS patients. Anemia is most common and responds to transfusion,
patients often suffer from iron overload. The two most serious complications
in MDS patients resulting from their cytopenias are bleeding (due to lack of
platelets) or infection (due to lack of white blood cells).
These are composed of two major groups: myeloid (granulocytic) and
Causes: The cause is unknown but some predisposing factors have
1. Myelodysplastic syndromes precede the onset of leukemia
2. Genetic factors may play a role, chromosomal syndromes
(Downs, etc.) are associated with increased risk of leukemias.
3. Ionizing radiation; there is increased incidence in those exposed
to radiation for treatment or otherwise.
4. Alkylating agents used in chemotherapy are associated with
5. Viruses: Human T-cell lymphocytic virus-1 (HTLV-1) is an RNA
oncogenic virus that causes T-cell leukemias
6. Endogenous oncogenes play a role and are associated with
chromosomal breaks, translocations or deletions. The
Philadelphia chromosome (translocation of fragments of
chromosomes 9 & 22) is associated with the formation of an
oncogene and are associated with the development of CML.
Types of Leukemias
1. Acute Lymphoblastic leukemia (ALL) ~30% of all leukemias, the
most common among children under 5 years old. The marrow
contains more than 30% lymphoblasts. The prognosis is
inversely proportional to age.
2. Acute myelogenous leukemia (AML) ~80% of acute leukemias in
adults. Marrow has >20% myeloblasts. Overall prognosis is poor
with relapse after chemotherapy and most do not survive more
than 5 years after diagnosis. Two forms; acute denovo AML or as
an end-stage of CML and myelofibrosis.
Types of Leukemias
3. Chronic lymphocytic leukemia (CLL) Peak incidence is in elderly
males >60years old. Bone marrow has >40% lymphoid cells,
peripheral blood has >15 X10↑6. Neoplastic cells resemble B-
lymphocytes. CLL has an indolent course over 7-10 years, it
responds poorly to chemotherapy. It is closely related to small
cell lymphoma and lymphadenopathy is common.
4. Chronic myelogenous leukemias (CML) Peak incidence is
~60years old. Symptoms are related to loss of normal marrow
functioning; anemia, bleeding & infection. Peripheral WBC counts
in the 20-50,000 range with large component of myeloid
precursors. Frequently terminates in a “blast” crisis with
peripheral WBCs of >100,000 with immature myeloid cells.
Prognosis is poor despite chemotherapy.
Plasma cell disorders
– Multiple myeloma
– Waldenstrom macroglobulinemia: A malignancy of plasmacytoid
lymphocytes that secrete IgM resulting in a hyperviscosity syndrome
with renal, retinal and cerebral ischemia as a result of microvascular
– Monoclonal gammopathy of unknown significance: often diagnosed in
asymptomatic elderly patients. It is present in ~1% of patients over 60
years old and 3% of patients over 70. There is a 1% risk of developing
– Tend to occur in those >45 years old.
– Neoplastic plasma cells produce a monoclonal immunoglobulin
component that can be identified by serum electrophoresis
– Deposition of light chain immunoglobulin may form amyloid deposits in
the kidneys, vessels and other organs.
• A neoplasm of mature plasma
cells that respond poorly to
chemotherapy and usually
survive ~3 years after
diagnosis. Renal damage due
to protein deposition is the
most common cause of death.
hyperviscosity and metabolic
disorders contribute to the
- Pts present in their middle fifties
or older (60-70 yr)
- Constitutional symptoms,
and renal failure;
- Approx 80% of pts have chief
complaint of bone pain w/
diffuse bone tenderness,
particularly over the sternum
- Pathological fracture of spine or
femur may be heralding event;
- Symptoms range in duration
from as short as few wks to as
long as 2 yrs.
• Neoplastic cells secrete a
IgG 60%, IgA 20% and IgD,
IgE or the heavy or light chain
suppressed increasing the risk
• Multiple bone lesions are
composed of nests of
neoplastic cells and appear as
“punch” lesions in bones.
Bony lesions may cause
metastatic calcification also
• Excess immunoglobulin may
be deposited in peripheral
tissue forming amyloid. They
may be secreted in the urine
as Bence-Jones proteins,
occasionally proteins obstruct
renal tubules resulting in renal
Neoplasms of lymphoid cells may be divided into two major groups:
• Non-Hodgkin’s lymphoma ~70%
• Hodgkins lymphoma ~30%
1. Oncogenes, both lymphomas & leukemias may share the same
2. Radiation increases the risk of lymphomas particularly radiation
therapy for neoplastic disorders.
3. Environmental factors, Burkitt lymphoma is related to EBV
4. Immunodeficiency states (congenital or acquired) are associated
with an increased incidence of lymphomas; HIV is associated with
Non-Hodgkin lymphomas are a heterogeneous group of neoplasms
arising from both T and B cells and their precursor cells.
• 85% of non-Hodgkins are of B-cell origin and involve marrow,
lymph nodes, spleen and extranodal lymphoid tissue.
Approximately 2/3rds of cases begin in lymph nodes, the
remaining begin in extranodal lymphoid tissue. Multiple nodes are
Four general categories have been identified based on cell origin, level
of differentiation, genetic abnormality and clinical presentation.
1. Precursor B-cell neoplasms: present as acute lymphoblastic
leukemia/lymphoma. ALL/L of infancy and childhood and is often
curable. Adult ALL/L usually responds but tends to recur and is
2. Precursor T-cell neoplasms ALL/L involving the mediastinum,
lymph nodes and spleen. These respond less well than B-cell
3. Peripheral B-cell neoplasms occur in several forms and affects
adults. B-cell types are the most malignant. The most important
1. Small cell lymphocytic lymphoma, the lymphoma equivalent of
CLL. This tends to have a protracted course surviving 7-10
years after diagnosis
2. Follicular lymphoma affects elderly patients responsible for
~45% of lymphomas. Like CLL this disorder has an indolent
course lasting 7-10 years.
3. Mantle cell lymphoma responds to chemotherapy but relapses
are common and most survive only 3-4 years after diagnosis.
4. Diffuse B-cell lymphomas account for ~20% of all lymphomas,
but represent 70% of all aggressive lymphomas in adults and
are the most common rapidly proliferating lymphomas. Despite
its aggressive nature ~50% are cured by chemotherapy.
5. Hairy cell leukemia is a low grade lymphoma associated with
splenomegaly. The proliferation of characteristic “hairy cells”
results in their appearance in peripheral blood (hence the
description as leukemia).
4. Burkitt lymphoma is a rapidly growing B-cell lymphoma
affecting children and adults. It is related to EB virus infection.
Solid tumors are often located in extranodal tissue.
Response to chemotherapy is inversely related to age.
Hodgkin’s disease comprise several closely related neoplastic lymph
node disorders that resemble lymphoma
Areas of involvement: This usually involves a neoplastic process in
contiguous lymph nodes usually in the neck and mediastinum.
Extranodal involvement and disease above and below the
diaphragm portend poor prognosis.
Affected nodes show an inflammatory response to tumor cells and
contain infiltrates of lymphocytes, plasma cells and
Reed-Sternberg cells (large binucleate cells (owl eyes)) surround
other cells that identify five types:
• Nodular sclerosis the most common type
• Lymphocyte predominant
• Lymphocyte depletion
• Mixed cellularity
Clinical features include fever, sweating, weight loss, etc.,
(characteristic of an inflammatory process).
Prognosis depends on the stage of disease at the time of diagnosis;
histological type has little influence on outcome. 5-years survival
is 75%, Relapse after initial treatment has ~50% survival rate.
Clinical Differences Between Hodgkin and
Hodgkin Lymphoma Non-Hodgkin
More often localized to a
single axial group of
Orderly spread by
Mesenteric nodes and
Waldeyer ring rarely
Waldeyer ring and