HEMATOLOGY
Hematopoiesis

Fetus: liver, spleen, bones
sometimes regain heatopoietic activity in the adult: i.e.
myelofibrosis

Child: long bones, skull, vertebrae etc.

Adult: vertebrae, sternum, ribs, pelvic bones
and long bones, skull
- about 1 kg tissue
producing 1011 cells/day
Hematopoietic cells

Pluripotent stem cell compartment
–

relatively small, lymphocyte-like cells
Proliferating cells
of committed lineage
myeloid, erythroid, megakaryocyte, lymphoid,
reticulum cell lines
Maturing (postmitotic) cells
 Mature cells

circulating half life: pmn.leukocytes 6 hours
platelets: 8-10 days
erythroid cells: 120 days
Erythropoiesis

Stimulus: hypoxia
erythropoietin
(in the kidney [and liver])
pluripotent stem cells
CFU-E
BFU-E
proerythroblasts
erythroblasts
normoblasts
mature red blood cells
Leukocyte production

Pluripotent stem cells

Myeloblasts

Promyelocytes

Myelocytes
Leukocyte production
Metamyelocyte
Leukocyte production
Band-form
Leukocyte
production
Mature
polymorphonuclear
granulocyte
Megakaryocyte line
Giant, multinucleated cells
Breaks up, releasing about 5000 platelets
Marrow lymphocytes
arising also in spleen and lymph nodes
lifetime: years
Bone marrow function
Hematopoiesis
 Antibody producing plasma cell differentiation
 Monitoring hematopoietic cell quality
 Important key nutrients: iron

folic acid
vitamin B12
regulatory hormones
(EPO, CSF-s)
interleukins
Hematological diseases
Anemia
Decrease in red cell mass or hemoglobin
content of blood below the physiologic need
 Not a disease itself! A clinical sign!
 Analysis of anaemia

–
seek the background mechanisms
 loss
of red blood cell - bleeding
 lack of red blood cell production
 excessive red blood cell damage
History

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Family history: anemia, splenomegaly, jaundice
Bleeding tendency in the family
Diet, alcohol intake
Menorrhagia
Drugs
Chronic diseases
Malnutrition, malabsorption
Transfusion, iron or other therapy against anemia
Anemia
Signs and symptoms vary with the rapidity of
onset:
 Rapid (bleeding or brisk hemolysis)

cardiovascular compensatory reactions:
tachycardia, postural hypotension, vasoconstriction
in the skin and extremities, dyspnea on exertion,
faintness, even shock
 Slowly developing anemias (ie.nutritional deficiency,
chr.bleeding, hemolysis etc.)
– there is time for compensation
– the patient remains asymptomatic for a long time
–
Anemia
Mild: often asymptomatic
 Moderate: symptoms on exertion
 Severe: symptoms on rest
heart failure

Anemia - physical findings
Non cause-specific
 Pallor of skin and mucous membranes
–
–
causes: Hb and blood redistribution from
the skin
colors
 greyish:
malignancy
 lemon-like: hemolysis, B12 deficiency
Tachycardia
 Hyperkinetic precordium
 Systolic murmur (reversible)

Anemia - physical findings
Cause-related
 Jaundice
hemolysis
 Hepatosplenomegaly - e.g.hemolysis
 Lymphadenopathy - lymphomas,
autoimmune diseases
 Cheilosis (fissura)
iron deficiency
 Koilonychia (spoon-shaped nails) iron def.
 Beefy red smooth tongue (Hunterglossitis) - pernicious anemia
 Neuropathy - pernicious anemia
 Rectal digital examination - bleeding
Laboratory evaluation of anemia
Complete blood picture
 Red cell indices

 red
blood cell count F:3,9-5,6, M:4,5-6,5 G/l
 hemoglobin level F:115-155 M:135-175 g/l
 hematocrit F:36-48 M:40-52%
 MCV: mean corpuscular volume 80-95 fl
 MCH mean corpuscular hemoglobin 27-34 pg
 MCHC: mean corpuscular hemoglobin concentration
300-350 g/l

Reticulocyte count (traces of endoplasmic reticulum) - good
marker of erythropoiesis 0,5-1,5%
MCV

Microcytic anemia (MCV<80 fl)
iron deficiency, thalassemia, sideroblastic anemia

Normocytic anemia (MCV 80-100 fl)
acute bleeding, renal failure, aplastic anemia

Macrocytic anemia (MCV>100 fl)
vitamin B12, folic acid deficiency, liver disease,
alcoholism, hypothyroidism
MCH

Hypochromic (MCH<27 pg)
–
–

Normochromic (MCH 27-34 pg)
–

Iron deficiency(i.e. chr. bleeding, malabsorption)
chr. inflammation, malignancy, chr. infection,
thalassemias, myelodysplastic sy.
acute bleeding, hemolysis, aplastic anemia, renal
anemia
Hyperchromic (MCH>34 pg)
–
megaloblastic anemia (B12, folic acid deficiency)
Clinical classification of anemias

Decreased cell production
–
–
–
–
–
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Aplastic anemia
Myelodysplastic syndrome
Deficiency anemias (iron, B12, folic acid)
Erythropoietin deficiency (renal failure)
Bone marrow suppression (malignancy, toxin,virus)
Increased red blood cell destruction/elimination
Extrinsic factors (immun, toxins, mechanic)
– Membrane defects
– Enzyme defects
– Hemoglobinopathy
 Blood loss (genitourinary, gastrointestinal, pulmonary
other bleeding)
–
Bone marrow investigation
Bone marrow biopsy or aspiration
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bone marrow cellularity
myeloid-erythroid ratio (norm: 2-3:1)
cell maturation
bone marrow infiltration
stromal cells (fibroblasts etc.)
Polycythemias
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Hyperviscosity
–
–
–
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Increased cell turnover
–
–

Decreased cerebral blood flow
tinnitus, lightheadedness, dizziness, stroke
Congestive heart failure
Thrombosis
Gout (due to hyperuricemia)
Itching
In polycythemia vera
–
–
Thrombocytosis
Hemorrhage
Polycythemias

Primary: polycythemia vera myeloproliferative disorder
–
–
–

other cell lines are affected (leukocytosis,
thrombocytosis)
hepatosplenomegaly
EPO level: low
Secondary:
–
hypoxia
EPO production
 chr.
pulmonary diseases
 morbid obesitiy (Pickwick’s syndrome)
 high altitude
–
EPO overproduction: tumors
Leukocyte disorders
1. Benign alterations
2. Malignant diseases
Neutrophil granulocytes

Functions:
 chemotaxis
 phagocytosis
 microbial

killing
Disorders
 neutropenia,
agranulocytosis: abs.count<1000
causes:drugs, autoimmun diseases, viral
infections (e.g. EBV,HIV,hepatitis), B12
deficiency, leukemias,alcoholism
increased risk of infection
 neutrophilia:infections,
 left
stress, drugs (steroids)
shift: bacterial infections
Mononuclear phagocytes
monoblasts, promonocytes, monocytes, tissue
macrophages

Functions
chemotaxis
 ingestion and killing
microorganisms
 secretion of several
factors
proteases, cytokines,
reactive oxygen
compounds,
colony stimulating factors
 interaction with
lymphocytes
 antigen processing and
presentation

Eosinophil granulocytes

Eosinophilia:
 Parasitic
infections
 Allergies
 Autoimmune
diseases
 Hematologic malignancies (CML, Hodgkin’s
disease etc.)
Basophil granulocytes

Important role in:
–
–

inflammation
hypersensitivity reactions
Basophilia: malignant hematologic
diseases
Acute leukemias

Agressive immature hemopoietic cell
proliferation, without differentiation
–
(hiatus leucemicus in the blood smear)
Subtypes:
 ALL
(acute lymphoblastic leukemia)
 ANLL (acute non lymphoblastic leukemia) or
AML (acute myeloblastic leukemia)
Acute leukemia syndrome
Susceptibility to infections - serious
infections
 Anemia due to bone marrow infiltration
and bleeding
 Thrombocytopenia - bleeding tendency
purpuras, petechiae, mucosal bleeding
 Organ infiltration

Chronic leukemias
Uncontrolled expansion of premature
hemopoietic cells which are able to
differentiate
 Subtypes:

–
–
Chronic myelogenous leukemia (CML or CGL)
a myeloproliferative disorder
Chronic lymphocytic leukemia (CLL)
a malignant lymphoma
CML

Abnormal blood count

Organomegaly (hepato)splenomegaly
CLL
Old patients
 Blood count abnormalities

 Leukocytosis
 Lymphocytosis
(small, mature lymphocytes)
 In advanced disease: anemia, tct-penia
Generalised lymphadenopathy
 Splenomegaly
 Susceptibility for infections (pneumonia)
 Sometimes hemolytic anemia
 Immundeficiency

Evaluation of leukemias
Complete blood picture
 Bone marrow investigation
 Cytochemistry
 Immunochemistry
 Genetic alterations

 chromosomal
aberrations
 gene anomalies
Chronic myeloproliferative
disorders
Polycythemia vera
 Myelofibrosis with myeloid metaplasia
 Essential thrombocythemia
 Chronic myelogenous leukemia

Diseases of the lymphoid system

Normal lymph nodes
–
–
–
–
Non palpable or <1 cm, except in the inguinal region
where can be 0,5-2 cm sized lymph nodes normally
Small lymph nodes can be remain after infection
Significant: one or more new nodes >1 cm (which
can’t explain by a previously recognised cause)
New lymph nodes in older age more significant
 children
more likely respond with lymphoid hyperplasia
 lymphyadenopathy under 30 years: 80% benign
over 50 years: 40% benign
Causes of lymphadenopathy
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(1) increase in the number of benign
lymphocytes and macrophages during
response to antigens
(2) infiltration by inflammatory cells in
infections (lymphadenitis)
(3) in situ proliferation of malignant
lymphocytes or macrophages
(4) infiltration of nodes by metastatic
malignant cells
(5) infiltration of lymph nodes by
metabolite-laden macrophages in lipid
storage diseases
Lymph node characteristics
Location
 Number (single, multiple, matted together)
 Size
 Tenderness
 Consistency (hard, rubbery, soft)
 Mobility
 Skin reactions above the lymph node

Lymphadenopathy- by region
–
–
–
–
–
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Cervical in young adult: infectious mononucleosis
Unilateral epitrochlear : hand infections
Bilateral epitrochlear : sarcoidosis, tularemia,
syphilis
Unilateral axillary: breast carcinoma, lymphomas,
infections of the upper extremities, cat-scratch
disease, brucellosis
Bilateral inguinal: venereal infections
Unilateral inguinal: lymphogranuloma venereum,
syphilis
Progressive inguinal lymph node enlargement
without obvious infection: malignant disease.
Lymphadenopathy- by region
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–
–
–
–
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Posterior cervical, occipital: scalp infections,
toxoplasmosis, rubella
Anterior auricular: infections of the eyelids and
conjunctiva
Lymphomas often involve cervical lymph nodes
and occasionally involve posterior auricular
and occipital nodes
Enlarged suppurative cervical nodes:
mycobacterial lymphadenitis (scrofula)
Unilateral jugular or mandibular lymph node:
lymphoma or head and neck malignancy
Supraclavicular (always significant): metastasis
from intrathoracic, breast, gastrointestinal
malignancies (Virchow’s lymph node) or lymphoma
Lymphadenopathy- by region

Hilar or mediastinal
–
–
–
–

Symptoms: cough,wheezing, hoarseness, paralysis of the
diaphragm, dysphagia
Bilateral mediastinal: lymphomas
Unilateral hilar: metastatic carcinoma (usually lung)
Bilateral hilar: sarcoidosis, tuberculosis, fungal infections,
lymphomas
Retroperitoneal, intraabdominal: lymphomas,
metastases, rarely inflammatory
(Tuberculosis can cause mesenteric lymphadenitis with large
matted and sometimes calcified nodes)

Generalised: lymphomas (CLL), systemic infections
(tbc),
autoimmune diseases
Lymphadenomegaly
Diagnostic evaluation
Complete blood picture
 Chest x-ray
 Ultrasonography (abdominal, cervical, axillar etc.)
 CT-scan
 Fine needle biopsy- cytology
 Lymph node excision

Splenomegaly - causes
–
(1) Reticuloendothelial or immune
system hyperplasia
infectious diseases
 immune diseases (Felty's syndrome - RA)
 abnormal red blood cell destruction:
hereditary spherocytosis, thalassemia,
sickle cell disease

–
–
(2) Altered splenic blood flow
(congestion): hepatic cirrhosis, splenic,
hepatic, or portal vein thrombosis
(3) Malignant neoplasms:
primarily: lymphomas
 secondarily: leukemias, metastatic solid

Splenomegaly
–
–
–
(4) Extramedullary hematopoiesis in the
spleen: myeloid metaplasia
(5) Infiltration of the spleen with
abnormal material: amyloidosis,
Gaucher's disease
(6) Space-occupying lesions of the
spleen: hemangiomas, cysts
Splenomegaly
–
–
–
Mild: congestive heart failure, malaria, typhoid
fever, bacterial endocarditis, systemic lupus
erythematosus, rheumatoid arthritis, thalassemia
minor
Moderate: hepatitis, cirrhosis, lymphomas,
infectious mononucleosis, hemolytic anemias,
splenic abscesses and infarcts, amyloidosis
Massive: chronic myelocytic leukemia, myeloid
metaplasia with myelofibrosis, hairy cell leukemia,
Gaucher's and Niemann-Pick diseases, sarcoidosis,
thalassemia major, chronic malaria, congenital syphilis,
leishmaniasis, portal vein obstruction
Splenomegaly
Diagnostic evaluation
Complete blood picture
 Serology (infections, autoantibodies)
 Blood culture
 Imaging technics (chest x-ray, ultrasonography,

Doppler US, CT, MR)

Histology
Malignant lymphomas
Arise in lymph nodes or extranodal
lymphoid tissue
 Subtypes:

–
–
Hodgkin’s disease
Non Hodgkin’s lymphomas
Hodgkin’s disease
Mostly young adults
 Asymptomatic lymphadenopathy

–
–
–
often cervical
mediastinal
abdominal
Hepatomegaly, splenomegaly
 Fever, night sweats, loss of weight
 Diagnosis: lymph node histology
(Reed-Sternberg cells)
Staging

Non Hodgkin’s lymphomas
Older patients
 More diffuse lymph node involvement
 General symptoms:fever, weight loss,
night sweat
 Frequent extralymphatic involvement
(50%: bone marrowanemia, tct-penia)
 Special forms: CLL
Skin infiltration (T-cells)
MALT-lymphoma
Multiple myeloma

Multiple myeloma
Plasma cell neoplasm
 Bone marrow infiltration
 Monoclonal immunglobulin production
 Osteolytic lesions, bone pain
 Renal lesion

Coagulation disorders
Bleeding tendency, thrombosis, embolism
Factors
 platelets (number, function)
 coagulation factors (amount, function)
 surface of the blood vessels, circulation
Bleeding - history

History of common hemostatic stresses:
 gum
extraction, minor surgeries
 menstruation, childbirth
 injuries

Family history of bleeding tendency
Bleeding

Primary hemostatic defect (platelets)
 occurs
immediately after trauma
 from superficial sites (skin, mucous membranes, nose,
rarely from gastrointestinal, genitourinary tract)
–
–
purpuras, petechiae
ecchymoses
 bleeding

time
Secondary hemostatic defect (coagulation)
 delayed
occurence (hours, days)
 from deep sites (joints, subcutaneous tissues, muscles,
retroperitoneum, body cavities, cerebrum)
–
–
hematomas
hemarthroses
 coagulation
time 
Bleeding - physical findings

From capillaries: purpuras, petechiae
small, superficial,dermal or mucosal pinpoint hemorrhages
characteristic for platelet disorders

From small arterioles and venules:
–
–
–

ecchymoses subcutaneous blood collections- bruises
hematomas deeper, palpable
in platelet and coagulation disorders
Hemarthros - bleeding into joints
characteristic for coagulation disorders (mostly hemophilia)
leads to chronic joint deformity
Thrombosis and embolism

Virchow’s triad
–
–
–
Hypercoagulability
Circulation disturbance- congestion
Pathological endothelial surface
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