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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
(normal myeloid to erythroid ratio in the b.m. : 2-3:1)
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 in the liver])
pluripotent stem cells
CFU-E
BFU-E
proerythroblasts
erythroblasts
normoblasts
mature red blood cells
Leukocyte production
Pluripotent stem cells
Myeloblasts (committed stem cells: CFU-C CFU-GM, stimulated by CSFs)
Promyelocytes largest leukocytes, with non specific
granulation
Myelocytes specific granulation (Neu.,Eo., Bas.)
last proliferating cells
Metamyelocytes
Band-form
Mature polymorphonuclear granulocytes
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
Haematopoiesis
Antibody producing plasma cell differentiation
Monitoring hematopoietic cell quality
Important key nutrients: iron
folic acid
vitamin B12
regulatory hormones
(EPO, CSF-s)
interleukins
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
–identify the cause of anaemia
–morphological evaluation
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History
Family history: anemia, splenomegaly, jaundice
Bleeding tendency in the family
Diet, alcohol intake
Menorrhagia (number of used tampons)
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 - symptoms
–fatigue
–dizziness, vertigo, headache, tinnitus
–cold intolerance
–increased irritability, difficult concentration
–sleeping disturbancies
–exertional intolerance
–abnormal menstruation, loss of libido, impotence
–Hb<75g/l : resting heart rate, stroke volume 
–dyspnea
–complaints of local vascular diseases 
(angina pectoris, cerebral ischaemia,
intermittent claudication)
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
Hepatopsplenomegaly - e.g.hemolysis
Lymphadenopathy - lymphomas, autoimmune diseases
Cheilosis (fissura) iron deficiency
Koilonychia (spoon-shaped nails) iron def.
Beefy red smooth tongue (Hunter-glossitis) - pernicious anemia
Neuropathy - pernicious anemia
Rectal digital examination - bleeding
Evaluation of anemia
The patient is truly anemic?
–Increased plasma volume: pregnancy, fluid overload, congestive heart
failure
–Falsely elevated Hb or Htc: acute dehydration:
plasma loss in burns, vigorous diuresis, bleeding
 Aquired or inherited?
Is there evidence of blood loss? (FOBT, menstruation)
Is there evidence of nutritional deficiency
or malabsorption?
Is there evidence of hemolysis?
Is there evidence for toxic exposure (drugs)
Is there „anemia of chronic disease”
chr. inflammation, renal failure, cancer
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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)
–Iron deficiency(i.e. chr. beeding, malabsorption)
–chr. inflammation, malignancy, chr. infection, thalassemias,
myelodysplastic sy.
Normochromic (MCH 27-34 pg)
–acute bleeding, hemolysis, aplastic anemia, renal anemia
Hyperchromic (MCH>34 pg)
–megaloblastic anemia (B12, folic acid deficiency)
Clinical classification of anemias
Decreased cell production
–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 aspiration or biopsy
bone marrow cellularity
myeloid-erythroid ratio (norm: 2-3:1)
cell maturation
bone marrow infiltration
stromal cells (fibroblasts etc.)
Polycythemias
Hyperviscosity
–Decreased cerebral blood flow
tinnitus, lightheadedness, dizziness, stroke
–Congestive heart failure
–Thrombosis
Increased cell turnover
–Gout (due to hyperuricemia)
–Itching
In polycythaemia vera
–Thrombocytosis
–Haemorrhage
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
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Leukocyte disorders
Granulocytes (neutrophil, eosinophil basophil)
Monocytes and tissue macrophages
Lymphocytes
Functions of leukocytes
Maintaining host defences agains disease
Killing microorganisms
Digestion of tissue debris
Releasing cytokines and mediators
Activation of immune system
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, stress, drugs (steroids)
leukemoid reaction: 30 000-50 000 G/l with mature cells
left shift: bacterial infections
neutrophil function disorders
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
Hematolgic malignancies (CML, Hodgkin’s disease etc.)
Basophil granulocytes
Important role in:
–iflammation
–hypersensitivity reactions
Basophilia: malignant hematologic diseases
Acute leukemias
Agressive immature hemopoietic cell proliferation, without
differentiation
Subtypes:
ALL (acute lymphoblastic leukemia)
ANLL (acute non lymphoblastic leukemia) or
AML (acute myeloblastic leukemia)
Acute leukemia syndrome
Susceptibility to infections - serious infections
Anaemia due to bone marrow infiltration and bleeding
Thrombocytopenia - bleeding tendency
purpuras, petechiae, mucosal bleeding
Organ infiltration
In ALL: lymphadenopathy, splenomegaly
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
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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
Causes of lymphadenopathy
–(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
Chronic myeloproliferative disorders
Polycythemia vera
Myelofibrosis with myeloid metaplasia
Essential thrombocythemia
Chronic myelogenous leukemia
Lymphadenopathy- by region
–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.
Diseases of the lymphoid system
Normal lymph nodes
–Non palpable or <1 cm, except in the inguinal region where can be 0,52 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% beningn
over 50 years: 40% beningn
Lymphadenopathy- by region
–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
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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 tumors
–(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
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Staging of Hodgkin’s disease
I. Involvement of a single lymph node region (I) or single
extralymphatic site (IE)
II. Involvement of two or more lymph node regions on the same side of
the diaphragm (II) or solitary extralymphatic site and one or more
lymph node area on the same side of the diaphragm (IIE)
III. Involvement of lymph node regions on both sides of the
diaphragm, accompanied by spleen involvement (IIIS), or solitary
involvement of an extralymphatic organ (IIIE)
IV. Diffuse involvement of extralymphatic sites with or without lymph
node enlargement
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