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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 CSF-s)
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
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
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
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
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% beningn
over 50 years: 40% beningn
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
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.
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
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
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 marrowanemia, 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