Prezentace aplikace PowerPoint

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Pathophysiology of red and white blood cells,
disturbances of hemostasis and coagulation
Prof. J. Hanacek, MD, PhD.
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• Remarks to physiology of blood
• Main functions of blood
• Transport of various substances (O2, CO2,
  nutrients,
• metabolites, minerals, ......)
• Transport of heat (heating, cooling)
• Signal transmission (hormons,...)
• Carrier proteins e.g. albumin
• Buffering and defence systems (antibodies,
  white
• blood cells, oxidants-antioxidants,
  buffer systems)
• Remove products of metabolism
• Body homeostasis-temperature, water,
  electrolytes

2. Composition of blood Blood cells
(RBC, WBC, platelets) Plasma
(electrolytes, nutrients, metabolites,
proteins, fat, carbohydrates, vitamins, gases....)
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3. Development of blood cells Hematopoietic
tissues - red bone morrow (in adult)
- spleen,
liver, other organs (pathologic
conditions)
Pluripotent stem cells ? myeloid, erytroid,
lymphoid
? precursor cells
?
hematopoietic growth factors Myeloid
precursor cells ? myelopoiesis ? monocytes ?
? tissue macrophages ? (in bone morrow)
?
? mast cells,
maturation
eosinofils,

neutrophils,

basophils Lymphoid precursor cells ?
lymphopoiesis ? LyT, LyB
? (in spleen and
lymph nodes)
maturation
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4. Factors and hormones involved in
prolifaration and maturation of blood cells
Erytropoietin (EPO)? proliferation and
maturation of ER (from kidney)
Thrombopoietin ? prolifaration and maturation of
(from kydney) megacaryocytes
? platelets Paracrine factors -
colony stimulating factors (CSF) (in
bone morrow) - stem cells factor ? release
CSF and IL
3, 6, 11, 12 ? Androgens, Thyroid
hormons CSF and IL formation are
inhibited by TGF beta and by TNF alfa
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• Abnormalities of red blood cells
• I. abnormalities in mass of RBC
• 1. Anemias
• 2. Polycythemias

Anemias Definition Reduction below the normal
level in the number of
RBC, the quantity of Hb, and the volume of
packed RBC (Htk) per 100 ml of
blood Classification
According to the mean corpuscular volume (MCV) of
RBC Normal MCV ? 90 fl -
micro- - normo cytic anemia
- macro
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According the mean corpuscular Hb (MCH)
Normal MCH ? 30pg - hypo - normo
chromic anemia - hyper
Etiopathogenetic classification a)
reflects steps in Er-poiesis ? ? RBC production

? defective RBC production b) reflects
life-span of Er ? ? RBC loss
Causes leading to defective RBC production ?
hemoglobinopaties - e.g. sickle cells disease,
? impaired globin synthesis e.g. thalassemias
? RBC membrane defects e.g. hereditary
spherocytosis ? enzyme deficiency - ?ATP due
to ?pyruvate kinase
- ? G- 6 - phosphate dehydrogenase
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Causes leading to decreased and/or defective RBC
production Disseminated malignancies - e.g.
brest cancer, leukemias... Serious chronic
disease - e.g. inflammatory, endocrine....
Lack of essential vitamins - e.g. B12, folic
acid, C vitamin... Lack of iron Bone
morrow failure
Causes leading to RBC loss Bleeding - e.g.
peptic ulcer, polyps in colon, GIT malignancies,
hemorhoids, esophageal
varices... Hemolysis - e.g. due to decreased
resistance of RBC (defects in
RBC membrane, defects in RBC metabolism)
or due to changed
microenvironment surrounding RBC
(mechanical, imunologic, toxic
influences)
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Aplastic anemia (AA) insufficient number of RBC
is
produced Pathogenesis - multifactorial
disease genetically determined - primary
proliferation defect of the hemopoietic
system
- immune reaction directed against hemopoietic
system Mechanisms
probably involved in AA development
immune reaction mediated by T-cells or less
frequently by B-cells many IL
are produced in excess in patients with AA, e.g.
IL-2, TNF they inhibit activity of
bone morrow function abnormal
sensitivity of hemopoietic cells is assumed, so
probably, hemopoietic tissue is
primarilly diseased
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Cosequences If the immune reaction is strong
enough it wipes out abnormal cells ? acute
severe aplasia If the immune reaction is
rather weak ? mild chronic pancytopenia will
develop
Causes of AA Direct toxicity Iatrogenic
causes -
radiotherapy
- chemotherapy
Benzen
Intermediate metabolites of some common
drugs Immune-mediated
causes Iatrogenic
causes, e.g. - transfusion-associated
graft-versus host disease
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• - Eosinophilic fasciitis
• Hepatitis-associated disease
• Pregnancy
• Intermediate metabolites of some common drugs
• Idiopathic AA

Iron deficiency anemias (IDA)
Characteristics - serum Felt0.4mg/l, serum
ferritin? Main causes - Blood loss the
most common cause of IDA
in adults (0.5mg Fe
lost/1ml blood) - Fe
recycling is decreased (the 2nd most common
worldwide)
occurs with chronic
infections (Fe regained by
the macrophages ? decreased
releasing of
Fe for Hb production ? ?reuse of Fe
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• - Fe uptake from GIT is too low (malnutrition)
• Fe absorbtion is reduced due to
• 1. Achlohydria (atrophic gastritis...)
• 2. Malabsorption in upper part of GIT,
• Fe-binding food components (fytates,
  tannic acid)
• ?Fe requirement (growth, pregnancy,
  breast-feeding)
• Apotransferrin defect

Iron deficiency ? inhibition of Hb synthesis ? ?
hypochromic microcytic anemia
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Sideroblastic anemia hypochromic
anemia caused by inability of
RBC to use of Fe in Hb synthesis Pathogenesis
genetic defect linkaged to
X-chromosome (men are more
severely affected) mitochondrial
lesions ? sequestration of Fe complexes
in the mitochondria of erythroblasts ?
sideroblasts
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Megaloblastic anemia due to abnormalities in DNA
synthesis
Main causes - abnormalities in the absorbtion
and metabolism of
folate or B12 vitamin Consequencies
inhibition of DNA synthesis ? cell cycle is
slowed down during erythropoiesis ?
delay in RBC maturation Hb synthesis in
cytoplasm is unchanged ? ?size of ER
(megaloblasts) ? megalocytes in blood
Megalocyte MCV gt 100 fl formation of
granulocytes and megacaryocytes is also
disturbed premature destruction of
megaloblasts in bone morrow
(inefficient erythropoiesis) and shorten life of
megalocytes (premature hemolysis)
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Main disorders of folate absorbtion and
metabolism ? folate uptake ? folate
requirement malabsorbtion, e.g. diseases of
small intestine(terminal part) cobalamine
deficiency Causes - too litle folate
uptake with food - intrinsic
factor deficiency -
competition for vitamin B12 (bacterias, broad
fish tapeworms-
Diphyllobothrium latum) -
absence of the terminal ileum or its
inflammation- site of absorbtion of
cobalamine - defective
transcobalamin II
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Pernicious anemia (PA) - the most common type
of megaloblastic anemia - pernicious highly
injurious and in the past fatal Pathogenesis
defective gastric secretion of intrinsic
factor - congenital deficiency
- atrophy of gastric mucosa -
partial or complex gastrectomy Consequences
- megaloblastic anemia -
neurologic disorders
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Posthemorhagic anemia normochromic,
normocytic anemia caused by sudden loss of
blood Main cause strong bleeding, lost of
large amount of blood
during relatively short time Course of
posthemorhagic anemia 1st step substitution of
lost plasma volume plus Er from depots 2nd step
acceleration of hemopoiesis ? ? mass of Er in
bone
morrow Recovery of
normal number of Er after bleeding afer 4 6
weeks Recovery of normal Hb concentration can
last 6 8 weeks
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Schyzocytes
Hemolytic anemias (HA) Characteristic signs
premature destruction of Er erythropoiesis can
be normal abnormally short life span of Er
erytropoiesis is accelerated
Causes and pathogenetic mechanisms of HA
development inherited acquired Causes of
acquired HA infections, systemic diseases
(e.g. lupus erythematosus) poisons drugs,
toxins (endo- or exogenous) disturbances of
liver and kidney abnormal immune reactions
e.g. transfusion reaction, hemolysis of
newborns, autoimmune reactions
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Causes and mechanisms of inherited
HA Mechanisms defect of Er membrane
defficiency of glycolytic
enzymes disturbances in
Hb synthesis others
Other pathomechanisms particiating in HA
development physical destruction trauma,
arteficial heart valves,
super-long march or run ? heat
and irradiation
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• Disturbances of white blood cells
• Leukemias
• Main pathogenic mechanisms
• structural changes of the normal genes
  (protooncogens ?
• ? oncogens)
• loss or inactivating genes (antioncogens)
• activation of oncogens and loss of
  antioncogens
• leads to increased proliferative
  activity of the cells
• cell loses ability to
  diferentiate and to apoptosis
• Some oncogens related to leukemias
• Philadelphia chromosome translocation of
  ABL gene from
• chromosome 9 to chromosome 22 and its
  fusion to gene BCR

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• Acute myeloblastic leukemia (AML)
• - disseminating, clonal proliferation of
  inmatured
• hematopoietic cells
• 90 of AL in adults is myeloid type
• Possible causes of AML
• irradiation
• chemical agents, e.g. benzene
• viruses

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• Main manifestations of AML
• - cytopenia and blast present in blood
• neutropenic fever
• anemia, thrombocytopenia
• hyperuricemia, hyperkaliemia, hyperphosphatemia
• number of blast cells in peripheral blood gt
  50,000/?l ?
• ? leucostasis
• Consequencies
• blood viscosity
• rigidity of blast cells ?increased risk of
  leucostasis
• agglutination
  ?
• -
  bleedinng to brain
• -
  lung and kidney failure

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Disorders of hemostasis Hemostatic system is
composed of plasma coagulation factors
platelets vessel wall inhibitory
(anticoagulant) factors fibrinolysis system
dissolving excessive fibrin clots
Hemorhagic diathesis (HD) increased bleeding
tendency Main causes - disorders of coagulation,
fibrinolysis, platelets -
vascular defects Consequences if coagulation
and fibrinolysis is inadequate
- minimal mechanical injury ?
hematomas
?
bleeding into

joints if
trombocytes and vascular wall are damaged
- punctate, tiny cutaneous
bleeding
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Pathogenetic mechanisms leading to
disturbancies of coagulation and fibrinolysis in
patients suffering from sepsa
sepsa ? (endo)toxin ? ?cytokines
? depression of inhibitory system
inhibition fibrinolysis by PAI-1
activation tissue factor
deposition of fibrin ? organ failure
Levi et al. Eur J Clin Invest 199727 3-9
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