MINISTRY OF PUBLIC HEALTH OF UKRAINE
BUKOVINIAN STATE MEDICAL UNIVERSITY
Approval on methodological meeting
of the department of pathophisiology
Protocol №
Chief of department of the pathophysiology,
professor
Yu.Ye.Rohovyy
“___” ___________ 2008 year.
Methodological Instruction
to Practical Lesson
Мodule 2 : PATHOPHYSIOLOGY OF THE ORGANS AND SYSTEMS.
Contenting module 4. Pathophysiology of blood system.
Theme 5: Alteration of hemostatic function.
Chernivtsi – 2008
1.Actuality of the theme. The liquid state of blood is provided with
difficult interaction of three systems – coagulative, ancoagulative and fibrinolytic.
Alteration each of them can cause to decrease or increase of coagulation of blood.
The decrease of coagulation(hypocoagulation) appears like hemorrhagic syndrome.
It’s
appears
as
results
of
alteration
thrombocytous-vessels
hemostatic(thrombocytopenia and thrombocytopathia) or disturbance of various
stages of coagulation of blood (hemophilia A, B, C, afibrinogenemia). The increase
of coagulation of blood (hypercoagulation) is considered as major mechanism
formation of thrombus. One of the most serious consequences alteration of
hemostasis, which includes both hyper- and hypocoagulation, is syndrome of
disseminated intravascular coagulation of blood – DIC-syndrome. It develops as
complication in traumatic, anaphilaxic or cardiogenic shock, malignant tumours,
acute kidney insufficiency, exfoliation of placenta, septicemia, massive hemolysis.
The consequences of disturbances coagulation of blood quite often acquire
menancing character and demand emergency measures from the medical staff.
2.Length of the employment – 2 hours.
3.Aim:
To khow: pathogenesis of the decreasing and increasing of blood
coagulation ability.
To be able: to analyse of the pathogenesis 4 basic mechanisms of
thrombocytopenia’s development: decrease of production, increased destroying,
increased consumption (clot formation), and redistribution of platelets.
To perform practical work: to analyse of the pathogenesis of the platelet
adhesion and aggregation. Von Willebrand factor functions as an adhesion bridge
between subendothelial collagen and the glycoprotein Ib (GpIb) platelet receptor.
Aggregation is accomplished by binding of fibrinogen to platelet GpIIb-IIIa
receptors and bridging many platelets together. Congenital deficiencies in the
various receptors or bridging molecules lead to the diseases indicated in the
colored boxes. ADP, adenosine diphosphate.
4. Basic level.
The name of the previous disciplines
1.
histology
2.
biochemistry
3.
physiology
The receiving of the skills
Vesseles-thrombocytous and
plasmatic
factors, which participate in coagulation of
blood.
Stage of blood coagulation.
Significance ancoagulative and fibrinolytic
systems of blood.
5. The advices for students.
1. What is hemostasis pathology. With the help of the system of hemostasis
blood carriers out one of its most significant functions –keeping itself in a liquid
state and coagulation in case of a vessel’s wall injury and, this way, stopping the
bleeding and keeping the initial volume and composition of blood. The system of
hemostasis has many components. These are platelets and other blood cells,
vessel’s wall, extravascular tissue, biological active substances, tissue factors
(extrinsic pathway), plasma factors of blood clotting (intrinsic pathway), begin in a
close interaction with anticoagulational, fibrinolytic and kallikrein-kinin systems.
Disturbance of any of these components leads to hemostasis pathology.
2. Classification of pathology of hemostasis.
Pathology of hemostasis is classified according to effecting of its components into
disturbance of the extrinsic and intrinsic pathways. According to the etiology, these
disturbances can be acquired and hereditary, as for the direction of pathological
changes they can be leading to decreasing of blood clotting (hypocoagulation) and
increasing of blood clotting (hypercoagulation), which can be local (thrombosis)
and generalized (DIC).
3. Normal hemostasis. A, After vascular injury, local neurohumoral factors induce
a transient vasoconstriction.
B, Platelets adhere (via GpIb receptors) to exposed
extracellular matrix (ECM) by binding to von Willebrand factor (vWF) and are
activated, undergoing a shape change and granule release. Released adenosine
diphosphate (ADP) and thromboxane A2 (TXA2) lead to further platelet
aggregation (via binding of fibrinogen to platelet GpIIb-IIIa receptors), to form the
primary hemostatic plug. C, Local activation of the coagulation cascade (involving
tissue factor and platelet phospholipids) results in fibrin polymerization,
"cementing" the platelets into a definitive secondary hemostatic plug. D, Counterregulatory mechanisms, such as release of t-PA (tissue plasminogen activator, a
fibrinolytic product) and thrombomodulin (interfering with the coagulation
cascade), limit the hemostatic process to the site of injury.
4. The classical coagulation cascade. Note the common link between the intrinsic
and extrinsic pathways at the level of factor IX activation. Factors in red boxes
represent inactive molecules; activated factors are indicated with a lower-case a
and a green box. HMWK, high-molecular-weight kininogen. Not shown are the
inhibitory anticoagulant pathways
5.Virchow's triad in thrombosis. Integrity of endothelium is the most important
factor. Injury to endothelial cells can also alter local blood flow and affect
coagulability. Abnormal blood flow (stasis or turbulence), in turn, can cause
endothelial injury. The factors may act independently or may combine to promote
thrombus formation.
6.Decreasing of blood coagulation ability.
Decrease of blood coagulation ability shows as increasing of bleeding (hemorrhage
syndrome) – repeating bleedings, hematomas appearing both spontaneously and in
case of not significant injuries.
Extrinsic pathway is disturbed in case of qualitative and quantitative changes in
platelets (thrombocytopenia and thrombocytopathies), and also under effecting of
vessels.
Thrombocytopenia means decreasing of platelets count in blood (180-320*109/l).
However, spontaneous bleedings occur only in case of decreasing of their number
down to 30*109/l. Thrombocytopathy means quantitative defects and dysfunction
of thrombocytes under normal or decreased content of them.
7. Thrombocytopenia and thrombocytopathy. Thrombocytopenia can also be
caused by immune reactions in case of changing of antigen structure of
thrombocytes under effecting by viruses, medicines, production of
antithrombocytic antibodies (under chronic lymphoid leukemia and idiopathic
thrombocytopenia), incompatibility of thrombocytic antigens of a mother and
embryo. Besides, thrombocytopenia develops as a result of affecting the
megakaryocytic branch of the bone marrow by ionizing radiation, chemical
substances or replacing of it by tumor metastases, leukemia infiltrates. Decreasing
of thrombocytopoiesis can be caused by deficiency of cyanocobalamin and folic
acid, hereditary defect of formation of platelets (including the deficiency of
thrombocytopoietines). Thrombocytopenia occurs as a result of mechanic injury of
platelets under splenomegaly, artificial cardiac valves and also increased usage of
platelets under local and generalized intravascular blood coagulation.
Thrombocytopathy can be caused by toxic substances and medications (alcohol,
acetylsalicylic acid) ionizing radiation, endogenous metabolites (under uremia,
cirrhosis of the liver); cyanocobalamin deficiency and hormonal disturbances
(hypothyreosis). Genetic defects of the membrane structure and biochemical
composition of platelets (deficiency of thrombostenin, factor 3, ATP, ADP, G-6-
PDG, membrane receptors for V, VIII, XI factors, etc.). Under hemorrhage
vasopathies the injury of vessels’ walls leading to disturbances of the extrinsic
pathway and bleedings, occurs as a result of increasing of blood vessels’ walls’
permeability and their destruction due to disturbance of collagen synthesis (under
nutritious deficiency of vitamin C, genetic defects of collagen synthesis), under
effect of biologically active substances (allergy), radiotoxins (radiation disease),
immune hemorrhage vasculites, decreasing of antiathrophic function of platelets
under thrombocytopenias, destruction of vascular walls by leukemia infiltrates.
One of the causes of bleeding can be lack of producing components of the VIII
coagulation factor by endothelium of vessels (hereditary disease of Villerbrant).
This factor accumulates in platelets and its released during their degranulation.
It is necessary for normal adhesion of platelets to collagen of a vessels’ wall and
thrombocytic clot can’t be formed without it. Hemorrhage syndrome is also
observed under increasing of peroxide oxidation of membrane phospholipids
resulting in hyperproduction and hypersecretion by endothelium of strong
inhibitors of platelets aggregation –prostacyclines. Besides, insufficiency of the
extrinsic pathway can result from a disturbance of the nervous and hormonal
regulation of vascular tonicity, decreasing of which leads to impossibly of
plugging small vessels with a platelet clot.
8. Increasing of blood coagulation ability.
Increase of blood coagulation shows in local (thrombosis) or generalized
intravascular blood clotting, which results from disturbance of the extrinsic and
intrinsic pathways.
Hypercoagulation may be caused by:
Increase of functional activity of the coagulational system due to increased
production of procoagulants and activators of blood clotting.
Increase of platelets count.
Decreasing of antithrombotic qualities of vascular wall.
Decrease of functional activity of anticoagulational system.
Fibrinolysis failure.
9. Generalized (disseminated) intravascular blood coagulation (DICsyndrome) –serious pathology of hemostasis that occurs under increased content
of protocoagulants and activators of blood clotting, which leads to formation of
numerous microclots in microcoagulation vessels, and then to development of
hypocoagulation, thrombocytopenia and hemorrhage due to cunning out of
coagulation factors and increasing of functional activity of anticoagulational
system and fibrinolysis of blood with further exhaustion of all three systems.
Etiology.
Can results of all kinds of shock, traumatic surgeries, obstetric pathology
(premature placental detachment, manual detachment of placenta), acute
intravascular hemolysis, uremia under renal insufficiency and all terminal states.
Pathogenesis.
The main link of pathogenesis of the generalized hypercoagulation is balance
disturbance of the kallikrein-kinin, coagulation, anticoagulation and fibrinolytic
systems under coming into the blood of big quantities of protocoagulants and their
activators. The phase of hypercoagulation is characterized by blood clotting in
vessels and stop of the coagulation with development of serious dystrophic and
functional disturbances in organs and tissues, often not compatible with life. In the
next phase of hypocoagulation thinning of blood and loss of the ability to coagulate
and aggregate platelets cause bleeding, which can rarely be stopped
therapeutically. In case of favorable result there comes the first stage –
rehabilitation phase, when the function of hemostasis normalizes.
5.1. Content of the theme. What is hemostasis pathology.
Classification of pathology of hemostasis. Normal hemostasis. The classical
coagulation cascade. Virchow's triad in thrombosis. Decreasing of blood
coagulation ability. Thrombocytopenia and thrombocytopathy. Increasing of blood
coagulation ability. Generalized (disseminated) intravascular blood coagulation
(DIC-syndrome).
1.
2.
3.
4.
5.
6.
7.
8.
9.
5.2. Control questions of the theme:
What is hemostasis pathology.
Classification of pathology of hemostasis.
Normal hemostasis.
The classical coagulation cascade.
Virchow's triad in thrombosis.
Decreasing of blood coagulation ability.
Thrombocytopenia and thrombocytopathy.
Increasing of blood coagulation ability.
Generalized (disseminated) intravascular blood coagulation (DIC-syndrome).
5.3. Practice Examination.
Task 1. In the patient in time accident on Chernobel atomic power station arose
hemorrhagic syndrome, which was showed by hemorrhage in skin and
mucous membrain, appearance of blood in urine, faces and phlegmon. The
mechanism of hemorrhagic syndrome consists of:
A. Activation of fibrinolytic system B. Accumulation of heparin in blood
C. Decrease amount of thromocytes D. Violation of structure of
fibrinogene E. Lesion vascular wall
Task 2. Victim in time catastroph of atomic submarine received doze of
irradiation 6 Gr (600 Rad). It is necessary to expect serious violations of
function and structure of cells in him:
A. Epithelium of skin B. Epithelium of intestine C. Pulpa of spleen
D. Thyroid gland E. Bone-marrow
Task 3. In the child with hemorrhagic syndrome was diagnosed hemophilia. В. It is
stipulated by deficiency of the factor:
A. ІІ (prothrombin) B. V ІІІ (antihemophilic globulin)
C. І Х (Christmas) D. Х І (thromboplastin) E. Х ІІ (Hageman)
Task 4. In the patient after operative interference on pancreas arose hemorrhagic
syndrome with expressed alteration of
coagulationof blood. The
mechanism of its development is explained by:
A. Insufficient formation of fibrine B. Activation fibrinolytic system
C. Decrease amount of thrombocytes D. Activation of anticoagulatic
system E. Activation of kalicrein-kinin system
Task 5. The patient suffers for hereditary form coagulopathy, in it basis lies the
deficiency of factor Х ІІ (Hageman). Essence violation of hemostasis in
the patient is reduced to:
A. Suppression of coagulative system B. Activation of kalicrein-kinin
system C. Activation of fibrinolytic system
D. Suppression of anticoagulative system E. Delay down retraction of
clot
II
Task 1. The process of blood clot formation on the inner surface of blood vessel in
the alive organism is called:
А. Stasis В. Embolism С. Thrombosis D. Atherosclerosis
E. Thromboembolism
Task 2. Occlusion of the vessels by the bodies carried in blood and lymph
is called:
А. Obliteration В. Atherosclerosis С. Thrombosis D. Embolism E. Stasis
Task 3. What main functional disorder is caused by embolism of the small blood
circulation?
А. Acute failure of left ventricle В. Increase of alveolar ventilation
С. Decrease of alveolar ventilation D. Increase of the arterial pressure
E. Decrease of arterial pressure
Task 4. Occlusion of the portal vein causes:
А. Increase of arterial pressure В. Portal hypertension syndrome
С. Acute right ventricle failure D.Acute left ventricle failure E. Acute
respiratory failure
Real-life situations to be solved: The patient was in surgical clinic because of
thrombophlebitis of the right leg. After careless sudden movement an acute
dyspnoe to bother him, pain in the chest and cyanosis appeared.
1. Did these disorders associate with thrombophlebitis of the leg?
2. In what cases such consequences of thrombophlebitis are possible?
3. Are such complications occasional in the patient?
4. Is thrombophlebitis complication possible in the other organs - brain,
kidneys, spleen?
Literature:
1. Gozhenko A.I., Makulkin R.F., Gurcalova I.P. at al. General and clinical
pathophysiology/ Workbook for medical students and practitioners.-Odessa, 2001.
2. Gozhenko A.I., Gurcalova I.P. General and clinical pathophysiology/ Study
guide for medical students and practitioners.-Odessa, 2003.
3. Robbins Pathologic basis of disease.-6th ed./Ramzi S.Cotnar, Vinay Kumar,
Tucker Collins.-Philadelphia, London, Toronto, Montreal, Sydney, Tokyo.-1999.