Министерство здравоохранения республики Беларусь

Учреждение образования
«Гомельский государственный медицинский университет»

Кафедра патологической физиологии

Обсуждено на заседании кафедры
Протокол №7 от 30.08.2017

МЕТОДИЧЕСКАЯ РАЗРАБОТКА
Для проведения занятия со студентами
3 курса ФПСЗС, обучающихся на английском языке
по патологической физиологии

Тема: Типовые формы нарушения микроциркуляции

Нарушения периферического кровообращения

Theme: Typical forms of microcirculatory disorders

Peripheral circulatory disorders

Время 3 ак. часа

 1.Actuality of the theme. Arterial hyperemia as a typical pathological process is observed in
inflammation, many infectious diseases (measles, spotted fever, scarlet fever), damages of nervous plexus,
neuralgias etc. Knowledge of causes, mechanisms and symptoms of arterial hyperemia matters practically.
Doctors use the surgical, pharmacological, physiotherapeutic influences, which cause artificial arterial
hyperemia. The aim of these influences is improve metabolism, blood and lymphatic circulation in
damaged area. Ischemia leads to development of many diseases, for example, ischemic heart disease, insult,
obliterative endarteritis. The ischemia consequences depend on whole row of factors – development speed,
duration and localizations of ischemia, character of collateral circulation blood, functional condition of the
organ.
Learning goals of the lesson: to study typical forms of microcirculation disorders, their etiology,
pathogenesis, manifestations; main forms of local circulatory disorders.

Educational goals of the lesson: formation of scientific outlook and theoretical basis of future
specialists on the basis of fundamental knowledge and the latest achievements of pathological physiology.

Objectives of the lesson:

1. To know causes, mechanisms, manifestations of intravascular, transmural, extravascular
disorders of microcirculation.
2. To know typical disorders of lymphodynamics, mechanisms and manifestations.
3. To know methods of diagnosis of microcirculation disorders and regional vascular pathology.

To repeat the following questions from related disciplines to ensure absolute mastery of the
material:
1. Structure of histion (histology, cytology, embryology disciplines).
2. Structure and function of blood vessels (human anatomy discipline).

Control questions of the lesson:

1. Typical microcirculatory disorders: classification, causes and mechanisms of development.
2. "Sludge" -phenomenon: definition, types, causes, mechanisms of development and manifestation.
Stasis: definition, types, causes, mechanisms of development and manifestations.
3. Typical disorders of lymphodynamics: types, causes, mechanisms of development and
manifestations. Capillary-trophic insufficiency.
4. Arterial and venous hyperemia: types, causes, mechanisms of development and manifestations.
5. Ischemia: types, causes, mechanisms of development and manifestations.
6. General changes and compensatory processes in a body with peripheral circulatory disorders.
7. Thrombosis: types of blood clots, causes, stages, mechanisms of thrombosis. Embolism: types, causes
and mechanisms of formation. Significance, outcomes and consequences of thrombosis and
embolism.
8. Principles of therapy of disorders of regional circulation and microcirculation.

Calculation of study time

Total study time 3 ac.hours
№ п/п Contents Calculation of study time
1. Introduction. Motivational characteristic of the theme 3 minutes
2. Written control of students on the topic of the lesson 15 minutes
3. Interviews with students about the topic of the lesson 60 minutes
4. Self-managed student work 15 minutes
5. Summing up the results of the lesson 5 minutes
6. Decision of situational tasks 20 minutes
7. Task for the next lesson 2 minutes
 Additional materials:

Typical disorders of peripheral blood flow

There are two groups of disorders of peripheral blood flow.

1) systemic disorders, which connecting with insufficiency of cardio-vascular system. (disoders
of general hemodynamic)
2) disorders of local peripheral flow – it is disorders circulation of the blood in organs and
tissues.
These disorders distinguish on two groups in dependence of sizes of vessels:
1 – disorders of microcirculation – the diameter of vessels is less 100 micrometer,
2 – disorders of macrocirculation – the diameter of vessels is more 100 micrometer.
Disorders of microcirculation.
There are two groups: disorders of hemomicrocirculation (in blood vessels) and lymphcirculation
(in lymphatic vessels).
Disorders of hemomicrocirculation – it is a typical pathological process, what characterized by
disorders of blood circulation in microcirculatory bloodstream.
Microcirculatory bloodstream consists of arterioles, precapillaries, precapillary sphincters,
capillaries, postcapillaries, venules, small veins, arteriovenular anastomoses, and lymphatic vessels.

Distinguish three groups of reasons (causes) of disorders of hemomicrocirculation:

1) intravascular disturbances
2) disturbances of structure and function of vascular wall,
3) extravascular disturbances.

Causes of intravascular disturbances

1. Slowing or excessive acceleration of blood flow and / or lymph

2. Violation of turbulence in blood flow and / or lymph.
3. Excessive increase in juxtacapillary blood flow

Reasons for the slowing of blood flow and / or lymph:

• disorders of hemo and lymphodynamics (eg, heart failure, venous congestion, ischemia,
lymphorrhea);
• an increase in blood viscosity (eg, as a result of hemoconcentration during prolonged vomiting,
diarrhea, plasmorrhages burns, polycythemia, hyperproteinemia disseminated intravascular
coagulation);
• narrowing of microvessels (due to compression them by tumor, edematous tissue, formation of
blood clots in them, embolism, swelling or hyperplasia of endothelial cells, formation of
atherosclerotic plaques and etc.).
Reasons for the excessive acceleration of blood flow and / or lymph:
• Violations of hemodialysis and / or lymphodynamics (for example, pathological arterial
hyperemia or shunt the arterial blood in the venous bed through arteriolo-venular shunts);
• Decrease in blood viscosity (at hemodilution, hypoproteinemia, renal failure, pancytopenia.
Violation of turbulence in blood flow and / or lymph.
• damage of microvessels walls and / or violation them smoothness (vasculitis, hyperplasia of
endothelial cells, arteriosclerosis, fibrotic changes in the vascular wall and the like).
• changes in blood aggregation (for example, the formation of parietal microthrombi violating
laminar blood flow).
Excessive increase in juxtacapillary blood flow
Develops at the opening of the arterio-venous and arteriolo-venular shunts and manifested an excess
discharge of blood from the arteries and arterioles in the veins and venules, bypassing the capillary network
of the microcirculatory bed. Reasons:
 • spasm of arterioles and precapillary sphincters closing with a significant increase in the level of
catecholamines in the blood (with hyper catecholamine crisis in patients with a tumor of the
adrenal medulla - pheochromocytoma);
• at excessive increase in tone of the sympathetic nervous system (under stress).

Transmural disturbances of microcirculation

They may be classified into two major groups:
1. Increased permeability of blood vessels
2. Decreased permeability of blood vessels
Mechanisms of an increase in vascular permeability include: formation of endothelial gaps,
cytoskeletal reorganization, increased transcytosis, direct endothelial injury, development of acidosis (non-
enzymatic hydrolysis of the basic substance vascular basement membrane), activation of hydrolases
(enzymatic hydrolysis of the basic substance vascular basement membrane), hyperextension of the
microvessels walls.
Mechanisms of an de crease in vascular permeability include: thickening of the microvessels walls
(chronic vasculitis), sealing of the microvessels walls due to their calcification.

In accordance with the classical theory of Starling (1909), the passage of liquid and dissolved
substances from the blood into tissues is carried out through a semipermeable membrane of capillary vessels
under the influence of filtration pressure (FP):
FP = (HBP + OTP) - (HTP + OBP), where:
FP is the filtration pressure;
HBP - hydrodynamic blood pressure on the vessel wall (in the arterial end of the capillary) - 32.5
mm Hg
OTP - oncotic tissue pressure - 4.5 mm Hg
HTP - hydrodynamic tissue pressure - 3 mm Hg
OBP - oncotic blood pressure - 25 mm Hg
Therefore, in the arterial capillary vessel, the effective filtration pressure is 9 mm Hg, which
transfers the liquid from the blood to the tissues.
In venous segment of capillaries and in venules, the hydrodynamic blood pressure is significantly
reduced (to 17.5 mm Hg) as a result of the partial transition of the fluid to the interstitium. As a result, FP
= (17.5 + 4.5) - (3 + 25) = -6 mmHg. , which cause a partial resorption of the liquid.

Extravascular disturbances
Extravascular disturbances include increased or decreased flow of interstitial fluid. Interstitial fluid
flow depends on diffusion, filtration and lymph production. The low rate of filtration results from a decrease
in hydrostatic capillary pressure, the density of capillary bed and the permeability of capillary wall. The
lowering of lymph flow may result from low interstitial hydrostatic pressure, high hydrostatic pressure in
lymphatic vessels and impairment contraction of endothelial cells forming lymphatic capillaries.
The reaction of the tissue basophils in connective tissue surrounding vessels to damaging agents. In some
pathological processes (inflammation, allergic tissue damage) from tissue basophils at their degranulation
released bioactive substances and enzymes in the interstitial space surrounding microvasculature. Under
the action of damaging agents on the tissue from lysosomes is released and activated proteolytic enzymes
they digest complex protein-polysaccharide complexes of the main interstitial substance. A consequence
are destructive changes in basement membrane of microvessels and in fibrous structures forming a skeleton,
which encloses microvessels. These defects lead to changes in vascular permeability, their lumen and
slowing blood flow.

Stasis

Stasis (stasis - stop) is arrest of blood flow in the vessels of microcirculatory system (capillaries).
The capillaries and veins are dilated paralytically and filled with blood. In the lumen of some capillaries
the homogenous eosinophilic masses can be seen. They are columns of erythrocytes sticked together, which
is called prestasis. Sludge syndrome (phenomenon) is regarded as a type of stasis. It is characterized by
sticking of erythrocytes, leukocytes and thrombocytes to each other, which is accompanied by blood
viscosity increase.
Stasis may be discirculatory as a result of venous hyperemia or ischemia. Causes of stasis:
• Physical factors (temperature elevation, cold).
• Chemical factors.
• Infection.
• Infectious-allergic factors.
• Autoimmune factors.
Types of stasis:
1. true stasis,
2. ischemic stasis
3. venous-congestive stasis.
True stasis begins with cell aggregation and cell adhesion to the vessel wall and is followed by
hemodynamic changes.
Reasons of the true stasis:
• damage to the capillary walls;
• chemical agents acting on the red blood cells;
• decrease in the rate of blood flow in the capillaries
Pathogenesis
The mechanism of a true stasis development is based on the intravascular aggregation of
erythrocytes (adherence) and formation of conglomerates, which make the flow difficult. It also causes
increasing of the peripheral resistance.
Aggregation of erythrocytes occurs as a result of changing of the physical properties of erythrocyte
plasmolemma under direct effect of the factors, entering the capillary. The surface of erythrocytes, which
is smooth under normal conditions, becomes "fuzzy". Aggregation of erythrocytes occurs as a result.
A significant role in pathogenesis of a true stasis belongs to a hemoconcentration and increased
permeability of capillary walls. Etiological factor itself and metabolites, produced in tissues, promote it. A
special significance in genesis of stasis belongs to the biological active substances (serotonin, bradykinin,
histamine), local acidosis and a change in the blood colloid state. It results in increasing of vessel
permeability and dilatation of vessels leading to hemocoagulation, slowing of the blood flow, aggregation
of erythrocytes and, consequently, to stasis. It is important to emphasize that stasis alone does not induce
thrombosis. Stasis of poorly oxygenated blood causes chronic tissue hypoxia.

Sludge-phenomenon

Sludge-phenomenon is defined as aggregation, adhesion and agglutination of blood cells, mainly

erythrocytes, with further separation of blood into small and large cell aggregates and plasma. Mechanisms
of the sludge-phenomenon are presented on the scheme above
 Figure 1 Mechanisms of the sludge-phenomenon

Types of sludge:
I. Depending on the nature of the impact:
• reversible (when only rouleaux (erythrocytes aggregates))
• irreversible (with the agglutination of red blood cells and the development of viscous
metamorphosis).

II. Depending on the size of aggregates, the nature of their, contours and the packing density of
erythrocytes:
• classic - the large size of the aggregates, the rough outline of the contours and the
dense packing of erythrocytes. This type of sludge occurs when an obstruction
(such as ligatures) prevents the free flow of blood through the vessel, and in many
pathological processes;

• dextran - aggregates of various sizes, round shape, the dense packing of

erythrocytes, the free space in the aggregates in the form of cavities;

• amorphous - a huge number of small aggregates in the form of granules consisting

of several erythrocytes. This kind of sludge occurs the introduction into the
bloodstream of ethanol, ATP, ADP, prothrombin, serotonin, noradrenaline

Consequences of sludge:
1. Violation of blood flow intravascularly (slowing down to stasis, turbulent blood flow, including
arteriolo-venular shunts), disorders of processes of transcapillary current of blood cells
2. Violation of metabolism in tissues and organs with the development of dystrophy and disorder of
plastic processes in them.
3. The development of hypoxia and acidosis in tissues and organs.
Thus, sludge, appearing first as a local response to tissue damage, eventually leading to the initiation
and severity of capillary-trophic failure.
 Capillary trophic failure

Capillary trophic failure (CTF) -a condition characterized by a violation of blood and lymph
circulation in the vessels of microcirculatory, disorders of transport fluid and blood cells through the walls
of microvessels, slowdown flow/outflow of interstitial fluid and metabolic disorders in the tissues and
organs.
The etiology of CTF
• Hereditary factors (hereditary defect in the mechanisms of regulation (kinin system)
(congenital angioedema).
• Acquired (disorder of neuro-endocrine-humoral mechanisms of regulation of pathogenic
factors directly on capillary-connective tissue structures)

Types of CTF:
By origin
• Primary (first damaged capillary-connective tissue structures, then the organs and tissues)
• Secondary (primary disorders localized in the tissues themselves, their parenchyma and
capillary-coupling structures are damaged by a second).
By the nature of defeat:
• Functional (transcapillary exchange violations result from disorders of regulation
mechanisms)
• Organic (violations occur as a result of morphological changes themselves capillary
connecting structures).
By the prevalence: systemic and regional.
By phases of violation transcapillary exchange: compensated and decompensated.

Consequences: dystrophy, a violation of plastic processes in the tissues, organs and disorder vital
activity of the whole organism.

Lymphatic insufficiency
The forms of lymphatic insufficiency:
I. By etiology:
1. Mechanical failure: due to the presence of organic (compression of the tumor, scar,
extirpation of the lymph nodes and blood vessels) or functional reasons (increased pressure in the main
blood vessels, lymph vessels spasm).
2. Dynamic failure: the volume of interstitial fluid extravasation exceeds the capacity of the
lymphatic system to ensure effective drainage fabric.
3. Resorption Failure due to structural changes in the interstitial tissue, the accumulation of
proteins and deposition of abnormal forms in the interstitium.
II. By volume of defeat: general and local.
III. By speed of the emergence and development: acute and chronic.
The main clinical and pathophysiological manifestations of lymphatic insufficiency is the
accumulation of proteins and their degradation products in the interstitial tissue and fibrosis.

Typical disorders of peripheral blood flow

There are two groups of disorders of peripheral blood flow.
1) systemic disorders, which connecting with insufficiency of cardio-vascular system. (disoders
of general hemodynamic)
2) disorders of local peripheral flow – it is disorders circulation of the blood in organs and
tissues.
These disorders distinguish on two groups in dependence of sizes of vessels:
1 – disorders of microcirculation – the diameter of vessels is less 100 micrometer,
2 – disorders of macrocirculation – the diameter of vessels is more 100 micrometer.
Disorders of microcirculation.
 There are two groups: disorders of hemomicrocirculation (in blood vessels) and lymphcirculation
(in lymphatic vessels).
Disorders of hemomicrocirculation – it is a typical pathological process, what characterized by
disorders of blood circulation in microcirculatory bloodstream.
Microcirculatory bloodstream consists of arterioles, precapillaries, precapillary sphincters,
capillaries, postcapillaries, venules, small veins, arteriovenular anastomoses, and lymphatic vessels.
Distinguish three groups of reasons (causes) of disorders of hemomicrocirculation:
1) intravascular disturbances
2) disturbances of structure and function of vascular wall,
3) extravascular disturbances.

Arterial hyperemia
Arterial hyperemia is characterized by a local deposition of the blood and an increase in blood flow
rate through the organ or tissue resulting from a dilation of arterial vessels.
Depended from etiologic factors and mechanisms of development there are types of arterial
hyperemia:
I. There are three types of physiological arterial hyperemia:
1) working – organ hyperfunction (muscle, intestine, etc)
2) emotional (psychogenic) – its conditional reflex (shame, excitement, confusion)
3) reactive (substitute) – hyperemia after short-term (transitory) ischemia.
II. There are types of pathological arterial hyperemia:
1. Neurotonic arterial hyperemia
2. Neuroparalytic arterial hyperemia (angioneurotic)
3. Postischemic – an increase in blood flow to an organ or tissue after temporary cessation of
circulation.
4. Inflammatory – it is a compensatory-adaptive process under the influence of vasoactive
substances, inflammatory mediators
5. Collateral – e. myocardial infarction - a vascular necrosis (ischemic, in fact) with a hemorrhagic
halo as determined by the development of collaterals. This arterial hyperemia bypassing in the small circle
is due to the presence of an interatrial or interventricular defects with discharge of blood from left to right.
Lung arteries elastic and muscular-elastic types are dilate and muscle type is constrict in law-Bayliss
Ostroumova. This is development of the precapillary pulmonary hypertension.
6. In arterio-venous shunts – marked in vascular damage, with the sucks action by veins, etc.
7. Vacuum – in the area with low pressure.

Mechanisms of arterial hyperemia:

I. Neurogenic mechanism has 2 types:
1. Neurotonic mechanism (predominance effects of parasympathetic nervous over sympathetic on
arterial vessel walls due to:
- activation of parasympathetic effector and an increase in level of acetylcholine in the
neuromuscular synapses of vascular walls (observed at irritation of parasympathetic ganglia, for example,
in inflammation, tumor compression, scars, trauma);
- increase the sensitivity of cholinergic receptors of vessels walls to the action of acetylcholine (with
an increase in the extracellular level of potassium, hydrogen).
2. Neuroparalytic mechanism is characterized by a reduction or absence ("paralysis") of sympathetic
nerve effects on the walls of arteries and arterioles when:
- inhibiting or stopping the conduction of nerve impulses along sympathetic fibers (in damage to the
sympathetic ganglia or nerve endings as a result of trauma, inflammation, during surgery);
- reduction in adrenoreactive properties of arteries (arterioles) walls (in the focus of inflammation
due to physico-chemical changes in it - acidosis, a decrease in the level of potassium ions, etc.).
II. The neuromyoparalytic mechanism is characterized by:
1. The depletion of catecholamine depot in the vesicles of sympathetic nerve endings in the walls
of arterioles and precapillaries.
2. Decreased tone of muscle fibers of arterial vessels and precapillaries.
 Causes: prolonged action on tissues or organs of various factors (heat, mustard plasters, therapeutic
mud, etc.), the termination of prolonged pressure on the walls of arteries (for example, ascitic fluid, tight
bandage, pressing clothing).
The effect of these factors over a long time significantly reduces or completely removes the
myogenic and regulatory (mainly adrenergic) tonus of arterial vessel walls.
III. The humoral mechanism:
1. Increase in the level of BAS with vasodilating action (adenosine, NO, PgE, PgI2, kinin).
2. Increased sensitivity of receptors of arterial (precapillaries) walls to vasodilators.

Manifestations and their mechanisms:

1. Redness – reduction of deoxygenated hemoglobin in the capillary bed.
2. Increased temperature – increased inflow of warm arterial blood.
3. Vessel pulsation.
4. Slight swelling – mild accumulation of fluid in the interstitial space resulted from an increase in
filtration rate.
5. Increased number of functioning capillaries - an increase in capillary hydrostatic pressure.
6. Increased arteriole diameter and blood flow rate – metabolic mechanism.
7. Increased lymphatic outflow – mild elevation of interstitial hydrostatic pressure.
Humoral mechanism is responsible for a reactive hyperemia, which is the most common form of
arterial hyperemia. When the blood supply to tissue is blocked for a few seconds to several hours and then
is unblocked, the flow through the tissue can increase to about five times normal. The duration of reactive
hyperemia depends on the duration of the ischemic period. Reactive hyperemia may have very harmful
effects on the myocardium and brain. It can be accompanied by increased production of free oxygen radicals
and an impairment of intracellular calcium exchange.

Venous hyperemia.

Venous hyperemia is characterized by a local deposition of blood and a decrease of blood flow rate
through the organ or tissue resulting from a delay or cessation of blood outflow via the venous vessels.
Mechanisms of venous hyperemia:
A) Heart disorders;
B) reducing the suction effect of the chest;
C) blockade (compression - tumor, swelling tissue, scar or tourniquet; obstruction by thrombus or
embolus
D) A decrease in venous wall elasticity combined with vein extension, venous valves failure,
development of collateral blood circulation.

Types of venous hyperemia:

1. general venous hyperemia -in heart pathology, reflecting acute or chronic cardiovascular
insufficiency.
2. acute general venous hyperemia. Due to lack of oxygen in venous blood, hypoxia and acidosis
developed in the tissues, vascular permeability is increased (primarily in the microcirculatory bed), it leads
to plasma saturation and edema, dystrophy. The organs that deposit blood - lungs, liver, skin with the
subcutaneous fat, kidneys, spleen - are affected.
3. chronic general venous hyperemia is characterized by the same processes as acute, as well as
atrophy of the parenchyma and sclerosis of the stroma due to the activation of fibroblasts and the
proliferation of connective tissue, leading to compaction (induration) of the affected organs.
4. local venous hyperemia: obturation of vein by thrombus, embolus, inflammatory process;
compression of vein by tourniquet, tumor, scar tissue; collateral, formed with difficulty of outflow of blood
along the main venous vessel.

Manifestations and their mechanisms:

1. Cyanosis: accumulation of deoxygenated hemoglobin in the capillary bed.
2. Edema: an elevation of hydrostatic pressure in veins and capillaries.
 3. Decreased local temperature – a decrease in the rate of metabolic process and reduced inflow of
warm arterial blood.
4. Increased diameter of venous vessels and decreased blood flow.
5. Decreased lymphatic outflow – compression of lymphatic capillaries caused by high interstitial
hydrostatic pressure.
6. Decreased capillary blood flow and stasis.

Morphology of congestion
Because of the increase in venous blood, organs become swollen and purplish. With long continued
over-distension, the wall of the venules shows reactive thickening and there is mild intestinal fibrosis of the
organs, giving them a very firm consistency. These changes are seen typically in the kidney and spleen.
Important additional changes are found in the lungs and liver.
Lungs. The lungs are burcly, congested and brownish in color. Pulmonary venous engorgement
leads to alveolar hemorrhage. Hemoglobin from intra-alveolar blood is transformed into hemosiderin,
which is then phagocytized by macrophages. These macrophages are known as heart failure cells.
Phagocytes full of brown pigment migrate into intestinal tissue and to the lymph nodus. The sectioned
surface is dark brown. It process in lungs is named as “brown induration” of the lungs.
Spleen. Chronic venous congestion of the spleen occurs in right heart failure and in portal
hypertension from cirrhosis of liver. The spleen in early stage is moderately enlarged while in long-standing
cases there is progressive enlargement and may weigh up to 500 g to 1000 g. The organ is deeply congested,
tense and cyanotic (“cyanotic induration of the spleen”). Sectioned surface is gray tan. The red pulp shows
congestion and marked sinusoidal dilatation with areas of recent and old hemorrhages. These hemorrhages
may get organized. This advanced stage seen more commonly in hepatic cirrhosis is called congestive
splenomegaly and is the commonest cause of hypersplenism.
Liver. Chronic venous congestion of the liver occurs in right heart failure and sometimes due to
occlusion of inferior vena cava and hepatic vein. The liver is enlarged and tender and the capsule is tense.
Cut surface shows characteristic “nutmeg liver” due to red and yellow mottled appearance. The changes of
congestion are more marked in the centrolobular zone due to severe hypoxia than in the peripheral zone.
The centrolobular hepatocytes undergo degenerative changes, and eventually centrolobular hemorrhagic
necrosis may be seen. The peripheral zone of the lobule is less severely affected by chronic hypoxia and
shows some fatty change in the hepatocytes. If the patient has periods of remission, the remaining liver
cells may undergo compensatory hyperplasia. This results in small, irregular, pale nodules alternating with
areas of fibrosis – so-called cardiac cirrhosis. It’s not true cirrhosis and does not causes hepatic failure.
Consequences of venous hyperemia: hypoxia, hypotrophy atrophy, hypoplasia, sclerosis, necrosis,
induration of organs, edema, stasis, hemorrhage, thrombosis.

Ischemia
Ischemia is an imbalance between the supply and demand of the organ or tissue for blood. It implies
insufficient oxygen and nutrients delivery and inadequate removal of metabolites.
Types of ischemia
a. Angiospastic (reflex).
b. Obstructive.
c. Compressive.
d. Because of redistribution of blood.
Mechanisms of ischemia:
1. Neurogenic mechanisms (neurotonic and neuroparalytic) of ischemia development.
- neurotonic mechanism is predominance of the effects of the sympathetic nervous system on the
walls of arterioles in comparison with the parasympathetic (increases releasing of catecholamines and / or
increases the sensitivity of adrenoreceptors of arterioles walls (f.e. stress, the effect on tissues of low
temperature, mechanical trauma, chemicals).
- neuroparalytic mechanism It is characterized by the elimination or reduction ("paralysis") of
parasympathetic influences on the walls of arterioles.
2. Humoral mechanism
 - increasing the content of substances with vasoconstrictive action (eg, angiotensin II,
thromboxane A2, adrenaline, PgF) in the tissues
- increasing the sensitivity of arteriolar wall receptors to agents with a vasoconstrictive effect (for
example, with an increase in tissues [Ca2 +] or [Na +]). This leads to a contraction of SMC walls of
arterioles, narrowing them and to the development of ischemia.
3. Mechanical:
- compression (compression) of the arterial vessel with a tumor, scar, edematous tissue,
tourniquet;
- obstruction (until complete closure: obturation), decrease of the arterioles lumen (for example,
thrombus, aggregate of formed blood elements, embolus).
- an increase in blood viscosity: polycytemia, massive hemoglobinemia or myoglobinemia.
4. Increase in metabolic demand outpacing the blood supply.
5. Rapid lowering of the systemic blood pressure as in shock or collapse.
6. Combination of the listed above.
Manifestations and their mechanisms:
1. A decrease in diameter and number of visible
vessels.
2. Pallor: reduction in the amount of hemoglobin.
3. A decrease or disappearance of pulsation.
4. A reduction of lymph output de to a decrease in
interstitial pressure caused by reduction of water
filtration from capillaries into interstitium.
5. A decrease in local temperature due to a reduced
blood inflow and decreased rate of oxygen-
depended metabolism.
6. A reduction in diameter of arterioles and
precapillaries, a decreased capillary bed and low
blood flow velocity.
The consequences of ischemia: coagulation
necrosis or infarct, apoptosis. Moderate ischemia
can result in hypotrophy, atrophy and sclerosis.
Figure 2 Mechanism of cell damage in
ischemia

Morphologic features
The primary response of acute ischemia is
cellular swelling or edema with dilation of the endoplasmic reticulum, dissociation of polysomes into
monosomes, swelling of mitochondria, and also increased concentration of water, sodium, and chloride and
decreased concentration of potassium into the cytoplasm. If the duration of ischemia is short, the structure
and the function of tissue may be restored.
If ischemia persists, irreversible injury ensures with severe vacuolization of the mitochondria
including their christae, extensive damage to cytoplasm membranes, and swelling of lysosomes. When the
lesion is continuous, infarction, atrophy or sclerosis may develop.

Infarction
Infarction is an area of ischemic necrosis within a tissue or an organ, produced by occlusion of either
its arterial supply or its venous drainage.
Types of infarctions:
Ischemic (white) infarction is encountered with arterial occlusion and in solid tissues (spleen).
Red (hemorrhagic) infarction is encountered with venous occlusion, in tissue as with double
circulation, and in tissue previously congested (lung, intestinum).
White infarction with hemorrhagic halo (kidneys, heart).
Pathogenesis
 The process of infarction takes place as follows localised hyperemia due to local anoxemia. Within
a few hours, the affected part becomes swollen due to edema and hemorrhage. Cellular changes such as
cloudy swelling and degeneration appear early. There is progressive autolysis of the necrotic tissue and
hemolysis of the red cells. An acute inflammatory reaction and hyperemia appear at the same time in the
surrounding tissues. Blood pigments, hematoidin and hemosiderin, liberated by hemolysis is deposited in
the infarct. Following this, there is progressive ingrowth of granulation tissue from the margin of the infarct.
Postischemic reperfusion phenomenon
There are two modern hypotheses of reperfusion mechanisms:
1. «Calcium» hypothesis — an overload of cardiomyocytes with calcium ions results in reperfusion
contracture, a decrease in diastolic volume and cardiac output.
2. «Free radical» hypothesis — the toxic effect of oxygen on the myocardium in reoxygenation after
ischemia.
Ischemic syndromes also include:
Ischemic preconditioning «intermittent ischemia» [Gurin, 1997], phenomeon of metabolic
adaptation that occurs after one or several short intermediate 5 minute ischemia reperfusion and to increase
the stability of myocardium to the damaging effect of a long period of ischemia and reperfusion.
The mechanism of the phenomenon is associated with activation of ATP-dependent potassium
channel => formed a tendency to normalization of intra-and extracellular ion balance.

Thrombosis
Thrombosis is a pathologic process, which denotes the formation of a clotted mass of blood within
the noninterruptured vascular system.
Influences predisposing to thrombosis:
1. Injury to endothelium;
2. Alterations in the normal blood flow;
3. Alterations in the blood coagulation system (hypercoagulability).
Blood vessels and platelets the first react to injury (primary hemostasis), followed by blood
coagulation occurs with the participation of plasma factors (secondary), although both of these mechanisms
are mutually potentiate each other and function conjugately.

Mechanisms of formation
The mechanism of vascular-platelet hemostasis
Activation of vascular-platelet (primary) hemostasis makes a complete stop of bleeding from
capillaries and venules and temporary stop of bleeding from veins, arterioles and arteries by forming the
primary hemostatic plug from which upon activation of the secondary (coagulation) hemostasis formed
thrombus.
Key mechanisms of thrombosis are: damage of vascular endothelium; local vasoconstriction;
adhesion of platelets to the site of naked subendothelium; platelet aggregation; activation of blood clotting
while reducing its lytic properties.
1. Damage of endothelium and the primary vasospasm
Microvessels respond to damage by short-term spasm, causing them bleeding does not occur in the
first 20-30 seconds. Reflex spasm of blood vessels by contraction of smooth muscle cells of the vascular
wall and supported by vasospastic agents secreted by the endothelium and platelets (serotonin, TxA2,
norepinephrine, and others).
Endothelial damage is accompanied by a decrease in of the vascular wall and thromboresistance
naked subendothelium that contains collagen and expresses the adhesion proteins - von Willebrand factor,
fibronectin, thrombospondin.
2. The adhesion of platelets to the site of naked subendothelium
Carried out in the first few seconds after endothelial damage due to:
• reducing amount of surface negative charge of the vascular wall in violation of its integrity;
• platelets receptor to collagen.
The stabilization of the resulting compound is carried adhesion proteins - von Willebrand factor,
fibronectin and thrombospondin, forming "bridges" between their complementary platelet glycoprotein and
collagen.
 3. Activation of platelets and secondary vasospasm
The activation of platelets is caused by thrombin that formed from prothrombin under the influence
of tissue thromboplastin, PAF, ADP (released together with thromboplastin at the vascular wall damage),
Ca2+, adrenaline.
The process of platelets activation is associated with the chemical modification of membranes and
induction of enzyme glycosyltransferase, phospholipase A2 in them. Glycosyltransferase interacts with
specific receptor on the molecule of collagen and thereby provides "landing" of platelets on the
subendothelium.
Phospholipase A2 starts the hydrolysis of phosphatidylethanolamine, that lead to the release of
arachidonic acid. From arachidonic acid by the action of COG formed prostaglandins PgG2, PgH2, that
transforming to the TxA2 (a potent inducer of platelet aggregation and vasoconstrictor) under the influence
of an enzyme thromboxane synthetase. Prostaglandins contribute to the accumulation of cAMP in platelets,
regulate protein phosphorylation and activation of calmodulin, that transporting Ca2+ from the dense
tubular system of platelets into the cytoplasm. As a result, there is an activation of contractile protein of
actomyosin complex, which is accompanied by a contraction of microfilaments of platelets with the
pseudopodia formation. This further enhances platelet adhesion to the damaged endothelium.
At the same time, by the Ca2+-induced contraction of microtubules occurs emptying of granules at
two phases: the first phase – release the contents from dense granules, the second – α-granules. TxA2 and
dismissed from the dense granules of platelets vasoactive substances cause secondary vasospasm.
4. Platelets aggregation
During degranulation of platelets are released TxA2, ADP, serotonin, β-thromboglobulin, platelet
factor 4, fibrinogen and others components of dense granules and α-granules. They cause sticking of
platelets together and with collagen. In addition, the appearance of the paf in the bloodstream (at endothelial
destruction) and components of platelet granules leads to the activation of intact platelet, their aggregation
with platelets that adherent on the endothelium.
Platelets aggregation does not develop in the absence of extracellular Ca2+, fibrinogen.
5. The formation of hemostatic plug
As a result of platelet aggregation formed primary (temporary) hemostatic plug that obturate
vascular defects (does not contain fibrin). Subsequently, on the surface of platelets aggregate adsorbed
plasma coagulation factors and starts the "internal cascade" of coagulation that ends by the precipitation of
stabilized fibrin fibers and the formation of platelet plug on the basis of a blood clot (thrombus).
At contraction of platelets thrombosthenin the thrombus compacted (clot retraction).
"External cascade" of blood clotting involves the release of tissue thromboplastin. Additionally,
platelets can independently (in the absence of contact factors) start of blood clotting by the interaction of
the factor Va (exposed on their surface) with factor Xa of plasma, catalyzes the conversion of prothrombin
to thrombin.
The mechanism of coagulation hemostasis
There are three stages of the blood clotting process. The first stage ends with the formation of active
prothrombinase complex on membrane phospholipids, which includes factors X, V, and Ca2 + by internal
and external mechanisms. The second stage is characterized by the formation of thrombin (the active form
of factor II). In the third stage (final phase of blood clotting) there is a formation and stabilization of fibrin
clot.
Normal hemostasis is attained by cooperation and interaction of primary (vascular platelet) and
secondary (coagulation) mechanisms of hemostasis impairments.
Types of thrombi
According to the degree of the lumen obstruction, thrombi may be:
• Occlusive thrombi most commonly develop in small arteries and veins.
• Wall-attached or parietal thrombi develop in large arteries and heart cavities.
• Axial.
• Globe-shaped (in the heart).
According to the morphology
Thrombi may be of various shapes, size and composition depending upon the site of origin and it is
attached to the vascular wall; it is dense, with corrugated surface. It is composed of branching bars of stuck
thrombocytes and bands of fibrin with erythrocytes and leukocytes located between them.
Morphological types of thrombi
• White thrombus – consists mainly of platelets, fibrin and leukocytes; forms slowly in rapid
circulation of the blood (usually in the arteries);
• Red thrombus – consists of platelets, fibrin and excessive amount of erythrocytes; forms rapidly
at slow blood circulation (usually in veins). Venous thrombi are dark-red colored dry masses with
dim surface.
• Mixed or laminated thrombus – has laminated structure, contains white and red elements of
thrombus (usually forms in veins, aneurysms of aorta and heart). Mixed thrombus consists of core
or head (white thrombus), body (white and red) and tail (has construction of red thrombus). Core is
connected with endothelium. Mixed thrombus is of gray-red color with rough dim surface, fixed to
the intima of the vessel. Body and tail are located freely in the vessel’s lumen.
• Hyaline thrombus consists of precipitating plasma proteins, destructed erythrocytes, leukocytes
and thrombocytes. They do not contain fibrin. They resemble hyaline and are located in the
microcirculatory bed.
• Agonal thrombus – consists of the yellowish fibrin and localizes in the apex of the right ventricle
of the heart and may extend into pulmonary artery. It is formed in the last minutes of the life when
the death occurs slowly. Red clot forms in case of the rapid death.
The distinguishing features between thrombi formed in rapidly-flowing arterial circulation and
slow-moving venous blood are given in Table 1.
TABLE 1. Distinguishing Features of Arterial and Venous Thrombi.
Feature Arterial thrombi Venous thrombi
Blood flow Formed in rapidly-flowing blood of Formed in slow-moving blood in -veins
arteries and heart
Sites Common in coronary, cerebral, iliac Common in superficial varicose veins, deep
and femoral arteries leg veins, popliteal, femoral and iliac veins

Thrombogenesis Formed following endothelial cell Formed following venous stasis,

injury, e.g. in atherosclerosis e.g. in abdominal operations, child-birth
Development Usually mural, not occluding the Usually occlusive, take the cast of the vessel
lumen completely, may propagate. in which formed, may propagate in both
directions.
Macroscopy Grey-white, friable with lines of Zahn Red-blue with fibrin strands and lines of
on surface. Zahn.
Microscopy Distinct lines of Zahn composed of Lines of Zahn with more abundant red cells.
platelets, fibrin with entangled red
and white blood cells.
Effects Ischemia leading to infarcts, e.g. of Thromboembolism, edema, skin ulcers,
heart, brain etc. poor wound healing.

Outcomes of the thrombosis

1. Favourable outcomes:
• Aseptic autolysis (dissolution) by fibrinolytic system, proteinolytic enzymes of macrophages
and leukocytes.
• Organization by the replacement of connective tissue.
• Recanalization is the re-establishment of the vascular lumen through occluding thrombus.
• Incorporation or vascularization means restoration of the circulation in the vessel because
of the formation of the new vessels through the thrombotic mass.
• Petrification or dystrophy calcification – accumulation of the calcium salts in the thrombotic
masses.
2. Unfavourable outcomes:
• Thromboembolism.
• Septic autolysis.
• Propagation with following obstruction of some critical vessel.
 Embolism
Embolism is the passage through the venous or arterial circulations of any material capable of
lodging in a blood vessel and they’re by obstructing the lumen. The transported intravascular mass detached
from its site of origin is called an embolus.
Types of embolism
According to localization:
• Small blood circulation.
• Large blood circulation.
• System of vena portae.
According to the direction of the movement of embolus:
• Orthograde (by blood flow)
• Retrograde (against blood flow). Metastasis of the carcinoma prostate in the spine takes
place.
• Paradoxical (emboli arising in the venous circulation may by pass the lungs by travelling
through an incompletely closed foramen ovale, subsequently blocking flow in systemic
arteries).
According to the nature of the embolus:
I. Exogenous embolism:
• Air – from large vein with a damage of neck and chest, and that is very important for iatrogenic
disease.
• Gas – is the result of bubbling in the blood soluble gas with rapid transition from high pressure to
normal or from normal to a low.
• Microbial – marked at septicopyemia, as a factor in the development of metastatic abscesses.
• Parasite – occurs when helminthiasis. For example, in ascariasis possible pulmonary embolism.
In tropical countries, common embolism lymph vessels of the extremities, leading to disruption of
lymph drainage from the extremities to the formation of elephantiasis.
II. Endogenous embolism:
• Thromboembolism: Venous – v.femoralis, pelvic vessels; - Arterial – left heart thrombus,
dissection.Is the most dangerous type of pulmonary embolism (PE) with the development
pulmocoronary reflex, leading to the death of patients.
• Fat: in trauma with fractures of long bones or crush fat, when the fat entry in the bloodstream. Often
a complication of crush syndrome (declamping shock, crush syndrome).
• Amniotic fluid embolism: marked pathological birth or wrong maternity aid. Is the major factor
initiating DIC (disseminated intravascular coagulation).
• Tissue - the fragmentation of tissue - chorionic villi, the tumor site - one of the ways of metastasis,
etc.
• Cell (highlighted by some authors – resembling with tissue type).

Thromboembolism
A detached thrombus or part of thrombus constitutes the most common type of embolism. These
may arise in the arterial or venous circulation:
The effects of arterial emboli depend upon their size, site of lodgement, and adequacy of
collateral circulation:
• Infarction.
• Gangrene.
• Arteritis and mycotic aneurysm.
• Myocardial infarction.
• Sudden death.
The most significant effect of venous embolism is obstruction of pulmonary arterial circulation
leading to pulmonary embolism.
Pulmonary thromboembolism
 Pulmonary embolism is the most common and fatal form of venous thromboembolism in which
there is occlusion of pulmonary arterial tree by thromboemboli. Pulmonary emboli are more common in
hospitalised or bedridden patients. The majority of emboli arise from the deep veins of the low extremities;
most of the fatal ones arise from the ileofemoral veins.
Condition that favor the development of pulmonary thromboembolism are:
• Stasis (heart failure, chronic venous insufficiency).
• Injury (trauma, surgery, parturition).
• Hormonal imbalance (oral contraceptive use).
• Advanced age.
• Immobilization (orthopedic, paralysis, bed rest).
• Sickle cell disease.
Pathogenesis
Detachment of thrombi from any of the above-mentioned sites produces a thromboembolus that
flows through venous drainage into the large veins draining into right side of the heart.
If the thrombus is large, it is impacted at the bifurcation of the main pulmonary artery (saddle
embolus), or may be found in the right ventricle or its outflow tract.
More commonly, there are multiple emboli, or a large embolus may be fragmented into many
smaller emboli.
Paradoxical embolism may occur by passage of an embolus from right heart into the left heart
through atrial or ventricular septal defect.
Consequences of thromboembolism
1. Consequences of pulmonary embolism. These include:
Pulmonary Syndrome (Infarction). The pulmonary syndrome clinically resembles pneumonia.
Pleural effusion is common and often bloody. Pathologically, pyramidal segments of hemorrhagic
infarction are seen at the periphery of the lung. Obstruction of terminal branches (endarteries) leads to
central pulmonary hemorrhage.
Circulatory Syndrome (Without Infarction). Embolism produces pulmonary hypertension by
mechanical blockage of the arterial bed. Reflex vasoconstriction and bronchial constriction due to release
of vasoactive substances may contribute to a reduction in the size of the functional pulmonary vascular bed.
Whether a patient develops the pulmonary or the circulatory syndrome depends on the thromboembolic
load and the availability of circulatory reserve of the bronchial arteries. Pulmonary hypertension may lead
to chronic cor pulmonale and pulmonary arteriosclerosis. Numerous small emboli may obstruct most of
the pulmonary circulation resulting in acute right heart failure (Acute cor pulmonale).
Massive Pulmonary Embolism. Massive pulmonary emboli typically cause sudden obstruction of
blood flow through one or both of the major pulmonary arteries. The patient often goes into shock
immediately - resumably because of certain: neurologic reflexes - and may die within minutes. This
catastrophe is characteristically precipitated when a patient who has been recuperating from surgery gets
out of bed for the first time.
2. Consequences of emboli in peripheral arteries. The heart is the most common source of
systemic emboli, which usually arise from mural thrombi (in atrial fibrilation, mitral valve disease,
myocardial infarction, left ventricular aneurysm, heart failure of any etiology, cardiomyopathy) or diseased
valves (bacterial endocarditis, marantic endocarditis).
Clinical and morphological features: arterial emboli to the brain cause strokes; in the mesenteric
circulation they cause infarction of the bowel; embolism of an artery of the legs leads to sudden pain,
absence of pulse, and a cold limb; renal artery embolism may infarct the entire kidney but more commonly
results in small peripheral infarcts; coronary artery embolism results in myocardial infarctions.
Thus, the effects and sites of arterial emboli are in striking contrast to venous emboli, which are
often lodged in the lungs.

Questions for self-control of knowledge:

1. Give a definition of "microcirculation". What are functions of microvasculature, methods for
studying microcirculation?
2. What are links of microcirculatory system, give characteristic of its components.
 3. Describe general causes of microcirculatory disorders.
4. What are etiology and pathogenesis of typical forms of microcirculatory disorders
(intravascular, transmural, extravascular)?
5. What is "sludge"-phenomenon? What is significance of sludge?
6. What are causes of true stasis and detect principal mechanisms of its development.
7. What are causes, mechanisms of development, manifestations of capillary-trophic insufficiency
syndrome?
8. Describe various forms of lymphatic insufficiency. What are main clinical and anatomic
manifestations of acute and chronic forms?
9. What are etiology, pathogenesis, clinical manifestations and types of arterial hyperemia?
10. Specify mechanisms and clinical manifestations of venous hyperemia (Muscat liver, brown
induration of lungs, etc.).
11. What are causes, mechanisms, forms and manifestations of ischemia in various organs.
12. Explain mechanism of postischemic reperfusion phenomenon in organ.
13. What is biological significance of stasis for typical pathological processes?
14. What are differences thrombus from emboli, significance, outcomes and consequences of
thrombosis.
15. Give a definition of "embolism." What are etiology and pathogenesis of embolism? Describe a
concept of pulmonary thromboembolism (PTE). Name types, manifestations and outcomes. What is basis
of pathophysiological pharmacological correction of PTE?
16. How manifest a disorder of microcirculation in arterial and venous hyperemia, ischemia?
Explain relation of violations of macro-and microcirculation during local circulatory disorders.

Tasks for self-managed student work:

1. "Sludge" phenomenon.
2. Capillary-trophic insufficiency.
3. Mechanisms of reperfusion tissue damage.
4. Modern ideas about mechanisms of blood clotting and thrombosis.
5. Pulmonary embolism.

Literature
Basis literature:
1. Литвицкий, П. Ф. Патофизиология = Pathophisiology: лекции, тесты, задачи : учеб.
Пособие / П. Ф. Литвицкий, С. В. Пирожков, Е. Б. Тезиков. – М. : ГЭОТАР-Медиа, 2016.– 432 с.
Additional literature:
2. Kumar, V. Robbins and Cotran Pathologic basis of disease, 7th Edition / V.Kumar, A.K. Abbas,
N. Fausto. — Philadelphia: Elsevier Inc., 2005. – 1629 p. Режим доступа:
http://www.rkmyat.in/up1/34/1629.pdf. – Дата доступа: 30.08.2016.
3. Кидун, К. А. Общая нозология = General nosology : учеб.-метод. пособие для студ. 3 курса
фак. по подг. спец. для зарубеж. стран, обуч. на англ. яз. по спец. «Лечеб. дело», мед. вузов / К. А.
Кидун.– Гомель : ГомГМУ, 2015. – 74 с.
4. Кидун, К.А. Test tasks on pathological physiology: Workbook for students of the faculty for
training specialists for foreign countries, studying in english on specialty «General medicine», for higher
medical education institution In three parts Part 1. General pathophysiology. / К.А. Кидун; под ред. Т.С.
Угольник — Гомель: ГомГМУ, 2016. — 108 с.
5. Научная электронная библиотека еLIBRARY.RU [Электронный ресурс] / Научная
электронная библиотека. – М., 2005. – Режим доступа: http://www.elibrary.ru. – Дата доступа:
26.08.2017.
Compiler:
senior lector ________________ K.A.Kidun