Lesson 22.

Hemostasis disorders
nitrite aceiaies
aie ime ee
YY What is the hemostatic system?
Fan y ? What are the mechanisms for stopping

The system of hemostasis is a System that

ensures, on the one hand, maintain-
ing the liquid state of the blood, on the other h i :
the blood vessels are damaged. ane te Stopping
of bleeding when
There are two mechanisms of hemostasis: (a)
vascular-platelet and (b) coag-
ulation.
Vascular, latelet (primary, microcirculato hemostasis ensures stopping the
bleeding from the vessels of the microcirculatory bed
with a diameter of i to
100 microns. It is caused by the interaction of the vascular wall with platelets
Due to the activation of vascular-platelet hemostasis, a white
platelet thrombus is
formed. Distuchances of this hemostasis mechanism
cause almost 80% of bleed-
ing and 95% of thrombosis cases. —
Coagulation (secondary, macrocirculatory) hemostasis ensures stopping
the
bleeding from the vessels lathan
rg100 ym in diameter. It is a continuation
er of
the vascular-platelet hemostasis and develops on its basis. As a resofult
its acti-
vation, a red blood clot consisting of fibrin and blood cells is formed.

What causes the involvement of the vascular wall in the hemostasis?

inccegming page
vascul
o the arend
he-vescular wall takes part in the realization of vascular-platelet hemostasis,
ng/of which is always associated with damage to the vascular endothe-
lium. This process has two important consequences.
|. Activation of hemostasis mechanisms:
a) unmasking collagen, resulting in the so-called contact activation of plate-
\‘ lets and Hageman factor (f. XII);
b) releaseof ADP from damaged cells of the vascular wall which is a potent
activator ofadhesion)and aggregation of platelets;
C) release of tissue thromboplastin (f.lll) which initiates the external mecha-
nism - iat coagulation and the formation of a small amount of throm-
bin d jat the sit e
of damage to the vessel;
d) release of von Willebrand factor glycoprotein formed in endothelial cells
—
and taking part in the adhesion
of platelets.
\l. Decrease in thromboresistance of the vascular wall:
a) decrease in the production of prostacyclin, a substance that is a potent
inhibitor of platelet aggregation; .
b) decrease in the formation and secretion of antithrombinjI!, which is a very
Strong natural anticoagulant;
c) decrease in the ability of the endothelium to fix a heparin-antithrombinIl!
283

Complex on its surface; /

cells to form and release Potent

d) disruption in the ability of endothelial
activators of fibrinolysis.

asis?
What is the role of platelets in hemost
isis 0 due to its four functions. ns.
latelets partiicicipate ini the hemostas to main tain the normal
y of plate lets
(“Angiotrophic function. This is the abilit belie ved to be physi
are
structure and function of microves sel walls. Platelets
logical breadwinners” i of the endothel
ium. Endot helial cells absorb thrombocyt 2s,
ural integrity and func.
fon which substances necessary to maintain the struct _
i ivity of microvessels are released.
aso onstrictor function. This is the ability
to maintain a spasm of damaged
tone - Vasoc line,
an ces from platelets: adrena
vesse. ls through the release of vasoactive subst
noradrenaline, and serotonin. _
3 ‘Adhesive-aggr egation functio n. This is an ability of platelets to adhere to the
damaged parts of the vascular wall and to stick
toge ther with each other forming
a platelet plug.
ith the release of the so-
4. Participation in blood clotting. It is connected
called platelet coagulation factors, in particular fact
actof 4, fact hrom-
bosthenin), et
 How is vascular-platelet hemostasis carried out?
Vascular-platelet hemostasis includes the following processes (Fig. 83).
1. Spasm of arterioles. There are (a) a primary and (b) a secondary delayed
spasm. The first occurs immediately after the damage to the vascular wall, lasts
a few seconds, the main mechanism of its development is(GeflexT he c
the secondary delayed spasm isbiogenic amines which are released byplatelets,
catecholamines and serotonin.
onl a

| Vascular wall injury }|—>| Spasm ofarterioles |

y
Adhesion andinitial | Relea aol
aggregation of platelets SEASE TER!

Reversible aggregation

Irreversible platelet | __ Relgasa reaction |

aggregation Pe

Thrombus consolidation
284

Fig. 83. Scheme of vascular-platelet hemostasis

2. Platelet adhesion — adhere

nce
cular wall. of platelets to the d amaged parts of the vas-
3. Aggregation of platelets — swelli
n and gl i
4. The release reaction. Itis the releas of
Two types of this are dis e faites fdas
tinguishe
d: (a) the release reaction | mt
leasé reacti
ctticon Il. The firs: t one is a reacti Ghee
o n of early release; it is carrne
ie ct ar
stage of initial aggregation of platelets, The consequence of this
type | granules (contain Piogenic amines) and type | is the release :
; .
particular, platelet factor 4, von Willebrand facta Eto Perens. in
The release reaction Il is a late release reaction
occurring at the stage of irre-
versible platelet a re lation. When platele: are damaged, granules of
types Ill and IV containing lysosomal naire
ymes,s factor
tot 3,"come
e out of the platelets.
5. Thrombus consolidation is its compaction resulting in the formation of the
final platelet thrombus. It occurs as a result of platelets viscous metamorphosis
and their retraction under the influence of thrombosthenin.
_— SS

How does platelet adhesion occur?

The main cause of platelets adhesion is the denudation (unmasking) of colla-
gen due to damage to the endothelium of the vessels.
There are (a) precontact and (b) contact phases of platelet adhesion.
|. During the precontact phase, before the contact with the damaged vessel
wall, the primary activation of platelets in the blood occurs. First, the shape of
platelets changes from disk-shaped to spherical (edema). Then, long threadlike
processes (3 to 10 in each platelet) are formed.
Il. During the contact phase, the processes of activated platelets interact with
elements of the vascular wall basal membrane.
In this case, such changes are of importance:
a) direct contact of the platelet processes with collagen;
i collagen throu h von
01 act of platelets with
cont on WiWillebran d factor, :
b) mediated
i the latter is damaged
c) the reversal of electrical charge in the intima when
the electrostatic inter
(the charge changes from "-" to “4"), This makes l wall
action of platelets, having a negative surface charge, with the vesse
possible; intima @) —> Platelets C>
vesse
d) slowing of blood flow in the damaged
of this rr
aa tion? What are the dynamics
What factors cause platelet aggregatic
Process?
substancesfaggregants.
@ Cause of pi: NN | won-pialelet (got
 sswith the
ge changes fom) a" the vessel wall
surf ace char ge, with
sort latelets, having a negative
possible; intima @) —> Plateles CD
d) slowing of blood flow in the damaged yeaa
namics of this
EZ What factors cause platelet aggregation? What are the dy
Process?
earance of eubstances/aggregants.>
and non-pla elet (got
piaet l oe or aoe’ latelets)
be ofc platel
Th eyThecanconi (released from i
Out from damaged ST inca, formed In Bice eee! =
yzed
en na es rvaraged ool of the vascular wall, hemol
——=
a) ADP It is relea sed from the dam
“erythrocytes, platelets durin ctivation;

and arachidonic acid. Thromboxane

A, is the Product of
(seeps pathway for the transformation of arachidonic acid int
Ss; :
c) Popa amines - adrenaline, serotonin. Their sources are blood plasma
and platelets; ; .
d) platelet activating factor (PAF). It is a substance of lipid nature. It is re.
leased by mast cells, basophils and blood neutrophils;
e) thrombin. It is a powerful aggregant in doses much smaller than those
causing blood clotting. Such small amounts of thrombin are alwa 5
formed in places of damage to the vascular wall. It is due to the external
mechanism of blood clotting, activation of which is caused by the appear-
ance of tissue thromboplastin;
f) thrombospondin. It is released from activated platelets, adsorbed on their
membrane, interacts with blood proteins.
In addition to substances-aggregants, there are factors that have antiaggre-
gation properties. These include, in particular, prostacyclin, fibrinolysis products,
and others.
In the process of platelet aggregation, the following stages are distinguished:
1) initial aggregation. It occurs simultaneously with adhesion of platelets. It is
caused by ADP of a non-platelet origin (released from damaged cells of the vas-
cular wall);
2) reversible aggregation. At this stage, the aggregation can be stopped, the
platelets are not damaged yet. Reversible aggregation is caused by platelet ADP
as well as thromboxane A, and arachidonic acid;
3) irreversible aggregation. During this period, platelets are damaged and die. It
is believed that the main cause of irreversible aggregation is locally formed throm-
bin.

What mechanisms are the basis of platelet aggregat

ion?
I Activation of platelets (Fig. 84). Substances-aggregants increase the perme
ability of the platelet membrane to calcium ions, as a result of which the
concer
tration of the latter in the cytoplasm of the blood platel
ets enhances. This causes
at least four functionally important effect
s:
1) contraction of microfibrils resulting in the formation of long threadlike pro
cesses;
2) increased ATP hydro lysis which results in the
formation of a powerful ad
gregant — ADP;
3) release of platelet granules,
4) activation of phospholipase A which chidonic
acid and then thromboxane A, caliaee the formation ofiare
Il. Gluing of platelets.
The essence of this is the formation
of “bridges” between the platelets. ans
are two kinds of such bridges. The
first one Consists of ADP and calcium vero
286

second one contains proteins of the blood

plasma. These proteins are called P

Biogenic amines
Pathogenic factors Factors of 280 of 522
wc mr bloodinjury
vessel
Ww e MSE NINE CONSISTS OT ADP and
“J second one contains proteins of
the blood plasma. These proteinscaicium !O!l as
arecalled pla

Biogenic amines
Pathogenic factors Factors of
blood vessel
Ye) ae hey
1 - Contraction ——
of microfibrils 4 - Activation of
(processes Phospholipase A,
formation) 4
Formation of
thromboxane A,
2 — Increased ATP 3 - Ejection
hydrolysis + [ADP]
of granules

Fig. 84. Mechanism of platelet acti

vation

ma aggregation cofactors. They include fibrinogen, albumins and

others. All these
proteins glue platelets together due to interaction with glycopr
otein receptors of
platelets (there are 5 types of such receptors) and with thrombospond
in - an ag-
gregant adsorbed on the platelet membrane.

What is the process of blood clotting? What factors are involved in it?
Blood clotting (coagulation) is a complex, multi-stage enzymatic
process
which eventually ends with the formation of a fibrin clot.
The basis of the blood clotting process is pro »tealytic reactions in which 12co-
agulation factors participate direc
or indirect!
tly ((all 9 them are of plasma origin,
except f. Ill) and platelet factor 3.
actors of blood clotting include: f. | — fibrinogen, f. Il — prothrombin, f. Ill - tis-
sue thromboplastin, f. |\V — calcium ions, f. V - proaccelerin, f. Vil — proconvertin,
f. Vill - antihemophilic globulin, f. 1X - factor of Christmas, f. X - Stuart-Prower fac-
tor, f. XI - plasma precursor of thromboplastin, f. Xl - factor of Hageman, f. XIll -
fibrin-stabilizing factor. ;
According to the functional properties, all factors involved in blood clotting can
be divided into the following groups.
I. Proteins-enzymes. These are mainly proteolytic enzymes: f. Il, III, VII, IX, X, XI,
XIl. One factor (f.XIIl) is transferase. ae
All these enzymes are contained in the blood and tissues in an inactive form.
Their activation is achieved by proteolytic splitting off the peptides that cover up
the active center of enzymes. Such reaction occurs with the participation of the
hated Previous coagulation factor (active peoteats) Thus, the activation reac-
°ns of blood coagulation are cascaded and chain-like.
I. Non-enzyme proteins - the accelerators. These include f. V and f. Vill. These
factors accelerate the enzymatic reactions of blood clotting hundreds of times.
Unlike enzymes, they are consumed in the process of blood coagulation.
iT Phospholipid matrix (micromembrane) on which the ordered blood clotting
287

"eactions take place. The role of such a matrix can be performed by:

a) platelet factor 3; .
. hoapholpid fragments of damaged cell membranes;
c) phospholipid fragments of hemolyzed erythrocyte membranes,
IV. Calcium ions. Their participation in blood clotting consists in fixin 9 Protein
factors to phospholipid matrices.
V. The substrate of blood clotting is fibrinogen (f. |).
Most clotting factors are synthesized in the liver. They are divideg into two
groups:
a) vitamin K-dependent: f. Il, Vil, IX, X. Vitamin K in coenzyme form is Part of
hepatic carboxylases which hake part in the formation of these factors;
b) vitamin K-independent: f. |, V, XI. Their formation does not require Vitamin
k.

What are the phases of the blood clotting process? 281 of 522

The proces webblacdelaiinggastiaaugbibceepbasas,

 OTe eee . n
ll.| pe
Ee 2e eee SS TE I pee
the ordere d blood clottin g i
ut Phospholipid matrix (micromembrane) on which
"S8ctions take place. The role of such a matrix can be performed by: N

let factor 3;
4 Pveepholipl fragments of damaged cell membranes;
c) phospholipid fragments of hemolyzed erythrocyte membranes,
\V. Calcium ions. Their participation in blood clotting consists in fixin 9 Pr
otein
factors to phospholipid matrices.
V. The substrate of blood clotting is fibrinogen (f. I). .
Most clotting factors are synthesized in the liver. They are divideg into two
groups: o
a) vitamin K-dependent: f. Il, Vit IX, X. Vitamin K in coenzyme form is Part of
hepatic carboxylases which'take part in the formation of these factors;
b) vitamin K-independent: f. |, V, XI. Their formation does not require vitamin k.

What are the phases of the blood clotting process?

The process of blood clotting goes through three phases.
Phase | ~ the formation of prothrombinase. There are three mechanisms for
activating this process (Fig. 85):
a) external (tissue) mechanism. It is activated when the cells are damaged.
In
this case, tissue thromboplastin (f. Ill) and phospholipid fragments of mem-
branes are released. The latter become a matrix on which clotting factors
of
blood are fixed. This is a very fast mechanism of blood clotting activation.
It
provides the coagulation of blood outside the vessels (with hemorrhages in
the tissues) and the local formation of small amount of thrombin
necessary
for irreversible platelet aggregation (see above);
b) internal (blood) mechanism. The beginning of it is contact
or enzymatic ac-
tivation of f. XII in the blood. The internal coagulation mechanism
is quite
long, therefore, its first phase essentially determines the time of the
whole
process of blood coagulation;
c) macrophage-monocyte mechanism. In contrast
to the previous two, it is 4
mechanism of pathological activation of blood coagul
ation. It is caused by

External mechanism
Internal mechanism
fIILV = LS Kallikrein- > f Xi XI IX Vil
PLofcellmembranes \< [Kinin system }« Platelet factor3

f. XXa f. Xa f.xXa
Tissue Blood
prothrombinase Macrophage prothrombinase
prothrombinase

Macrophage-monocyte mec
hanism
288

Fig. 85. Mechanisms of blood Clotting

activation (PL - phospholipids)

the action of bacterial endotoxins on macrophages, immune complexes,

complement and decayed products of tissues. In this Case, active prothrom-
binase (f. Xa) is released from macrophages. This mechanism has a certain
adaptive value, because due to blood clotting, the distribution of pathogenic
factors in the body is limited.
Phase II - the formation of thrombin. It occurs with the participation of active
prothrombinase and f. V.
Phase Ill — formation of fibrin. Itincludes a number of consecutive stages (Fig. 86):
a) formation of fibrin-monomer from fibrinogen under the action of thrombin;
b) formation of soluble fibrin-polymer (fibrin S);
c) formation of insoluble fibrin (fibrin |) under the action of active f. XIII.

282 of 522

(amie
 c) formation of insoluble fibrin (fibrin 1) under the action of active f. XIII.

Fibrinogen (A,B)

Fibrin-monomer + 2A + 2B

y
Soluble fibrin-polymer
(fibrin S)

f.XIIl — f.Xilla] ——>

Insoluble fibrin (fibrin 1)

Fig. 86. Phase III of blood coagulation — fibrin formation

How are hemostasis disorders classified?

Disturbances of hemostasis - hemostasiopathy - are divided into three
groups. ;
|. Hemorrhagic hemostasiopathies — hemorrhagic diathesis. _
\l. Thrombohemorrhagic hemostasiopathies — a syndrome of disseminated in-
travascular coagulation (DIC-syndrome). /
Ill. Thrombophilic hemostasiopathies — thrombosis and thromboembolism.

ean What is hemorrhagic diathesis? How is it classified?

Hemorrhagic diathesis is a tendency of the body to repeat bleeding and hemor-
Mages that occur spontaneously or after minor injuries.
Hemorrhagic diathesis is divided into two large groups (Fig. 87).
|. Disorders of vascular-platelet hemostasis:
8) vasopathy; (b) thrombocytopenia and (c) thrombocytopathy.
- Disorders of coagulation hemostasis - coagulopathy.

289
[ Hemorrhagic diathesis ]

Violation of vascular-platelet Violation of coagulation

hemostasis hemostasis — coagulopathies

- Decrease in blood
Vasopathies coagulation activity

- Increase in the anticoagulant

Thrombocytopenias system activity

: Increase in the fibrinolytic

Thrombocytopathies system activity

Fig. 87. Classification of hemorrhagic diathesis

What is vasopathies? How are they classified?

Vasopathies are hereditary or acquired hemorrhagic diathesis, which arises as
a result of primary disturbances of the vascular wall.
Depending on the mechanism of development, vasopathies are divided into
two groups:
1) inflammatory vasopathies - vasculitis;
2) dysplastic vasopathies - lesions of the blood vessels associated with dis
ruption of their connective tissue (inferiority of the vascular wall).

What are the etiology and pathogenesis of inflammatory vasopathies?

Depending QoGausessi
the nfammataneissanathiageseedivided into:
 What is vasopathies? How are they classified?
Vasopathies are hereditary or acquired hemorrhagic diathesis, which arises as
a result of primary disturbances of the vascular wall.
Depending on the mechanism of development, vasopathies are divided into
two groups:
1) inflammatory vasopathies - vasculitis;
2) dysplastic vasopathies — lesions of the blood vessels associated with dis-
ruption of their connective tissue (inferiority of the vascular wall).

What are the etiology and pathogenesis of inflammatory vasopathies?

Depending on the causes, inflammatory vasopathies are divided into:
1. Infectious vasculitis, It is a manifestation of a number of infectious diseases
(Viral hemorrhagic fevers, typhus, and sepsis).
2. Immune vasculitis. It develops as a consequence
of immunocomplex dis-
eases (type Ill allergicreactions by the Coombs and Jel classification, see lesson
6), for example, with systemic lupus erythematosus, nodular
periarteritis, hemor
thagic vasculitis (Henoch-Schonlein
Purpura).
3. Infectious-immune vasculitis. It combines the two previous mechanis
ms.
In the pathogenesis of inflammatory vasopathies, the leading
role belongs to
damage to the endothelium which
may be due to:
a) cytopathic action of endotheliotropic
viruses;
b) toxins of microbes, for example, verotoxin secreted by bacteria of i
the '"
testinal group;
c) antigen-antibody complexes and
complement.
The consequences of damage to the vascular endothel
ium are as follows:
290

1. Diapedesis of erythrocytes which is clinically

of small (1-2 mm) red or purple spots
manifested by the appea’@n°
(petechiae).

2, Intensive formation of microthrombi Causing the disorders of microcircula-

tion and tissue nutrition.
3. Thrombocytopenia of consumption (the result of microthrombi formation).

pals What are the main causes and mechanisms of dysplastic vasopathies?

The causes of dysplastic vasopathies are (a) acquired or (b) hereditary disor-
ders of the connective tissue of the blood vessel wall.
Examples of such violations are:
1. Hypovitaminosis C. Ascorbic acid is a necessary component of the proline
hydroxylation reaction, as a result of which prolin is converted into hydroxyproline.
This is a key reaction in the formation of collagen. With hypovitaminosis C, forma-
tion of a full-fledged collagen is disrupted which is manifested by fragility of the
vessels, loss of teeth, etc.
2. Telangiectasia. These are local defects in the connective tissue of the ves-
sels which cause thinning of their walls and widening of their lumen. Telangiecta-
sia can be a source of life-threatening bleeding, especially when localized in the
internal organs.
3. Hemangiomas. These are vascular tumors that often bleed.
4. Ehlers - Danlos syndrome. It is resulted from the hereditary defects of col-
lagen structure.
Dysplastic vasopathies are characterized by:
a) thinning of the microvascular walls and widening their lumen;
b) inadequate local hemostasis. It is due to the lack or inferiority of collagen
in the subendothelium of the vessels. As a result of this, platelet adhesion
is impaired;
c) slight vulnerability of blood vessels.

EZRER What is thrombocytopenia? What mechanisms can underlie the

development of thrombocytopenia?

Thrombocytopenia is a decrease in platelet count per unit volume of periph-

eral blood below 150 x 1091. Hemorrhagic manifestations of thrombocytopenia
285 of 522
appear with a decrease in the number of platelets below 50 x 10°/I.
By origin, mromibecytspata can be (a) ates and (b) acquired.
The following sy a chanicm
 ee Fee eee ee EEE UE EIN VSI

122.15. | What is thrombocytopenia? What mechanisms can underlie the

development of thrombocytopenia?

Thrombocytopenia is a decrease in platelet count per unit volume of periph-

eral blood below 150 x 1091. Hemorrhagic manifestations of thrombocytopenia
appear with a decrease in the number of platelets below 50 x 10°/I.
By origin, thrombocytopenia can be (a) hereditary and (b) acquired.
The following types of thrombocytopenia are distinguished by the mechanism
of development.
I. Thrombocytopenia associated with disorders of platelet formation:
a) myelotoxic thrombocytopenia. It arises due to damage to the hemato-
Poietic cells. Very often it is combined with anemia and leukopenia. The
reasons of its development are the same factors that cause hypoplastic
anemia (see question 19.26);
deficient thrombocytopenia. It is due to the deficiency of vitamin B,, or
folic acid (see lesson 19);

291
c) dysregulatory thrombocytopenia. |t is associated with the iMpaire
duction of thrombocytopoietins - substances that stimulate the . Pro.
tion of platelets; orma.
d) thrombocytopenia associated with a decrease in the Platform of
topoiesis. It develops in the cases of leukemia and Metastases of maf.
nant tumors. Alig.
ll. Thrombocytopenia associated with increased destruction
of Platelets
This destruction can be caused by: .
a) immune damage due to antibodies against the own com
Ponents Of the
platelets or against drugs adsorbed on the platelets. Aut
olmmune dam.
age is considered to be the most likely mechanism for the development
of
idiopathic thrombocytopenic purpura (Werlhof disease);
b) hypersplenism — hyperfunction of the spleen, often accompanied by spi.
nomegaly. As a result of the increase in phagocytic
activity of macro.
phages, there is an intensive destruction of all blood elements,
including
platelets;
c) mechanical damage of platelets. It often occurs with hemangiomas and
the imposition of artificial heart valves;
d) acquired membranopathies (hemolytic anemia of Marchiafava-Micheli)
Somatic mutations of the hematopoietic cells lead to the formation of cell
pools (erythrocytes, granulocytes, platelets) with membrane defects. Asa
result, the sensitivity of such cells to the action of complement increases
and their destruction occurs (see lesson 19).
Ill. Thrombocytopenia of consumption. It occurs as a result of increased use of
platelets for the thrombi formation (Henoch-Schonlein purpura, Moshkovich dis-
ease, DIC syndrome).

What is the pathogenesis of hemostasis disorders in thrombocytopenia?

The following changes are important for the pathogenesis of hemorrhagic
syndrome with thrombocytopenia:
1) disturbances of platelet angiotrophic function, resulting in dystrophic chang-
es in the endothelium and increasing the fragility of microvessels. This leads to
an increase in the vulnerability of blood vessels, diapedesis of erythrocytes,
hem
orrhages. The latter are manifested by petechiae on the skin, bleeding from the
gums and nose, hemorrhages in the brain and retina of the eye;
f
2) disorders of platelet adhesion and aggregation. This causes disruption °s
the platelet thrombus formation and leads to an increase in bleeding time (Duke
test);
3) disturbances of damaged arteriole secondary spasm. With thrombooytor
nia, there are few biogenic amines (catecholamines, serotonin) that cause the
traction of smooth muscles of blood vessels.
4) insufficient blood clotting. It is due to a decrease in the release of factor 3
and thrombosthenin from platelets. As a result, the first phase of blood c° agule:
292

tion and retraction of the clot are disrupted. 286 of 522

para What are thrombocytopathies? How are they classified?

Thrombocytopathies are disturbances of the platelet functional properties

their qualitative inferiority. In this case, the number of platelets may remain nor-
mal.
|. By origin, thrombocytopathies are (a) hereditary and (b) acquired.
II. By the nature of platelet qualitative defects, thrombocytopathies are divided
into (a) endothrombocytic and (b) exothrombocytic.
Endothrombocytic thrombocytopathies are caused by disturbances of the
platelet constituent parts and, in turn, are divided into (a) membranopathies, (b)
granulopathies and (c) enzymopathies.
Membranopathies occur (a) with hereditary anomalies of membrane glycopro-
teins which function as cellular receptors; (b) when these receptors are blocked
by abnormal blood plasma proteins (paraproteins); (c) with damage to the mem-
branes of platelets by pathogenic factors.
Granulopathies are manifested by deficiency of granules of types | and II.
Enzymopathies can be related to a decrease in the activity of cyclooxygenase,
thromboxane synthetase, enzymes of glycolysis, and ATPase.
In the cases of exothrombocytic thrombocytopathies, the causes of platelet
function abnormalities lie outside the platelets. In this regard, exothrombocytic
thrombocytopathy can be:
a) associated with changes in blood plasma (deficiency of plasma proteins
which are plasma cofactors of platelet aggregation);
b) due to changes in vascular wall (a disturbance of the von Willebrand fac-
tor formation by vascular endothelium, disorders of the blood coagulation
external mechanism).
Ill. Depending on the nature of hemostasis disorders, there are:
1) thrombocytopathies with primary impairment of platelet adhesion;
2) thrombocytopathies with primary disorders of platelet aggregation;
3) thrombocytopathies with primary disruption of the release reactions in
which the platelet contents come out;
4) thrombocytopathies associated with a deficiency or impaired availability of
Platelet factor 3.

122.18. | Give examples of thrombocytopathies with different mechanisms

of hemostasis disorders.
I, Thrombocytopathies with primary impairment of platelet adhesion:
by genetic distur-
a) von Willebrand disease - angiohemophilia. It is caused
bances in the synthesis of von Willebrand factor by endothelial cells (au-
tosomal dominant type of inheritance);
is a
b) Bernard - Soulier disease - macrothrombocytic dystrophy. The cause
hereditary defect of platelet membrane glycoprotein (Gplb) interacting with
dimensions. The
Von Willebrand factor. In this case, platelets take on giant
293

type of inheritance is autosomal recessive.

I. Thrombocytopathies with primary disturbances of platelet aggregati

most common is Glanzmann’s thrombasthenia which occurs as a conse. te
The
defects in membrane glycoproteins of types | and II that Participate in a se at
In this case, adhesion of platelets and the release of their granules mai boon
is no aggregation, despite the action of such powerful aggregants as ADP
cae
line, thrombin. The type of inheritance is autosomal recessive. vere
Ill. Thrombocytopathies with primary impairment of platelet release reacti
a) disturbance of platelet degranulation - “paresis of the release i
occurs, in particular, when the formation of thromboxane
A, is distor a
~ the action ee acid. It was shown that a single aed
oon oiaslae
spirin irreversiblyso ha y
“paralyzes” the release of granules up to 6 days, unti

b) insufficiency of accumulation and preservation of the pl

_ Contents. It occurs, as a rule, with genetically jeternie
lasie
a oe of granule release reactions cause disturbances in the
second ove
mie The initial aggregation of the platelets ends with their dis-
 Platelet factor 3.

EZRER Give examples of thrombocytopathies with different mechanisms

of hemostasis disorders.
|. Thrombocytopathies with primary impairment of platelet ina diana
a) von Willebrand disease - angiohemophi lia. It is cause ; 1a ee te tae
bances in the synthesis of von a factor by endothe
tos inant type of inheritance),
b)Bernard g Sore an - macrothrombocytic ee ilieaclig)
hereditary defect of platelet membrane glycoprotein (Gp RE
;
Von Willebrand factor. In this case, platelets take on gian

293
type of inheritance is autosomal recessive.

I. Thrombocytopathies with primary disturbances of platelet aggregation,

most common is Glanzmann's thrombasthenia which occurs as a Consequence of
defects in membrane glycoproteins of types | and II that participate in AQgregation
In this case, adhesion of platelets and the release
of their granules Occur, but thera
is no aggregation, despite the action of such powerful aggregants as ADP adreng.
line, thrombin. The type of inheritance is autosomal recessive.
Ill. Thrombocytopathies with primary impairment
of platelet release reactions:
a) disturbance of platelet degranulation - “paresis of
the release reaction" |t
occurs, in particular, when the formation of thromboxa
ne A, is disturbeq
by the action of acetylsalicylic acid. It was shown that a Single
dose of
aspirin irreversibly “paralyzes” the release of granules up to 6
days, until
new platelets appear;
b) insufficiency of accumulation and preservation of
the platelet granules
contents. It occurs, as a rule, with genetically determined
disturbances.
Disorders of granule release reactions cause disturbances
in the second wave
of platelet aggregation. The initial aggregation of the
platelets ends with their dis-
aggregation.
\V. Thrombocytopathies associated with a deficiency
or impaired availability
of platelet factor 3. They can be based on either genetically
caused defects in the
Structure of this factor or disturbances of its release
from damaged platelets. In
this case, blood clotting (coagulation hemostasis) is disrup
ted. Adhesive-aggrega-
tion properties of platelets do not change.

What can cause disturbances of coagulation hemostasis?

Disturbances of blood clotting (coagulopathy) may be due to (1) a
decrease in
the activity of the blood coagulation system, (2) an
increase in the activity of the
anticoagulant system, (3) an increase in the activi
ty of the fibrinolytic system (see
Fig. 87).

What could cause a direct violation of the first phase of

blood clotting?
Depending on the nature of disturbances, three groups of disorders in the first
phase of blood coagulation are distinguished.
|. Isolated disturbances of the blood clotting
activation through the external
mechanism. It occurs with f. Vil deficiency — hypoproconvertinemia.
may be (a) hereditary (autosomal recessive type This deficit
(hypovitaminosis K, liver damage).
of inheritanc e) or (b) acquired
Il. Isolated disorders of the blood clotting activation through the interna
anism:
l mech"
,
a) f. Vill deficie ncy - haemophilia A. \t occurs most often as a genetic om t
of the f. Vill Coagulant part (the type of inheritance is linked to the X
© 0
mosome). The formation of autoantibodies against the protein
comp!
nents of this Clotting factor is possible;
294

b) f. IX deficiency - hemophilia B. The cause of its development could be 288 of 522

Hereditary pathology (type of inheritance linked to the X chromosome),
vitamin K deficiency or liver damage, antibodies against f. IX can be the
 anticoagulant system, (3) an increase in the activi
ty of the fibrinolytic system (see
Fig. 87).

What could cause a direct violation of the first phase of blood clotting?
Depending on the nature of disturbance
a
es, three gro i i the first
a Coagulation are distinguished
- Isolated disturbances of the blood clott en
. : in 9 activivati
ation through the externa
a eee fant f. VII deficiency - demoatooenwertenne This
deficit
: itary (autosomal recessi
i io
(hypovitaminosis K, liver damage). TRG a FP)
slate
Il. Isolated d disorders
di of the blood clotting activation through the internal mech -

a) ae aoucency ~ haemophilia A. It occurs most often as a genetic defect

ef. Vill coagulant part (the type of inheritance is linked to the X cht”
mosome). The formation of autoantibodies against the protein comp”
nents of this clotting factor is
possible;
294

b) f. IX deficiency - hemophilia B. The cause of its development could be

Hereditary pathology (type of inheritance linked to the X chromosome),
vitamin K deficiency or liver damage, antibodies against f. IX can be the
causes of its development;
c) f. XI deficiency — hemophilia C. \t occurs with genetic disorders (autosomal
recessive type of inheritance) or liver damage;
d) f. XII deficiency. It is a very rare hereditary pathology. Thanks to the
kallikrein-kinin system, this defect is well compensated since the start of
the internal coagulation mechanism occurs through the external one;
e) platelet factor 3 deficiency. \t may result from thrombocytopenia or certain
types of thrombocytopathies (see above).
\Il. Combined disorders of external and internal coagulation mechanisms. They
develop with a deficit of f. X, which can be (a) hereditary (autosomal recessive type
of inheritance) or (b) acquired (hypovitaminosis K, liver damage).

What could cause a direct violation of the second phase of blood clotting?
1) deficiency of f. Il - hypoprothrombinemia. Most often it has acquired charac-
ter and develops due to hypovitaminosis K or liver damage.
2) deficiency of f. V - parahemophilia. The disruption of the proaccelerin forma-
tion can be due to liver lesions or autoantibodies against f. V.

What could cause a direct violation of the third phase of blood clotting?
1. Deficiency of fibrinogen:
a) afibrinogenemia - complete absence of fibrinogen (hereditary disease
with autosomal recessive type of inheritance);
b) hypofibrinogenemia — a decrease in the synthesis of fibrinogen in the liver
in its lesions.
2. Dysfibrinogenemia — qualitative disorders of fibrinogen. They develop as a
consequence of genetic defects (autosomal dominant type of inheritance). They
are manifested by the formation of abnormal fibrin.
3. Disturbances in the polymerization of fibrin. They result from the formation
of complexes of fibrinogen with fibrin monomer and intermediate products from
Which the peptides A and B have not fully cleaved yet. In this case, a so-called
blocked fibrinogen” (“thrombin-resistant fibrinogen”) is formed. It cannot be ex-
Posed to thrombin.
4. Deficiency of f. Xill. It occurs as a consequence of hereditary disorders (au-
tosomal recessive type of inheritance). It is manifested by disturbances in the
transformation of soluble fibrin (fibrin S) into insoluble one (fibrin !).

tay What anticoagulants make up anticoagulant system of the blood?

I Primary anticoagulants. They are constantly synthesized in the body and wn
oO
therefore are always contained in the blood plasma. These include: N
289 of 522
 ee ye ae ye gee
transformation of soluble fibrin (fibrin S) into insoluble one (fibrin |).

22.23 | What anticoagulants make up anticoagulant system of the blood?

I Primary anticoagulants. They are constantly synthesized in the body and

295
therefore are always contained in the blood plasma. These include:

a) antithrombin Ill - the main universal anticoagulant that is 4 protease inhip.

itor, tis synthesized by the vascular endothelium. It inhibits the ACtivity o¢
all proteolytic enzymes of the blood, including thrombin, kallikrein, Plas.
min, f. Xlla, f.Xla, f.Xa, f. Xa, f. Vila;
b) heparin (antithrombin I!) - glycosaminoglycan released by mast cells and
blood basophils during their degranulation. Anticoagulant properties are
not possessed by heparin itself, but by the heparin complex with antithrom.
bin Ill. Thanks to heparin, antithrombin III is fixed on the surface of the vas.
cular endothelium where its anticoagulant properties increase many-fold,
c) a,-antitrypsin, a,-macroglobulin, inhibitor of the C1-component of comple.
ment - all of them are nonspecific inhibitors of proteases, including blood
coagulation factors.
\l. Secondary anticoagulants. They are not normally contained in the blood
plasma, normally contained. They are formed in the process of blood clotting and
fibrinolysis. These include:
a) antithrombin | - fibrin which adsorbs and thus inactivates a large amount
of thrombin;
b) products of fibrinolysis. They prevent the processes of fibrin polymeriza-
tion and the formation of fibrin structures.

What can cause an increase in the activity of blood anticoagulant system?

The increase in an activity of the blood anticoagulant system naturally occurs
when:
1. An increase in the content of heparin in the blood — hyperheparinemia. This
may be due to (a) increased degranulation of mast cells and blood basophils, par-
ticularly in type | allergic reactions according to the classification of Coombs and
Jell (see lesson 6); (b) destruction of basophilic leukocytes in leukemias; (c) intro-
duction of heparin from the outside. /
2. The appearance of “pathological” anticoagulants, which include (a) ant
thrombin V which disrupts fibrin-monomer polymerization; (b) “lupus” anticoagu’
lant that disorders the formation of the prothrombinase complex; (c) parapr oteins
that disturb the fibrin polymerization.

What is fibrinolytic system?

The fibrinolytic system is a system that provides lysis (proteolysis) of fibrin
the blood vessels. Thus, it takes part in maintaining the liquid state of the bloo
and in restoring blood circulation in thrombosed vessels.
The fibrinolysis system consists of (Fig. 88): pte at
1) plasminogen (profibrinolysin) — an inactive proteolytic enzyme which '$
ways present in the blood plasma; as 4
2) plasmin (fibrinolysin) - the active form of plasminogen. It is formed the
result of the action of active proteases on plasminogen and the cleavage ©
296

peptide, which “closes” the active site of this enzyme;

mechanism mechanism

Factor XIla, Activators:

kallikrein endothelial;
tissue;
| bloody;
Activators renal (urokinase);
bacterial
streptokinase)
 Ways present in te Diood plasma, med as 4
2) plasmin (fibrinolysin) - the active form of plasminogen. It is for
cleav4
ge of the
result of the action of active proteases on plasminogen and the

296
peptide, which “closes” the active site of this enzyme;

Internal E
mechanism xternal
mechanism

Factor XIla, Activators:

kallikrein endothelial;
| tissue;
bloody;
Activators renal (urokinase);
bacterial
(streptokinase)

INHIBITORS

Fig. 88. Scheme of fibrinolysis

3) fibrinolysis activators - a large group of substances that are either prote-

ases themselves and are capable of converting plasminogen to plasmin or can
cause the appearance of such proteases;
4) inhibitors of fibrinolysis. These include protease inhibitors, among which
a,antiplasmin is of the greatest importance.
There are (a) internal and (b) external mechanisms of the fibrinolysis activa-
tion. The internal mechanism is caused by the activation of the blood coagulation
appear-
factor XI! and the formation of kallikrein. These two enzymes cause the
ance in the blood of a large number of fibrinolysis activators.
preexisting fibrino-
The external mechanism is associated with the entry of the
(streptokinase)
lysis activators of endothelial, tissue, renal (urokinase), bacterial
origin into the blood. |

activity of the blood fibrinolytic

What factors cause an increase in the
system?
t ators into the blood-
nolysis activ
1) enhanced formation and the ent ry of fibri to cells by
damage: large injuries, damage
stream. It occurs with extensive tissue
toxins; surgery, leukemia, etc. rs in the blood. It occurs (a)
2) decrease in the content of proteolysis inhibito
insufficient formation of them or (b) their increased use.

E2BFA What are the clinical signs of coagulation hemostasis disorders?

coagulopathies are char-
Unlike disturbances of vascular-platele t hemostasis,
from larger vessels -
acterized not by capillary (spot) bleeding, but by bleeding
arteries and veins.
Such bleeding is clinically manifested by: ra
in the mus cle s, under the skin, into th the ~
a) hematomas — major hem orrhages
joint cavity (hemarthrosis); ‘ i etc. q
interventions (tooth extraction, ).
b) prolonged bleeding after surgical

De

What is DIC-syndrome?

Syndrome of disseminated intravascular coagulation (DIC-syndrome) i

eralized coagulation of blood inside the vessels which causes the forte 2 gen.
large number of microclots and blood cell aggregates that disrupt mic on Of a
tion in organs and tissues. "Ocircula.
This syndrome is often described as a catastrophe for the body.

What could be the cause of DIC-syndrome?

Depending on the reasons, the following types of DiC-syndrome are distin
guished:
Oo NC UOUS diieilimtbitiiiien
itis ee,
 What could be the cause of DiC-syndrome?
Depending on the reasons, the following types of DiC-syndrome ar @ distin.
guished: ;
a) infectious-septic (it develops with sepsis);
b) post-traumatic (with crush syndrome, burn disease, multiple fractures of
bones);
c) shockogenic (for all types of shock);
d) surgical (after operations with large tissue trauma);
e) obstetric (with premature detachment of the placenta, entry of amniotic
flu-
id into the blood);
f) toxigenic (after a snake bite);
g) tumor (with malignant tumor growth);
h) allergic (with immune tissue damage), etc.

What is the pathogenetic basis for the development of DIC-syndrome?

In the pathogenesis of DIC-syndrome, the major role is
played by the so-called
“humoral protease explosion ", ie. simultaneous
activation of all proteolytic err
zymes of the blood plasma, which are the constituents of
four extracellular bio-
chemical systems (Fig. 89): (
a) the coagulation system; (b) the fibrinolytic system;
(c) the kallikrein-kinin system; (d) the syste
m of complement.
The main principle of extracellular Prot
eases activa tion is cleavage of peptides
that cover the active sites of the Se enzyme
s. The formation of active proteases in
the blood has its own peculiarities:

Cellular Extracellular
proteases Exogenous
proteases _. protease
$e

Blood coagulation : - Fibrinolytic - L lement

system _ Kallikrein-kinin Comple
system system system

Protease inhibitors
298

Fig. 89. “Humoral Protea

se explosion”

a) the self-activation of enzyme

pei . s is possible, . An active enzyme,
inactive form of it, can turn the , acti acting ona
b) some active proteases are latter into an active form;
2 "
capable of activating the others
tion); (cro ss-a ctiv a-
c) the chain nature of activation. Th eoretically,
the appearance of even one
molecule of active protease can Cause
activation of all available blood
proteolytic enzymes.
However, in the norm the reactions of proteolytic
enzymes activation are lim-
ited, which is explained by the existence of a large group of protease
In pathology, when large amounts of active prote inhibitors.
ases enter the bloodstream,
the power of existing inhibitors may not be sufficient. In this case, the chain char-
acter of proteases activation fully manifests itself. Such activation becom
es gen-
eralized and involves all blood proteases - a “humoral protease explosion” occurs
.

What are the main sources of active proteases entering the bloodstream
in DIC-syndrome?

There are three main sources of such enzymes.

|. Damaged cells. With acute damage to a large number of cells, the lysosomal
proteases and tissue thromboplastin enter into the extracellular space and blood
from there.
Inflammation, as a local process that occurs when cells are damaged (see
lesson 9), restricts the entry of decay products into the blood localizing the injury
and preventing the development of DIC-syndrome.
ll. Large quantities of extracellular proteases can enter the blood in some pa-
thology conditions. These may include trypsin in acute pancreatitis; enzymes con- 292 of 522
tained in the amniotic fluid.
Tea es Or sepsis, snake
Ill. Exogenous p
 acter of proteases activation fully manifests itself. Such activation becomes gen-
eralized and involves all blood proteases - a “humoral protease explosion” occurs.

What are the main sources of active proteases entering the bloodstream
in DIC-syndrome?

There are three main sources of such enzymes.

|. Damaged cells. With acute damage to a large number of cells, the lysosomal
proteases and tissue thromboplastin enter into the extracellular space and blood
from there.
Inflammation, as a local process that occurs when cells are damaged (see
lesson 9), restricts the entry of decay products into the blood localizing the injury
and preventing the development of DIC-syndrome.
ll. Large quantities of extracellular proteases can enter the blood in some pa-
thology conditions. These may include trypsin in acute pancreatitis; enzymes con-
tained in the amniotic fluid.
Ill. Exogenous proteases. Their sources can be bacterial cells for sepsis, snake
venom, etc.

By What events are characteristic for the pathogenesis of DIC-syndrome?

In the pathogenesis of DIC-syndrome, two phases are distinguisistinguished.

Phase | - aes of hypercoagulation and platelet aggregation. The basis a
this phase is the generalized activation of the blood clotting system, i. eh
the formation of fibri
pearance of thrombin (thrombinemia) which leads to
aggregates of platelets.
There are three triggers for this phase:
of active proteases and
1) enzymat ic mechanism ~ the entry of a large number
tissue thromboplastin from damaged tissues into the blood;
it comes into contact with
2) contact Frestanietn ~ activation of f. XII when
reign surfaces (extracorporeal circulation, hemodialysis, At ee
3) platelet mechanism — primary activation of platelet aggrega f ssuartion of
alized damage to the vascular endothelium, disorders of rheological prop

299
°0d, acute intravascular hemolysis of erythrocytes.

As aresult of these mechanisms realization, a large number of Microclots ‘

aggregates of blood cells is formed. This leads to microcirculation disorders th
development of the sludge-syndrome (see lesson 8). 7
All these disturbances result in the appearance of such clinical Manifestation
as (a) hypoxia, (b) acidosis, (c) intoxication with decay products, (d) acute faye
of external respiration (lung capillaries are clogged by microclots), (e) acute renal
failure (capillaries in the glomeruli are clogged with microclots), (f) disorder, of
cerebral circulation.
Phase II - the phase of hypocoagulation (hemorrhagic syndrome). This Dhase
develops as a consequence of depletion in the mechanisms of Vascular-platelet
and coagulation hemostasis.
Its emergence is due to:
a) decrease in an activity of the coagulation system (consumption of factors
1, V, VII);
b) activation of the fibrinolytic system (the influx of a large number offibrinoly.
sis activators into the blood);
Cc) an increase in anticoagulant blood activity due to the formation of fibrinoly-
sis products;
d) development of thrombocytopenia as a result of increased platelet con-
sumption;
e) an increase in the permeability of the vessel walls (the effect of kinins
formed in large amounts).
The phase of hypocoagulation is clinically manifested by large hard-to-stop
bleeding.

What is thrombophilic diathesis? What can be the basis of its

development?

Thrombophilic diatheses are diseases and syndromes in which the propensity

to form blood clatsai i A asis mechanisms.
 of external respiration (lung capillaries are clogged ; by microclots),
, (e) acute rena}
failure (capillaries in the glomeruli are clogged with microclots), (f) disorders of
cerebral circulation.
Phase II - the phase of hypocoagulation (hemorrhagic syndrome). This phase
develops as a consequence of depletion in the mechanisms of Vascular-platelet
and coagulation hemostasis.
Its emergence is due to:
a) decrease in an activity of the coagulation system (consumption of factors
1, V, Vill);
b) activation of the fibrinolytic system (the influx of a large number offibrinoly.
sis activators into the blood);
c) an increase in anticoagulant blood activity due to the formation of fibrinoly-
sis products;
d) development of thrombocytopenia as a result of increased platelet con-
sumption;
e) an increase in the permeability of the vessel walls (the effect of kinins
formed in large amounts).
The phase of hypocoagulation is clinically manifested by large hard-to-stop
bleeding.

What is thrombophilic diathesis? What can be the basis of its

development?

Thrombophilic diatheses are diseases and syndromes in which the propensity

to form blood clots is caused by primary disorders of hemostasis mechanisms.
The pathogenetic basis of thrombophilia can be:
1) endothelial mechanisms which cause a decrease in the thrombus resistance
of the vessel wall;
2) platelet mechanisms associated with an increase in the aggregation capac:
ity of thrombocytes;
3) diminished anticoa gulant blood activity (a decrease in the formation of ar
tithrombin I11);
4) decreased fibrinolyt I¢ system activity jal
(reduced formation of endothelt
plasminogen activator, the a Ppearance of
potent plasmin inhibitors, plasminod
deficiency);
5) disturbance of the blood coa
gulation system - dysfibrinogenemia.
Clinically, thrombophilic diathe ses are manifested by thrombosis and
boembolism of venous and arteri al vessels in different organs and tissues
| © lesson 8).
So

a
oO

CONTENT MODULE 5.
pathophysiology of systemic circulation
and external respiration

L esson 23. Heart

failure. Arrhythmias

pee What is circulatory failure? What can cause it?

i , or insuff
-pylatory failure i icienc ion, isi acon dition in which
i ation,
i y of blood circul
neler system cannot provide the organs and tissues of the body with
us
me necessaty amount of blood. It is the most frequent manifestation ofo vario
, of the circulatory system.
Se ieny of blood circulation can be caused by: (1) heart failure; (2) insuf
taneous failure
ficiency of blood vessels; (3) cardiovascular insufficiency, i.e. simul
of the heart and blood vessels.

What CONSE iN iii i

anit iecNes ance boas ile le e has