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ОБЗОР

R E VI EW DOI:10.23888/PAVLOVJ2019272274-285

МЕСТНЫЕ ГЕМОСТАТИЧЕСКИЕ СРЕДСТВА


И ПУТИ ИХ СОВЕРШЕНСТВОВАНИЯ

© Е.В. Будко, Д.А. Черникова, Л.М. Ямпольский, В.Я. Яцюк

ФГБОУ ВО Курский государственный медицинский университет Минздрава России,


Курск, Россия

В последнее время за рубежом и в нашей стране всѐ большее распространение полу-


чают местные гемостатические средства (МГС). Они действуют направленно и могут быть
использованы как при повреждении крупных сосудов, так и при диффузном кровотечении.
В статье рассматриваются химическая природа, физико-химические характеристики мате-
риалов и механизмы активности МГС, возможные направления их совершенствования.
МГС чаще всего классифицируют по механизму действия.
На сегодняшний день популярными группами являются «мукоадгезивные агенты»
(хитозан, амилопектин) и «концентраторы факторов свертывания» (цеолиты, каолин).
Также выделяют группу «стимуляторы агрегации и адгезии» (коллаген, целлюлоза). При
этом, представители вышеуказанных групп имеют общие характеристики – очень высо-
кую пористость и гидратационную способность. Еще одна группа объединяет вещества,
«способствующие денатурации белков» (неорганические соли металлов, а также соли ак-
риловой кислоты и ее производных). Полиакрилаты также являются основой клеев с ге-
мостатической активностью. Однако, большинство современных МГС являются ком-
плексными и именно эта группа является наиболее перспективной. Все средства, начиная
от гемостатических губок производства Зеленая Дубрава (Россия) и Nycomed, Такеда
(Австрия, Норвегия), до гемостатических материалов производства MedTrade (Велико-
британия), Etiguette и Z-Medica (США), сочетают в себе сорбционные и собственно тром-
бообразующие свойства. Часто под торговыми марками скрываются оригинальные ком-
позиции и, тем более, технологии: Quick Relief, BioSeal, BallistiClot, Hemaderm, CELOX
Gauze PRO, OMNI-STAT Hemostatic Gauze for minor external bleeding. Наиболее эффек-
тивными признаны МГС на основе хитозана и каолина в форме повязок, обработанных
тромбоформирующим средством, например искусственными тромбоцитами или другими
факторами свертывания.
Ключевые слова: местные гемостатические средства; гемостатические губки; цео-
литы; хитозан; метилцеллюлоза; коллаген; желатин.
______________________________________________________________________________

LOCAL HEMOSTATIC AGENTS AND WAYS OF THEIR IMPROVEMENT

E.V. Budko, D.A. Chernikova, L.M. Yampolsky, V.Y. Yatsyuk


Kursk State Medical University, Kursk, Russia

Recently, local hemostatic agents (LHA) have become increasingly popular abroad and in
our country. They act in a targeted way and can be used both in damage to large vessels and in
diffuse bleeding. In the article, chemical nature, physical and chemical characteristics of materials
and mechanisms of LHA activity are considered, directions of their improvement are shown. LHA
are mostly classified by mechanism of action.

РОССИЙСКИЙ МЕДИКО-БИОЛОГИЧЕСКИЙ ВЕСТНИК I.P. PAVLOV RUSSIAN M EDICAL


имени академика И.П. Павлова. 2019. Т. 27. №2. С. 274-285 274 BIOLOGICAL HERALD. 2019;27(2):274-85
ОБЗОР

DOI:10.23888/PAVLOVJ2019272274-285 R E VI EW

To date, the popular groups of hemostatic agents are «mucoadhesive agents» (chitosan,
amylopectin) and «coagulation factors concentrators» (zeolites, kaolin). Other authors distinguish
the group of «aggregation and adhesion stimulants» (collagen, cellulose). Here, representatives of
these groups have common characteristics – very high porosity and hydration ability. Another
group includes substances that «promote protein denaturation» (inorganic salts of metals, as well
as salts of acrylic acid and its derivatives). Polyacrylates are the basis of adhesives with hemostat-
ic activity. However, most modern LHA are complex drugs and it is just this group that is most
promising. All means, from hemostatic sponges produced by Zelyonaya Dubrava (Russia) and
Nycomed, Takeda (Austria, Norway), and to hemostatic materials of MedTrade manufacture
(Great Britain), Etiguette and Z-Medica (USA), combine sorption and, actually, thrombotic prop-
erties. The trademarks often imply original compositions and, especially, technologies: Quick Re-
lief, BioSeal, BallistiClot, Hemaderm, CELOX Gauze PRO, OMNI-STAT Hemostatic Gauze for
minor external bleeding. The most effective LHA are those based on chitosan and kaolin in the
form of dressings with embedded clot-forming substance, for example, with artificial platelets or
other coagulation factors.
Keywords: local hemostatic agents; hemostatic sponges; zeolites; chitosan; methylcellu-
lose; collagen; gelatin.
______________________________________________________________________________

There exist many methods of arresting fluid agents and sealants [5]. Passive agents
capillary-parenchymal bleeding – compres- trigger a natural cascade of clot formation
sion of the liver or spleen tissue with a clamp through sorption and aggregation, they in-
or catgut mesh, application of hemostatic su- clude collagenous drugs, drugs on cellulose
tures, and other physical and pharmacological and gelatin basis. Active hemostatic agents
methods of hemostasis. Recently, local he- contain components of clot formation cas-
mostatic agents (LHA) referred to «sparing» cade. Two other categories – fluid hemostatic
means of blood arrest have been gaining pop- agents and sealants include fibrin adhesives,
ularity both in Russia and abroad [1]. They polymers of polyethylene glycol (PEG), al-
act in a targeted way and can be used in dam- bumin, glutaric aldehyde and cyanoacrylate.
ages to large vessels and in diffuse hemorr- Besides, there also exist absorbing, biologi-
hages (parenchymal organ, cancellous bone) cal, synthetic dressings [6]. Modern hemos-
when physical and systemic methods of he- tatic materials used in surgical practice, are
mostasis appear non-effective [2]. classified into two groups by mechanism of
Application LHA are produced in dif- hemostasis: those accelerating local chemical
ferent forms: gels, adhesions, woven and non- hemostasis and those performing the role of
woven materials, hemostatic sponges, solu- physical (mechanical) agents starting aggre-
tions and powders. The aim of all LHA gation of platelets. A representative of the first
known today is imitation of specific processes group most popular among surgeons is micro-
of natural hemostasis, their acceleration or a fibrillar collagen, and in the second group the
rapid formation of a fibrin clot by some other preference is given to gelatin sponges, oxi-
mechanism [3]. Here, a hemostatic agent that dized cellulous fiber and amylopectin
fails to stop diffuse bleeding within two minutes, By mechanism of activity, local hemos-
should be considered non-effective [4]. tatic agents are categorized into:
By the mechanism of activation of he- • vasoconstrictors and pro-aggregants;
mostasis, the local hemostatic agents, or he- • plasma coagulation factors;
mostats, are classified into passive, active, • inhibitors of fibrinolysis;

РОССИЙСКИЙ МЕДИКО-БИОЛОГИЧЕСКИЙ ВЕСТНИК I.P. PAVLOV RUSSIAN MEDICAL


имени академика И.П. Павлова. 2019. Т. 27. №2. С. 274-285 275 BIOLOGICAL HERALD. 2019;27(2):274-85
ОБЗОР

R E VI EW DOI:10.23888/PAVLOVJ2019272274-285

Table 1
LHA Included into Register of Medical Remedies of Russia in 2018

Basic Material Added Components Tradename (Company, Country)

Collagen + platelets Trombokol (Belkozin plant, Luga, Russia)


KollapApan (ООО Intermediapatit, Russia)
+furacilin+boric acid Collagen sponge (ОАО Belkozin plant, Luga, Russia)

+methyluracil Meturakol (ОАО Belkozin plant, Luga, Russia)

+platelets+plant antiseptic sang- Trombokol-AS


viritrin Trombokol AG (ОАО Belkozin plant, Luga, Russia)
+ +gentamycin
+thrombin TachoComb (Takeda Austria, Norway)
+fibrinogen+albumin+sodium
chloride+sodium citrate
+riboflavin

+ degestase enzyme ЗАО Zelyonaya Dubrava, Russia)


(collagenase)
+colloid silver or lincomycin / KollapApan-S, KollapApan-L, KollapApan-G, KollapA-
gentamycin / metronidazole pan, KollapApan-К, KollapApan-R, KollapApan-D, Kolla-
/klaforan, dioxydine / rifampicin pApan-I (ООО Intermediapatit, Russia)
/ isoniasid

Gelatin Spongostan (Johnson & Johnson, USА),


Surgiflo (Johnson & Johnson, USA)
+ kanamycin Zhelplastan (Tanais, Russia)

Chitosan HemСon (Hemorrhage Control Technologies Inc., USA)


Celox (MedTrade, Great Britain)
Hemofleks Combat (ООО Inmed, Russia)

Oxidized cellul- Surgicel (Johnson & Johnson, USA)


ous fiber
Amylopectin sodium alginate+furaginum Hemostatic bandages Koleteks-SAFG-Gem (ООО Kole-
Alginic acids teks, Russia)
calcium alginate+oak tree Polihemostat (ООО Tekhnopark-Center, Russia)
bark,nettle, St. John wort,
bottlebrush extracts
Zeolite QuikClot (Z-Medica, USA)
Hemostop (НПЦ Farmzashchita, Russia)

• stimulators of aggregation and adhe- tary Forces started using local hemostatic
sion; agent on the basis of synthetic zeolite Quik-
• promoting protein denaturation; Clot (Z-Medica, USA), which was followed
• mixed [2,7]. by a drug based on chitosan (Hemorrhage
Recently, Russian and international Control Technologies Inc., USA). These
manufacturers supply many materials of local agents, respectively, served the basis for de-
application to the market. In 2003 US Mili- velopment of two LHA groups – concentra-

РОССИЙСКИЙ МЕДИКО-БИОЛОГИЧЕСКИЙ ВЕСТНИК I.P. PAVLOV RUSSIAN M EDICAL


имени академика И.П. Павлова. 2019. Т. 27. №2. С. 274-285 276 BIOLOGICAL HERALD. 2019;27(2):274-85
ОБЗОР

DOI:10.23888/PAVLOVJ2019272274-285 R E VI EW

tors of coagulation factors and mucoadhesives Dispersed collagen in the concentration


capable of sticking to mucous membrane [8]. above 0.5% forms stable emulsions of M/B
These two groups are supplemented with a type. In dehydrating conditions, non-brittle
group of procoagulant agents [1]. transparent films are formed from a thin dis-
In the periodical literature there is persion layer, and in spray drying – powders.
much discussion of a choice of methods of The production technology of a collagen
hemostasis, of a hemostatic agent and of sponge is based on the method of lyophiliza-
probable mechanisms of their action. Here, tion of a thin layer of collagen solution. In the
hemostatic agents are usually described not process of sublimation of crystals of frozen
by classification principle, but by the sub- water in deep vacuum, highly-porous sponges
stance they contain – fibrin-containing, are obtained in which the volume of through
cyanoacrylates, agents containing cellulose, and dead-end pores makes 50-90% of the to-
collagen, gelatin, etc. tal volume of a sponge. Such a sponge pos-
The given work considers a chemical sesses a high sorption property and accom-
structure and physico-chemical characteristics modates the amount of moist many times ex-
of LHA materials. In most cases it is a biode- ceeding its weight, almost without enlarge-
gradable material adapted to living tissue. In ment in size. Hemostasis takes 2-5 minutes.
the work, patented names and characteristics Collagen forms water- and air-proof gel-like
of hemostatic agents widely discussed in lite- layer; however, the sponge plate should be
rature, are used. LHA included into Register tightly pressed against the wound surface (the
of Medical Remedies of Russia 2018, are giv- preparation poorly adheres to rough wound
en in Table 1. surface because of rigidity of collagen fibers).
Let us consider hemostatic means ac- Collagen sponges prove effective only in
cording to their chemical structure. moderate parenchymal bleedings. In massive
Hemostatic Drugs of Protein Origin mixed bleedings they are «swept away» from
Collagen is protein that makes the basis the wound surface. In an organism collagen
of connective tissue of animal organisms. undergoes enzymatic breakdown with a com-
Structural and chemical stability of collagen, plete resorption period 4 weeks. In in vivo
its physical peculiarities are provided by experiment, a friable mass forms at the site of
unique organization of three-spiral macromo- the plate, and the adjacent tissues have ele-
lecules which, at physiological temperature, ments of moderate inflammation. Later, the
pH and ionic strength, undergo aggregation plate material is replaced and in histological
with formation of a three-dimensional mesh of examination looks like connective tissue or an
intermolecular bonds of different origin. In area of sclerosis [9].
contact with the «loops» of collagen spirals the Most modern LHA based on collagen,
entering molecules and cells form inclusions contain substances that influence certain stages
(clathrates). Collagen accelerates the natural of blood coagulation [4]: platelets (Trombokol),
way of coagulation and starts blood coagula- thrombin, fibrinogen (TachoComb), epsilon-
tion process when fibrils of the material come amino capronic acid, hydroxyapatite, etc. In
into the first contact with platelets. Aggregated interaction of collagen with calcium-
platelets undergo normal morphological containing solutions, cations tightly bind
changes, in particular, degranulation, with re- when entering triple helix, and it changes the
lease of ADP, serotonin, thromboxane A2 that conformation in such a way that water mole-
help in clot formation. Thus, the main hemos- cules are no longer held by this portion of the
tatic mechanism of collagen consists in aggre- triple helix. This causes local loss of water
gation and activation of platelets. and «cross-linking» of the structure with for-

РОССИЙСКИЙ МЕДИКО-БИОЛОГИЧЕСКИЙ ВЕСТНИК I.P. PAVLOV RUSSIAN MEDICAL


имени академика И.П. Павлова. 2019. Т. 27. №2. С. 274-285 277 BIOLOGICAL HERALD. 2019;27(2):274-85
ОБЗОР

R E VI EW DOI:10.23888/PAVLOVJ2019272274-285

mation of a more solid spongy material. Or- latin into a cut may prevent connection and
ganic cations – alkaloids, like heavy metal healing of the edges of the skin wound. The
ions, are stereochemically bound by collagen, main disadvantage of gelatin is its easy con-
while low- and non-ionized substances do not tamination with bacteria, due to which it can
form strong bonds. This property permits to become a focus of infection.
control the activity of medical drugs in the Gelatin product may have different con-
structure of collagen-containing forms. sistency. For example, Spongostan of a fine
The most popular in Russia «Hemostat- powder. For effective application it is mixed
ic collagen sponge» (Belkozin, Luga, Russia) with saline to obtain a loose mass which may
contains furacilin and boric acid antiseptic be applied with hands or with an applicator,
drugs. The most popular international hemos- Surgiflo is made of pig gelatin and is a fluid
tatic agent in Russia is fibrin-collagen biopo- foamy mass. It is used in the form of gel with
lymer TachoComb [10] that consists of a col- which hard-to-reach bleeding places and cavi-
lagen plate covered on one side with highly ties are treated. In mixing with saline and body
concentrated thrombin, fibrinogen and aproti- fluids it expands in volume. Gelatin sponge
nin. After contact with a bleeding wound or Spongostan is made of neutralized gelatin
other fluids, blood coagulation factors dis- foam, it is not used in infected areas or should
solve and create bonds between a carrier – be eliminated from them after hemostasis; in-
collagen and the wound surface. TachoComb soluble in water, but completely resolves with-
possesses the ability to seal the surface which in several weeks. In histological examination
is necessary in certain cases. Its Russian ana- may resemble suturing materials [9].
log is Trombokol sponge [11]. In Russia, Zhelplastan preparation is
Gelatin is a product of a partial destruc- registered (Patent 2067447 RU) - a powder
tion of collagen. Like collagen, it provides a substance with hemostatic activity. Treatment
physical matrix for initiation of blood coagu- of experimental gastric ulcers with Zhel-
lation. Gelatin effectively controls bleeding plastan in combination with granulated sor-
from small vessels and is recommended for bent – diovin – accelerates ulceration phases
use as a hemostatic plug wrapped in oxidized and reliably accelerates repair of gastric tis-
cellulose. pH of gelatin sponges approaches 7 sues [12]. The given LHA owes its effective-
which makes it possible to use them in com- ness to sorption (absorption of fluid and con-
bination with thrombin or with other sub- centration of clotting factors) and adhesion
stances for enhancement of hemostatic action. (initiation of coagulation) properties of powd-
Gelatin granules permit concentrated throm- ers with no damaging effect on tissue.
bin to rapidly react with patient’s fibrin to Polysaccharides. High-molecular car-
form a mechanically stable fibrin clot. As bohydrates are long linear or branched chains
soon as blood impregnates gelatin matrix, of monosaccharide residues linked with gly-
granules of the agent swell 20% in 10 minutes coside bond. As hemostatic agents cellulose,
restricting leakage of blood and providing chitin (in nature they perform structural func-
soft tamponade that conforms the form of the tions), starch (reserve function), and other
wound. The formed clot is resorbed within 6- substances are used.
8 weeks. A disadvantage of gelatin-based An advantage of cellulous fiber mate-
means is a probability for embolism in case of rials is their existence in different forms: tis-
their getting into a vessel, and compression of sue (gauze), non-woven and knitted fabric,
tissues by swelling in case of sealing of the cotton wool, etc. Gauze possesses a high ad-
wound. Besides, gelatin should not be used hesion to wound; but high hygienic, sorption
for closure of skin cuts because getting of ge- and physico-mechanical properties of ban-

РОССИЙСКИЙ МЕДИКО-БИОЛОГИЧЕСКИЙ ВЕСТНИК I.P. PAVLOV RUSSIAN M EDICAL


имени академика И.П. Павлова. 2019. Т. 27. №2. С. 274-285 278 BIOLOGICAL HERALD. 2019;27(2):274-85
ОБЗОР

DOI:10.23888/PAVLOVJ2019272274-285 R E VI EW

dages on the basis of cellulous fibers can nei- a change of color of the hemostatic agent in
ther be denied. Woven and non-woven mate- the wound from the initial white or yellowish
rials are most common carriers of hemostatic to brown at the moment of interaction with
factors of the following groups: plasma coa- blood. On the other hand, low level of pH
gulation factors, vasoconstricting and pro- promotes coagulation necrosis which consi-
aggregation agents, inhibitors of fibrinolysis, derably restricts application of oxidized me-
etc. thyl cellulose as hemostatic agent. The ma-
After chemical modification cellulose terial usually dissolves turning into gel-like
acquires physiological activity of its own substance which covers the area of damage
which permits its use as a therapeutic form of blood vessels and completely resolves in
without addition of medical drugs. Thus, car- 1-2 weeks, without histologically detected
boxymethyl cellulose containing functional traces of its presence in tissues.
groups of acid type is capable of binding pep- LHA based on oxidized regenerated
tides in the wound, in particular, elastase, and cellulose Surgicel Fibrillar is non-woven 7-
thus can suppress its activity. A well-known layer material that does not break up in cut-
material is monocarboxy cellulose used as ting, has a good adhesion to tissues; its fi-
blood-arresting gauze. A high biological in- brillar structure easily models the size and
ertness of carboxymethyl cellulose permits to shape of the fragment. It can be applied as a
use it as a barrier means for instance, in the whole, in layers, in bundles and turundas and
form of hydrogel (Mesogel) for prevention of therefore is convenient for use in hard-to-
adhesive processes in the abdominal cavity. reach places. The average time for blood ar-
Na-carboxymethyl cellulose possesses a pro- rest is 2-4 minutes.Polymers of a group of
nounced stimulating effect on reparative nitrogenous polysaccharides: chitin (N-
processes, accelerates formation and matura- acetyl glucosamine) and chitosan (N-
tion of granular tissue and produces an active deacetylated glucosamine) have been widely
effect on fibrillogenesis. Na-carboxymethyl used in medicine since the early 2000s [13],
cellulose powder swells and forms transparent although they had been known to science for
gels and viscous gel-solutions that form films about 200 years. Chitosan, unlike chitin, is
after drying off. These transformations of not degraded in an organism by specific en-
carboxymethyl cellulose are effectively used zymes. Absence of biodegradation in chito-
in hemostasis. san is compensated for by its polyelectrolyte
Oxidized methyl cellulose in local ap- properties – formation of gels with abnor-
plication absorbs blood, promotes formation mally high viscosity in reduction of polymer
of a platelet and later on of a fibrin clot. The concentration. Chitosan forms strong bonds
material has a cotton-like consistency and with proteins, anion polysaccharides, forms
does not adhere (Patent №2563279 RU). chelate complexes with metals. It concen-
Oxidized cellulose acts as a caustic sub- trates erythrocytes, blood coagulation factors
stance bringing an artificial component of and platelets at the bleeding site. Polymer
clot formation into hemostasis. Contact with carries charge which facilitates coagulation
moist medium triggers degradation process of blood in contact with erythrocytes and
with release of cellulous acid and reduction stimulates release of vasoconstrictors, such
of the local pH. Low pH of oxidized cellu- as thromboxane and endothelin [5].
lose induces vasoconstriction with simulta- Powder consisting of D-glucosamine
neous lysis of erythrocytes. Hemoglobin re- and N-acetyl-D-glucosamine, for instance,
leased from erythrocytes reacts with cellul- Celox [8], can absorb blood 11 times its
ous acid to form acid hematin. This explains weight. Celox granules may be applied di-

РОССИЙСКИЙ МЕДИКО-БИОЛОГИЧЕСКИЙ ВЕСТНИК I.P. PAVLOV RUSSIAN MEDICAL


имени академика И.П. Павлова. 2019. Т. 27. №2. С. 274-285 279 BIOLOGICAL HERALD. 2019;27(2):274-85
ОБЗОР

R E VI EW DOI:10.23888/PAVLOVJ2019272274-285

rectly on the wound and arrest bleeding disadvantage is a lower, in comparison with
without mechanical compression. Celox gelatin, speed of hemostasis.
products are mainly used to stop bleeding in Modern studies of starch are aimed at in-
emergency cases. Bandages «Celox gauze», crease in the rapidity of swelling and in solubili-
«Celox Rapid» are considered to be more ty. Polysaccharide hemostatic system PerClotR
effective than powder. Increase in hemostatic consists of particles of purified modified plant
effectiveness was shown on an example of a resorbable starch (AMPR). The study of 2009
combined impregnation of non-woven ma- demonstrated the effectiveness of hemostatic
terial with chitosan and PolySTAT polymer powder in the form of microporous polysaccha-
with clot-forming activity. In comparison of ride «hemospheres» [16].
the obtained material with a commercially Acrylic acid derivatives. Acrylic acid is
available gauze containing Celox Rapid chi- a simplest representative of monobasic unsa-
tosan, no noticeable differences in size of turated carbonic acids. Acrylic acid strongly
fibers, morphology and size of pores were irritates skin and mucosa of eyes (irritation
seen. However, PolySTAT on chitosan basis threshold 0.04 mg/l). It possesses chemical
demonstrated a more rapid absorption of properties of carbonic acids: forms salts, acid
blood [14]. chloride, anhydrates, esters, amides, etc. In
A possibility to obtain derivatives ana- the presence of initiators of polymerization
logous to cellulose derivatives, led to synthe- acrylic acid forms polyacrylic acid.
sis of chitin/chitosan esters. Composite he- Polyacrylic acid interacts with albumin
mostatic sponge was obtained from carbox- molecules by ionic bond mechanism with
ymethyl chitosan and sodium alginate as the formation of a stable complex – matrix – and
main materials with addition of CaCl2 as a with further formation of a strong polymetha-
cross-linking agent [15]. On the contrary, N- crylate film. This property is used for suturing
и О-sulfated derivatives of carboxymethyl the edges of wound using biological adhesive
chitin/chitosan prevent blood coagulation due based on polyacrylate. With use of hydro-
to selective adsorption and antithrombin. phobic cyanoacrylate adhesive, hemostasis is
Amylopectin. Hemostasis with prepara- realized via formation of an adhesive film on
tions of amylopectin (starch) is considered to the wound surface. At the same time, cyanoa-
be close to mechanical hemostasis. Amylo- crylate adhesives are characterized by local
pectin is formed by branched chains of α- and systemic toxicity and induce necrotic
glucose residues linked with glycoside changes in the zone of application. Due to a
bonds. Chains of amylopectin have more rapid vitrification of such adhesives on the
branches than amylase and less branches surface of wound and a weak bond with tis-
than glycogen; in general a macromolecule sues, there are reported cases of early rejec-
has a spherical shape. Amylopectin granules tion of the adhesive plate with renewal of a
actively absorb a fluid fraction of blood, and threatening bleeding [17].
hydration leads to irreversible alteration of Feracryl is a partial iron salt of polyacryl-
structure – separation of chains and swelling ic acid containing from 0.05 to 0.5% of iron. A
of granules. Absorption of water from blood unique hemostatic effect of feracryl is based on
results in concentration of formed elements its ability to form polycomplexes with proteins
and of coagulation proteins. Starch (amylo- in blood at pH from 2.9 to 4.0 even in the ab-
pectin) loses to hemostatic agents of gelatin sence of fibrinogen.
and oxidized cellulose in terms of volume of Hemoblock is a silver salt of polyacryl-
absorbed fluid and resorption rate. Another ic acid containing nanoparticles of silver
which accounts for bactericidal and bacterios-

РОССИЙСКИЙ МЕДИКО-БИОЛОГИЧЕСКИЙ ВЕСТНИК I.P. PAVLOV RUSSIAN M EDICAL


имени академика И.П. Павлова. 2019. Т. 27. №2. С. 274-285 280 BIOLOGICAL HERALD. 2019;27(2):274-85
ОБЗОР

DOI:10.23888/PAVLOVJ2019272274-285 R E VI EW

tatic effect of the drug. Hemoblock is applied reasonable to pour the powder directly on the
externally in case of parenchymal and capil- bleeding source and apply cotton tampon or
lary bleedings. For this, sterile cotton and bandage. Negative sides of zeolite include
gauze bandages are soaked in Hemoblock and formation of burns due to emanation of heat
applied on the bleeding, preliminary dried in hydration and the necessity or manual
surface. Hemostatic effect is achieved within compression within 5-7 minutes until suffi-
1-2 minutes through formation of a clot with cient soaking of the powder. To compensate
blood plasma proteins, first of all, with albu- for negative effects of zeolite it is partially
min. Further on, albumin molecules reduce hydrated (reduction of heating) and placed
silver ions which provides the bactericidal into a meshy carrier [20]. For instance, Quik-
effect of the film. Fibrin gradually replaces Clot Combat Gauze (QCG) – non-woven
the superficial structure «hemoblock- bandage impregnated with kaolin – was ap-
protein», and polyacrylate matrix is plasmo- preciated by medics because of its rolled
lyzed [18]. shape that combines chemical and compres-
Polystat is a synthetic polymer on the sion hemostasis [21].
basis of metacrylate and imitates F XIIIa- So, analysis of scientific publications on
mediated stabilization of fibrin [19]. A proto- the given topic shows a permanent attention
type of PolySTAT is XIII blood coagulation to studying experience in application of a
factor – blood protein that strengthens a clot. considerable quantity of hemostatic products
PolySTAT induces hemostasis via cross- for local arrest of bleeding, and also to new
linking of fibrin matrix inside the clot. Be- development in this field. It is worth to men-
sides, synthetic PolySTAT binds specially tion a wide range of LHA manufactured by
with fibrin monomers and uniformly inte- specialized companies. With this, imported
grates into fibrin fibers during fibrin polyme- products are more variable in forms, but Rus-
rization which results in strengthening of hy- sian manufacturers work to diversify the
brid polymer mesh with enhanced resistance range of drugs within the same form.
to enzymatic degradation. Most effective are combined LHA.
Alumino silicate minerals – zeolites Accordingly, their activity is also based on
(kaolin). Structural porosity of inorganic po- combined mechanism. The majority of con-
lymer AlSiO4 defines application of alumino- sidered hemostatic components activate
silicates as adsorbents. Open scaffold-cavitary natural coagulation processes via concentra-
structure has a negative charge which enables tion of coagulation factors, adhesion and
it to hold back a high amount of cations, for aggregation of platelets. Adhesion and ag-
instance, calcium – a cofactor in coagulation gregation of coagulation factors on LHA
cascade. On the basis of synthetic zeolite, based on collagen, gelatin, cellulose, chitin,
several effective LHA are developed. The starch is due to high hygroscopicity of these
preparations are insoluble, but biocompatible. materials. Concentration of coagulation fac-
In the US Army QuikClot preparation was tors on kaolin is also due to a high absorb-
adopted for stoppage of external massive ing capacity of this sorbent. Drying of the
bleedings. The hemostatic mechanism of place of application, and increase in blood
QuikClot powder includes adsorption of wa- viscosity and in concentration of coagula-
ter from blood, concentration of blood coagu- tion factors because of this, is a common
lation factors, activation of platelets and fur- principle of hemostatic activity of proteins,
ther implementation of coagulation cascade. cellulous, alumino silicate materials, and
Another preparation on the basis of zeolite – other sorbents. Ability of polymers to create
Hemostop – was developed in Russia. It is meshy structures and ability of kaolin to

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имени академика И.П. Павлова. 2019. Т. 27. №2. С. 274-285 281 BIOLOGICAL HERALD. 2019;27(2):274-85
ОБЗОР

R E VI EW DOI:10.23888/PAVLOVJ2019272274-285

form ion complexes equally result in effec- weaving; hemostatic agents carriers – powd-
tive holding back of macromolecules and, er applicators which may stop bleeding from
accordingly, to increase in probability of deep wounds with a narrow input holes, and
clot formation. in cavities; Z-fold bandages (impregnated
Despite the existence of many various with the agent and fanfold); meshes holding
active components and the possibility of their kaolin; return to old and unfairly forgotten
use in different combinations, not a single materials (cotton bandages); synthesis of
hemostatic agent has been created so far, that new polymers, as for example, PolySTAT,
could fully meet the demands of the modern synthesis of artificial platelets and other coa-
medicine. A hemostatic agent should: stop gulation factors.
bleeding (clot formation) within 2 minutes or One more trend is creation of complex
faster; act in a wide temperature range; not preparations combining sorption and clot-
damage the adjacent tissues; not cause painful forming properties which include the majority
sensations form compression or thermal dam- of modern local hemostatic agents starting
age; be ready for application and be easily from hemostatic sponges manufactured by Ze-
used in extreme conditions; be suitable for lyonaya Dubrava (Russia) and Nycomed, Ta-
use with complicated wounds; should degrade keda (Austria, Norway) and ending with he-
and be easily eliminated from the wound; mostatic materials of MedTrade (Great Brit-
have a long storage period; be bactericidal; be ain), Etiguette and Z-Medica (USА). Most ef-
applicable in case of derangement of coagula- fective are local hemostatic means on the basis
tion function; be economically efficient. of non-woven materials or sponges processed
Conclusion with a clot-forming substance. It is worth to
At present, most effective trends in mention a wide range of LHA manufactured
improvement of hemostatic agents are: syn- by specialized companies. With this, imported
thesis of drugs on the basis of derivatives of products are more variable in physical forms
chitosan or kaolin, creation of new forms of the basic material, while Russian manufac-
(powders or granules, poured on the bleeding turers work to create more combinations of
area, pastes, woven materials of special drugs on the basis of the same basic form.

______________________________________________________________________________________________

Литература 5. Kumar S.M.P. Local hemostatic agents in the man-


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имени академика И.П. Павлова. 2019. Т. 27. №2. С. 274-285 282 BIOLOGICAL HERALD. 2019;27(2):274-85
ОБЗОР

DOI:10.23888/PAVLOVJ2019272274-285 R E VI EW

сивного смешанного наружного кровотечения // Fibrin-Crosslinking Polymer for Modulating Clot


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on bleeding after endoscopic sinus surgery. Ran- MEJ.0000000000000318

______________________________________________________________________________________________

Дополнительная информация [Additional Info]

Источник финансирования. Бюджет ФГБОУ ВО Курский государственный медицинский университет Минздрава России. [Financing of
study. Budget of Kursk State Medical University.]

Конфликт интересов. Авторы декларируют отсутствие явных и потенциальных конфликтов интересов, о которых необходимо сооб-
щить, в связи с публикацией данной статьи. [Conflict of interests. The authors declare no actual and potential conflict of interests which should
be stated in connection with publication of the article.]

Участие авторов. Будко Е.В. – концепция обзора, написание текста, редактирование, Яцюк В.Я. – сбор, анализ материала, написание
текста, Ямпольский Л.М. – сбор, перевод и анализ материала, написание текста, Черникова Д.А.– сбор материала, написание текста.
[Participation of authors. E.V. Budko – concept of the review, writing the text, editing, V.Y. Yatsyuk – collection and analysis of material, writ-
ing the text, L.M. Yampolsky – collection, translation and analysis of material, writing the text, D.A. Chernikova – collection of material, writing
the text.]

______________________________________________________________________________________________________________________

Информация об авторах Authors Info

Будко Елена Вячеславовна – д.фарм.н., профессор, зав.кафедрой общей и биоорганической химии, ФГБОУ ВО Курский государствен-
ный медицинский университет Минздрава России, Курск, Россия. [Elena V. Budko – PhD in Pharmaceutical Sciences, Professor, Head of the
Department of General and Bioorganic Chemistry, Kursk State Medical University, Kursk, Russia.]
SPIN: 1517-2863, ORCID ID: 0000-0001-8861-7491, Researcher ID: Н-2806-2013.

Черникова Дарья Александровна – аспирант кафедры общей и биоорганической химии, ФГБОУ ВО Курский государственный меди-
цинский университет Минздрава России, Курск, Россия. [Daria А. Chernikova – PhD-Student of the Department of General and Bioorganic
Chemistry, Kursk State Medical University, Kursk, Russia.]
SPIN: 7440-0789, ORCID ID: 0000-0002-3540-6700.

*Ямпольский Леонид Михайлович – к.х.н., доцент кафедры общей и биоорганической химии, ФГБОУ ВО Курский государственный
медицинский университет Минздрава России, Курск, Россия. [Leonid M. Yampolsky – PhD in Chemical Sciences, Associate Professor of the
Department of General and Bioorganic Chemistry, Kursk State Medical University, Kursk, Russia.]
SPIN: 6556-5302, ORCID ID: 0000-0001-7575-9140. E-mail: yampolsky.leonid@yandex.ru

РОССИЙСКИЙ МЕДИКО-БИОЛОГИЧЕСКИЙ ВЕСТНИК I.P. PAVLOV RUSSIAN M EDICAL


имени академика И.П. Павлова. 2019. Т. 27. №2. С. 274-285 284 BIOLOGICAL HERALD. 2019;27(2):274-85
ОБЗОР

DOI:10.23888/PAVLOVJ2019272274-285 R E VI EW

Яцюк Валентина Якoвлевна – д.фарм.н., профессор, профессор кафедры общей и биоорганической химии, ФГБОУ ВО Курский госу-
дарственный медицинский университет Минздрава России, Курск, Россия. [Valentina Y. Yatsiuk – PhD in Pharmaceutical Sciences, Profes-
sor, Professor of the Department of General and Bioorganic Chemistry, Kursk State Medical University, Kursk, Russia.]
SPIN: 7605-3467, ORCID ID: 0000-0002-7954-9076.

______________________________________________________________________________________________________________________

Цитировать: Будко Е.В., Черникова Д.А., Ямпольский Л.М., Яцюк В.Я. Местные гемостатические средства и пути их совершенст-
вования // Российский медико-биологический вестник имени академика И.П. Павлова. 2019. Т. 27, №2. С. 274-285. doi:10.23888/ PAV-
LOVJ2019272274-285

To cite this article: Budko EV, Chernikova DA, Yampolsky LM, Yatsyuk VY. Local hemostatic agents and ways of their improvement. I.P. Pav-
lov Russian Medical Biological Herald. 2019;27(2):274-85. doi:10.23888/PAVLOVJ2019272274-285

Поступила/Received: 17.01.2019
Принята в печать/Accepted: 17.06.2019

РОССИЙСКИЙ МЕДИКО-БИОЛОГИЧЕСКИЙ ВЕСТНИК I.P. PAVLOV RUSSIAN MEDICAL


имени академика И.П. Павлова. 2019. Т. 27. №2. С. 274-285 285 BIOLOGICAL HERALD. 2019;27(2):274-85

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