Hemostasis
and anticoagulation agents
BIRBILIS
C. [1], SOFIANOS I.P. [2], PYROVOLOU N. [2], SAVAKIS G. [1], PAPATHANASIOU
V. [2]
[1] Department of Internal Medicine, General Hospital of Livadia
[2] Orthopaedic Department, General Hospital of Livadia
ABSTRACT
Hemostasis is a complex physiologic process aiming at the protection
from bleeding and the preservation of regular blood flow. It depends
on three elements: (1) blood vessels, (2) platelets, and (3) plasma
proteins. Immediately after an injury, blood vessels constrict, while
platelets aggregate to form a primary plug, which, afterwards, gets
stabilized by fibrin derived from the action of thrombin on soluble
fibrinogen. A range of natural anticoagulants prevent the inappropriate
intravascular thrombin formation. Moreover, blood coagulation is normally
controlled by enzyme ranges which constitute the fibrinolytic system,
dissolve the clot and restore the blood flow inside the vessel. Any
disruption of this balance may lead to bleeding and/or thrombosis.
Thrombus formation may be induced by the presence of (1) endothelium
injury of any cause, (2) blood flow slowing down, and (3) genetic
factors that lead to hypercoagulability states.
Venous thromboembolism including deep venous thrombosis and pulmonary
thromboembolism constitutes a serious health problem. Unfractionated
heparin, low-molecular-weight heparins, warfarin and aspirin are widely
used for prevention and treatment of arterial and venous thrombotic
disorders. In this study, we will also present the pharmacology, therapeutic
potential, safety and tolerance of the anticoagulation agents.
Key words: Hemostasis, fibrinolysis, thrombosis, deep venous
thrombosis, pulmonary thromboembolism, heparin.
INTRODUCTION
Hemostasis is a complex defense mechanism that prevents blood loss,
after smaller or bigger blood vessel injuries, and preserves the normal
blood flow. The intact function of the hemostatic system depends on
the vascular network integrity, the quantitative and qualitative platelet
adequacy, the coagulation proteins, and the accurate dynamic interaction
between all of these.
On the other hand, the natural fibrinolytic system is activated in
order to dissolve the clot and restore the regular blood flow. These
two systems, the hemostatic and the fibrinolytic, are delicately balanced
thanks to the cooperation of complex activating and suppressing enzymatic
systems, which are linked together by negative feedback and self-regulating
mechanisms. Disorder of these systems may lead to bleeding and/or
thrombosis.
THE NORMAL HEMOSTATIC SYSTEM
Being aware of the normal hemostatic mechanism is essential to the
diagnosis, treatment and prophylaxis of patients with coagulation
disorders. Hemostasis is activated when the vessel endothelium is
disrupted by injury, surgical operation or other disease; then blood
is exposed to the subendothelial collagen and/or the underlying tissue.
The physiologic hemostatic system can be divided, for instructive
reasons, in three components: primary hemostasis, secondary hemostasis
or blood coagulation, and fibrinolysis.
Figure 1. Normal hemostasis.
Figure 2: Thromboxane A2 and Prostacyclin (PGI2) production.
Primary
hemostasis
Primary hemostasis takes place immediately, within seconds, and consists
firstly in the injured vessel constriction. Vasoconstriction is induced
by nervous stimuli due to pain, release of vasoconstrictive substances
by the platelets, such as serotonin, and external pressure by blood
extravasation. Vasoconstriction may last for 20 to 30 minutes, decreasing
the blood flow, thus giving time for further activation of the hemostatic
mechanism.
The main process of the primary stage starts at the same time, with
the participation of platelets, and leads to the formation of a temporary
platelet plug (white clot) at the injury spot. This process is a "first
aid" mechanism, and is brought to completion in three stages:
platelet adhesion, platelet activation and granule release, and platelet
aggregation.
Platelets are small anucleate cells deriving from the bone marrow
megakaryocytes, by the action of the growth factor thrombopoetin.
The normal platelet count ranges between 150,000 and 400,000/μl of
blood, and their life expectancy is about 8-10 days.
A few seconds after the endothelium rupture, receptors of the platelet
surface attach to the fibers of the subendothelial collagen, so that
platelets adhere to the injury site. Adhesion is strengthened by the
binding of another membrane platelet receptor to the von Willebrand
factor (vWF). Von Willebrand Factor is an adhesive glycoprotein of
the plasma and vessel wall, produced by the endothelium and the platelets.
The binding mentioned above, as well as collagen, epinephrine, and
thrombin of the injury site, stimulate the platelets resulting to
a cascade that leads to a further activation of the platelets. The
content of their granules (adenosine diphospate (ADP), thromboxane
A2 (TXA2), von Willebrand factor (vWF), platelet activating factor
(PAF), serotonin, and other agents) is released at the circulation
(outburst reaction), thus magnifying platelet activation and attracting
even more platelets to the injury site. This way, the platelet plug
is enlarged (aggregation), while, at the same time, the primary stage
meets the secondary stage, the one of coagulation.
TXA2, an arachidonic acid product derived from the platelets, stimulates,
as mentioned above, the platelet activation and secretion. On the
other hand, prostacyclin, another product of arachidonic acid metabolism,
derived from the endothelium, inhibits the platelet activation and
aggregation, thus preventing thrombus extension across the blood vessel
(figure 2).
The platelet plug plays a major role in the management of minor, automatic
or not, ruptures of small vessels and capillaries, which happens hundreds
of times every day. In thrombocytopenia, small bleeding areas appear
on the skin (especially of the lower extremities) and the mucosa.
Secondary hemostasis (blood coagulation)
While the platelet plug is formed, the plasma coagulation proteins
are activated and the secondary hemostasis begins, to end up 3-6 minutes
later in the formation of the hemostatic clot.
More than 30 different coagulation promoting or suppressing factors
of the blood or the tissues have been identified. Normally, the anticoagulation
agents (antithrombin III, C and S proteins) prevail over the precoagulants,
that's why there is no thrombus formation in the blood. However, when
a vessel is intersected or damaged, the precoagulant activity predominates
at the injury site, and clot formation begins. Extension of the plug
across the vessel beyond the injury site may happen only if the circulation
slows down or stops, otherwise the blood flow lyses and carries away
thrombin and other coagulation factors that were locally released,
preventing their accumulation that would lead to the continuation
of the process. Activated factors and thrombin are removed from the
circulation by the liver Kupfer cells.
The main objective of the coagulation process is the thrombin mediated
polymerization of soluble fibrinogen into insoluble fibrin. Fibrin
surrounds and traverses the platelet plug, forming a network. This
network is stronger and more stable than the unstable platelet plug,
and protects the vessel from a subsequent damage or a second hemorrhage.
Next, fibroblasts enter this scaffold, and form connective tissue.
The final conversion of the plug into connective tissue will be completed
within 7-10 days.
Fibrinogen is a large protein (MW=340kDa) produced by the liver, and
circulating in the blood plasma in a concentration of 200-400mg/dl.
A severe hepatic disease or hepatic failure may lead to reduction
of its production. The fibrinogen plasma concentrations increase during
pregnancy, tissue injury, inflammation or malignancy.
Prothrombin and other factors (VII, IX, X) are synthesized in the
liver. Vitamin K is essential for the production of these factors.
Vitamin K insufficiency, caused by lack of bile salts, which are necessary
for its absorption, or severe hepatic disease, may reduce prothrombin
production, resulting in a fast decrease to its plasma concentration
below its desirable level, within 24 hours.
Thrombin, the major coagulation enzyme, is a proteolytic enzyme, which,
apart from its main role in hemostasis, that is the conversion of
fibrinogen into fibrin, has many more functions, such us the activation
of coagulation factors V, VII, and XIII and the induction of the platelet
secretion and aggregation. Thrombin exerts its action on fibrinogen,
by converting it into fibrin monomerics, which, afterwards, polymerize
together with other fibrin molecules to form an insoluble gel.
A large number of fibrin monomerics polymerize within seconds to form
the fibers of the clot network, stabilized afterwards by the coagulation
factor XIIIa, via cross links between the solitary chains. This network
attaches firmly to the injured surface, entrapping platelets, red
blood cells and plasma. The coagulation process or coagulation cascade
is the sequential activation of a large number of plasma proteins,
the coagulation factors (mainly β-globulins).
We descriminate two different pathways, the extrinsic and the intrinsic
pathway of blood coagulation. Both pathways result to the activation
of factor X. Thereafter, the common pathway begins: the activated
factor X (Xa), together with two cofactors, factor Va and phospholipids,
form the prothrombin activator. Prothrombin activator, in the presence
of calcium ions, converts prothrombin into thrombin, on the surface
of activated platelets and tissue cells. The prothrombin activator
formation by both pathways is described in details below.
a. Extrinsic coagulation pathway
When blood is exposed to extravascular tissue or injured vascular
wall, injured tissues release an enzyme, the ubiquitous tissue thromboplastin
(coagulation factor III), an essential element of the cell membrane,
which forms a cluster with coagulation factor III and calcium, ending
in the activation of factor X and the sequential formation of prothrombin
activator. These reactions are quick, and can lead to clot formation
within 15 seconds (figure 1).
b. Intrinsic coagulation pathway
After an injury of the vascular wall, and the sequential exposure
of subendothelial collagen to the circulating platelets and to factor
XII (Hageman factor or contact factor), a cascade of reactions begins,
resulting in the activation of factor X and the formation of the prothrombin
activator. Calcium ions play here an important role that can be proven
by the fact that if calcium ions are in vitro neutralized by citric
or oxalacetic salts, coagulation is halted. In vitro, coagulation
is possible only by the intrinsic pathway. The intrinsic pathway develops
more slowly, and requires 2-6 minutes to form a clot (figure 1).
Natural coagulation inhibitors
As mentioned above, hemostasis is controlled by an intrinsic natural
mechanism which prevents its inappropriate activation and preserves
its strictly local nature.
There are two factors that prevent the contact activation of the intrinsic
coagulation pathway: the integrity and continuity of the vascular
endothelium, and the negative charge of its surface which repel coagulation
factors and platelets. Moreover, plasma contains factors, such us
antithrombin III, C and S protein, which inhibit the activated coagulation
factors and facilitate the intravascular clot lysis. The accurate
control of the coagulation system is extremely important. It is enough
to say, that the "coagulation potential" of only a cubic
centimeter of blood is sufficient to cause thrombosis of the whole
body fibrinogen within 10-15 seconds.
Antithrombin III is a protein synthesized by the liver and the endothelium.
It binds and deactivates thrombin and factors IXa, Xa and XIa, thus
preventing the conversion of fibrinogen into fibrin. This binding
is especially facilitated by heparin.
Heparin is present in the blood basophils and tissue mastocytes, mainly
of the lung and liver. Its presence is essential, since the lungs
and liver receive many emboli formed into the peripheral veins. This
way, heparin can prevent the further enlargement of these emboli.
C protein inhibits the activity of factors VIII, and V, while S protein
enhances the results of C protein. It is well known that patients
with inefficient production of the above proteins present an increased
thrombosis rate.
Fibrinolysis
Fibrinolysis is the capability of the organism to lyse fibrin clots
via a proteolytic enzyme, called plasmin. Plasmin is formed by the
action of activators, mainly the tissue plasminogen activator (tPA)
on its inactive precursor, plasminogen. tPA is a product of almost
every tissue of the human body, except for the liver. Urokinase (uPA),
secreted by the kidneys, is also capable of converting plasminogen
into plasmin. This conversion may also be achieved by therapeutic
administration of activators, as well as by some bacteria (e.g. Streptococcus
secreting streptokinase).
Plasminogen is absorbed on the fibrin clot so that it can promote
the local thrombolytic action of plasmin. Plasmin degrades the fibrin
polymeric into small fragments of low molecular weight, the fibrin
degradation products (FDP), which are removed from the circulation
by the monocyte-macrophage system. The major action of the fibrinolytic
system is the lysis of small clots, formed in the small peripheral
blood vessels that would be otherwise obstructed. Besides, we can
achieve the same result by the therapeutic use of plasminogen activators.
On the contrary, "opening" of large blood vessels is hardly
ever necessary.
Fibrinolysis is a slowly progressing phenomenon, which is in constant
balance with the hemostatic system. It begins 2-3 hours after fibrin
formation and is completed up to 72 hours later. Its function is controlled
by the plasminogen activator inhibitors (PAI-1 and PAI-2) released
by the endothelium and the activated platelets, while any plasmin
excess is neutralized by antiplasmins, like A2-antiplasmin and others.
LABORATORY TESTS
Ordinary laboratory testing for primary hemostasis control comprises:
- Platelet count
- Bleeding time
- Coagulation time
When the platelet count is:
- > 100,000/μl, the bleeding time is normal
- 50,000-100,000/μl, the bleeding time is slightly prolonged
- <10,000/μl, there is a serious danger of spontaneous hemorrhage
(the cut off point was at 20,000/μl some years ago).
In patients with acute bleeding the platelet count must not fall under
50,000/μl. Bleeding time, although a rough test, constitutes a sensitive
marker of platelet function and must be carried out by an expert.
To evaluate the secondary hemostasis function we use:
- prothrombin time (PT)
- activated partial thromboplastin time (aPTT)
- thrombin time (TT)
PT reflects the function of the extrinsic coagulation pathway, while
aPTT reflects that of the intrinsic coagulation pathway. Since both
these tests evaluate the common coagulation pathway when they are
both found pathologic, TT or quantitative fibrinogen measurement must
be performed too. When it is difficult to interpret any of the laboratory
tests, special coagulation factor measurements must be performed,
in order to define the kind of the disorder.
The fibrinolytic system evaluation requires more specialized tests.
The major laboratory test abnormalities and their causes are shown
in table 1.
DISORDERS OF HEMOSTASIS
As mentioned above, hemostasis is accurately regulated by a range
of activators and inhibitors. Any abnormality of the interaction between
them may cause a disorder of the natural hemostatic system towards
one or another direction.
Deflection of the hemostatic mechanism towards the direction of hemostasis
inefficiency emerges with bleeding and may be due to inherited or
acquired disorders of the hemostatic mechanism. A large number of
this kind of disorders is already identified. This subdivision will
not be further discussed in this article.
Deflection of the hemostatic mechanism towards thrombus formation
results in thrombosis. Some patient groups are particularly sensitive
to thrombosis and thromboembolism, but in most of them we can't detect
any hemostatic disorder. However, there are patient groups that suffer
from an inherited or acquired "prethrombotic" state, or
hypercoagulability state, that predispose to relapsing thrombosis.
Considering that the pathophysiologic mechanism of thrombosis is less
comprehensible than the one of hemostatic insufficiency, there are
no useful laboratory tests to approach these patients so far.
THROMBOSIS
During normal hemostasis, the uncontrolled extension of the clot is
limited by the intervention of the fibrinolytic system. The borderline
between useful and abnormal clot formation is very thin: clot may
be formed inside a vessel without rupture, under abnormal circumstances,
and this process is called thrombosis. Someone could say that thrombosis
is coagulation taking place at the wrong site, the wrong time.
According to thrombus location, we can distinguish two different conditions:
venous thrombosis and arterial thrombosis. The pathogenic mechanism
is different, and consequently the treatment is different too.
Thrombi formed inside arteries comprise mainly of platelets and a
small amount of fibrin (white thrombi), while thrombi formed inside
veins are rich in fibrin and contain many erythrocytes and few platelets
(red thrombi). White thrombi, when detached from the arterial wall,
may cause ischemia of the brain or other organs, while the fragile
ends of the red thrombi, when detached, may form emboli and lead eventually
to pulmonary thromboembolism.
Arterial occlusion due to thrombosis is an emergency, because of the
acute ischemia and the potential necrosis (acute myocardial infarction,
ischemic stroke, peripheral artery occlusion, etc).
Thrombosis is stimulated by arterial injury (in most of the cases
a spontaneous or mechanical rupture of an atherosclerotic plaque),
which causes endothelium rupture, leading to local platelet adhesion
and aggregation, and then to activation of the coagulation system.
Therefore, the prevention and treatment of arterial thrombosis is
achieved with antiplatelets and anticoagulants.
Venous thrombosis, in contrary, is mainly associated with blood flow
allowing down and/or interruption, and the eventual activation of
coagulation factors, which cannot be dissolved and removed from the
circulation. It usually occurs in large cavities (varicose veins,
cardiac cavities) and on the valves of the deep veins of the lower
extremities.
As mentioned above, some patient groups are very sensitive to thrombosis
and thromboembolism. Thrombotic disorders may present in patients
with:
Hereditary disorders, such as C or S protein insufficiency, antithrombin
III insufficiency, V Leiden factor mutation, prothrombin mutation
G20210A, homocystinemia, etc. Reduction of the levels of C or S protein
and antithrombin III, in a random sample of healthy individuals in
Greece, rises up to 1%.
Acquired hypercoagulability state. This category includes:
b1. "Normal conditions" predisposing to thrombosis, such
as immobilization, post surgical states, old age, obesity, pregnancy,
puerperium etc.
b2. Diseases and syndromes, such as antiphospholipid syndrome, malignancies,
myeloproliferative diseases, hyperviscosity syndrome, hyperlipidemia,
diabetes mellitus, nephrotic syndrome, paroxysmal nocturnal hemoglobinuria
etc. Smoking, contraceptive use, hormone substitution treatment, and
history of venous thrombosis are also predisposing factors.
Several surgical procedures, such as major orthopaedic knee or hip
operations and neurosurgical operations, are extremely thrombogenic
due to production of large amounts of tissue thromboplastin, in combination
to a number of other aggravating factors. We may mention that the
danger for venous thromboembolism in a total hip or knee arthroplasty,
without prophylaxis, ranges between 45 and 70% and the danger for
fatal pulmonary thromboembolism between 1 and 3%. It is though important
that the danger isn't restricted to the immediate postoperative period,
but it is present for several weeks.
VENOUS THROMBOEMBOLISM
AND ANTICOAGUALATION TREATMENT
Venous thromboembolism comprises deep venous thrombosis of the lower
extremities and pulmonary thromboembolism, while postphlebitic or
postthrombotic syndrome (venous insufficiency, edema, venous ulcers)
and pulmonary hypertension are its long-term complications. The incidence
of deep venous thrombosis, in the general population, rises up to
1-2 cases/1000 individuals/year. 1-2% of them will have a fatal massive
pulmonary thromboembolism (obstruction of more than 50% of the pulmonary
circulation).
The goal of the venous thromboembolism treatment, weather it is hereditary
of acquired, is:
:: to prevent:
-thrombus extension
-pulmonary thromboembolism
-early relapse
:: to protect against:
-late relapse
-pulmonary hypertension
-postphlebitic syndrome
The goal of the prophylactic anticoagulation treatment is the protection
from thrombosis of patients with thrombophilic predisposition and
those who get exposed to prethrombotic states. Apart from the essential
mechanical measures used to prevent venous stasis in the lower extremities,
pharmaceutical regimen, for both prevention and treatment, consists
in administration of substances that interfere with the coagulation
mechanism, like heparins (classic heparin, low molecular weight heparins),
pentasaccharides, coumarin anticoagulants and other drugs like hirudin,
DNA recombinant desirudin, antithrombin III etc. These drugs do not
have any thrombolytic effect on the already formed thrombus. Antiplatelet
agents like aspirin, thienopyridines (ticlopidin and clopidogrel)
and dicoumarole are also considered as anticoagulants.
In conclusion, venous thromboembolism is multifactorial. Risk factors
may act individually or together, resulting in morbidity increase.
The significance of each risk factor, as well as the interactions
between them, are not completely understood, that's why the instructions
concerning the primary and secondary prevention are not clear. The
decision about treatment duration in each patient must be individualized
according to clinical experience and evaluation of risk factors. Virtually,
we can divide the patients in three categories: high, middle and low
risk. The treatment duration can be decided according to this classification,
and will be long-lasting for high risk patients, and shorter for low
risk patients. For middle risk patients, bibliographic data is controversial;
therefore there are no specific directions. Many points have to be
clarified in future clinical studies regarding primary and secondary
prevention, in order to effectively treat these patients.
ANTICOAGULATION AGENTS
Unfractionated heparin
Unfractionated heparin (UH) is a heterogenic mixture of glucose-amino-glycane
sulphate in sodium or calcium salt form. Its molecular weight varies
between 3 and 30kDa, and its plasma half-life time is short (60-90
minutes). Heparin forms a complex with a natural coagulation inhibitor,
antithrombin III, resulting in the inactivation of thrombin (IIa)
and the activated factors Xa and IXa.
Unfractionated heparin prevents the extension of the already formed
thrombus and facilitates its lysis by the intrinsic fibrinolytic system.
Furthermore, it inhibits platelet activity and increases blood vessel
permeability. It may be administrated by continuous intravenous drop
infusion, or subcutaneously.
Its action begins immediately after intravenous administration and
it presents important variability from patient to patient, because
of its heterogeneity and its not specific binding to plasma proteins
and to the endothelium. Its biocompatibility is poor (30%), especially
when given for prophylaxis. Patients who undergo heparin treatment
must be hospitalized, because the continuous intravenous administration
is preferable and also because the therapeutic response - which differs
from patient to patient - must be readjusted according to frequent
aPTT monitoring.
Several protocols are used to achieve the therapeutic goal. The most
familiar is the administration of a single intravenous dose of 5,000IU,
followed by continuous intravenous infusion of 1,280 IU/hour for the
next 6 hours, and then adjustment of the dose according to aPPT level.
The vast majority of patients present an obvious clinicolaboratory
improvement after a dose of 4,000IU/kg/day. After the first 48 hours,
per os anticoagulation agents (i.e. warfarin) are added. Five or 6
days later, when PT gets stabilized, heparin is discontinued and the
treatment continues with coumarin only. In order to control the effectiveness
of the treatment, the target aPTT is 1.5-2.5 times the healthy control
value. It is proven that by keeping aPTT at these levels, the risk
of venous thrombosis recurrence decreases, while for values over 2.5
times the healthy control, the bleeding risk increases.
During the last decade, heparin administration was very popular for
the treatment of disseminated intravascular coagulation. Today, this
use is questioned in many cases, because the hemorrhage syndrome exceeds
the thrombotic one.
The most common side-effect of heparin treatment is bleeding, the
incidence of which depends on the age, dose, administration route
etc. In case of bleeding or hypersensitivity, heparin can be neutralized
by 0.5-1.0mg protamin sulphate /100IU of heparin, administrated intravenously,
and slowly because of the hypotension risk. If bleeding continues,
despite protamin sulphate administration, fresh frozen plasma is used.
Another serious, life threatening side effect is heparin induced thrombocytopenia,
emerging in 1-3% of the treated patients. It emerges 5 to 9 days after
the treatment initiation and it is caused by antibody formation against
heparin complex and platelet factor 4.
When heparin induced thrombocytopenia is present (platelet count decrease
more than 30% compared to the count before treatment initiation),
heparin administration - even venous catheter heparin coating - must
be immediately discontinued, and substituted by another regimen. Unfortunately,
in this case, low molecular weight heparins become useless, because
of cross reaction potential, and the treatment of choice consists
in recombinant hirudin agents, drugs available in Greece. If the syndrome
shows up, it must be always mentioned in the patient's history. Emergence
of the syndrome after the 14th day of treatment is very rare.
Severe osteoporosis after longlasting administration, modest rise
of AST and ALT levels, and hypokalemia in patients with hyperaldosteronism
are other side effects.
Hypersensitivity to the drug, active bleeding (peptic ulcer), old
age, and previous heparin induced thrombocytopenia are the major contraindications.
Low
molecular weight heparins
The last 2 decades, a new class of anticoagulants, the low molecular
weight heparins (LMWHs), was invented, via chemical or enzymatic depolymerization
of unfractionated heparin.
These drugs have a molecular weight of 2-7kDa, and are administrated
mostly subcutaneously. They inhibit factor Xa and thrombin (IIa) in
a different way than the classic heparin: anti-Xa/anti IIa ratio varies
between 2:1 and 5:1, whereas the same ratio with classic heparin is
1:1. This enhanced proportion for factor Xa results to an increased
antithrombotic action and a weaker "hemorrhagic" one. Anti-Xa
activity presents a linear and inversely proportional relation with
their molecular weight. Low molecular weight heparins have a better
biocompatibility (60-90%) because of their much weaker and reversible
binding to proteins and cells, and of their longer half-life time,
compared to classic heparin. That's why they are administered once
or at most twice daily, in a standard dose (depending on the compound),
and usually there is no need for laboratory monitoring. Because of
their more specific action on factor Xa, they do not cause aPTT prolongation,
in contrast to heparin.
Several controlled studies have shown that their anticoagulant activity
during prevention and for some of them, during thromboembolic disease
treatment as well, is the same or even superior of that of heparin,
while they present fewer side effects, such as bleeding, thrombocytopenia,
or osteoporosis. Furthermore, they do not cross the placenta, like
classic heparin. Nowadays, low molecular weight heparins tend to replace
the intravenous administration of classic heparin, in most of the
cases of prevention or treatment, while they also give the potential
of outpatient treatment, with all the consequential benefits on the
treatment cost and life quality of the patient (table 2).
Deep venous thrombosis can be cured with a single dose of anti-Xa
175-200IU/kg of body weight or by two doses of 100IU/kg of body weight
each, for 5 days, followed by coumarins for 5-6 months. Laboratory
monitoring is essential in patients with severe renal failure, hepatic
failure, during pregnancy, in children and in patients with body weight
over 90kg, or under 50kg, as well as when the treatment lasts for
more than five days.
We must point out that LMWHs, unlike classic heparin, cannot be effectively
neutralized by protamin sulphate, therefore they are inappropriate
for surgical procedures that require extracorporeal circulation.
Longlasting anticoagulation treatment in patients with thrombophilic
states is carried out with per os anticoagulation agents. The LMWHs
are used only occasionally, in transient high risk situations, like
pregnancy, contraceptive use, immobilization, surgical operation,
or when per os anticoagulation treatment is difficult or dangerous,
as in patients with malignancies (risk of bleeding because of interactions
with other drugs), psychiatric patients, mentally retarded or elderly
persons, inhabitants in distant places etc.
In general surgery, LMWHs are widely used to prevent venous thromboembolism
in patients with thrombophilic states, or those who undergo high risk
operations. In these cases, the administration begins 12-24 hours
before the procedure and continues for 4 or, according to other writers,
6 weeks postoperatively. The dosage, as with classic heparin, is reduced
when given for prophylaxis, but doesn't require laboratory monitoring.
Hypersensitivity, active bleeding, or previous heparin induced thrombocytopenia
are the major contraindications.
In spite of their obvious similarity, LMWHs have differences regarding
their production, molecular weight, and anticoagulation action; therefore
they present differences in pharmacokinetics and pharmacodynamics
too. Consequently, each one of these drugs must be considered as a
distinct drug. Recently, a second LMWH generation was invented, with
a molecular weight of 3,600Da and anti Xa/anti IIa ratio equal to
8:1 (table 3).
Although LMWHs appear safe and effective in clinical practice, one
should consider the possibility of bleeding complications, which are
dose-depended. It is well known that classic laboratory tests are
not affected by LMWHs. On the other hand, we don't have a useful and
simple test for the dosage and effectiveness control of these drugs,
therefore their anticoagulation action in clinical practice is virtually
unmeasurable. Consequently, although they look safe, we must pay attention
when we use them.
Coumarin
anticoagulants
Coumarin anticoagulants, represented by warfarin, exert their action
in the liver, by inhibiting the production of vitamin K depended coagulation
factors (factors II, VII, IX, X, C and S proteins). That means that
they lead to a similar condition as the one caused by vitamin K insufficiency.
Warfarin is completely absorbed by the intestine and can be detected
one hour later in the plasma. Its maximum activity is exerted 48-72
hours after its administration, and lasts for 6 days. The initial
loading dose is 5-10mg for 2 days, followed by a maintenance dose
according to the PT count. In emergencies, it can be given together
with heparin for 5-6 days, till PT reaches the desirable level. Coadministration
with other drugs (corticosteroids, NSAIDs etc) may enhance or diminish
the anticoagulant effect.
As mentioned above, the anticoagulation treatment control is based
on PT monitoring, according to the clinical indications of each patient.
PT can be estimated using the INR (International Normalized Ratio)
method, according to the type: INR = patient PT/normal PTISI (International
Sensitivity Index). The goal varies: for example, in patients with
deep venous thrombosis, the desirable INR level is 2-3, in patients
with atrium fibrillation or a pig valve heterograft, it is 1,5-2,
while in patients with a metallic valve prosthesis, it is 3-4. The
minimum duration of coumarin treatment is a week, even if the INR
goal is fulfilled much earlier.
Although coumarin anticoagulants are useful drugs for venous thromboembolism,
they may cause bleeding; therefore repeated measurements of PT are
necessary. Yet, irrespectively of their prudent administration, they
may cause PT fluctuations, something very important, mainly when they
are used for months or for a lifetime. In case of severe hemorrhage,
vitamin K is administrated along with fresh frozen plasma. If the
hemorrhage is not severe, discontinuation of the drugs for 1 or 2
days is enough to improve hemostasis and stop bleeding.
Longlasting anticoagulation treatment is the major indication of these
drugs. Their contraindications include hepatic failure, vitamin K
insufficiency, severe renal failure, pregnancy, active bleeding (i.e.
peptic ulcer), old age, and NSAIDs use.
Hirudin and human antithrombin III
Hirudin is a potent anticoagulation agent deriving from the leech,
which inhibits directly and irreversibly the action of thrombin, without
the mediation of circulating antithrombin. The interest about hirudin
has risen the recent years, because we can produce it via DNA recombination.
A drug of this class, disposable in Greece, is desirudin; however
the indications and clinical experience are limited.
Pentasaccharides
The recent years, a new class of anticoagulation agents has developed,
the factor Xa indirect inhibitors, known as pentasaccharides, represented
by fondaparinux sodium (Arixtra).
Pentasaccharides, synthesized by the chemical bond between mono- or
di- saccharides, selectively bind to one and only plasma target, antithrombin
III, which is the major intrinsic inhibitor of blood coagulation.
Under normal circumstances, antithrombin III neutralizes factor Xa
among others. However, when the pentasaccharide binds to antithrombin
III, the chemical affinity of the latter to factor Xa increases to
a large extent, enhancing its inactivation. Inactivation of factor
Xa results in the inhibition of thrombin production (IIa), so blood
coagulation is halted at its focal point, preventing thrombus formation
or extension.
Pentasaccharides do not interact with platelets and do not affect
the classic laboratory tests (bleeding time, PT, aPTT). As with every
other anticoagulant, the potential of hemorrhagic complications should
always be taken into consideration.
Up to date, their use is advisable in venous thromboembolism prevention,
after major orthopaedic operations, where they seem to have a better
benefit/risk ratio. Extension of their use on other conditions is
under investigation, while further clinical experience is essential
in order to evaluate the side effects and the contraindications of
these drugs.
Antiplatelet drugs
The last 10 years, antiplatelet drugs are used more and more for the
prevention of arterial thromboembolism. There is data derived from
many studies that demonstrates their effectiveness in primary and
secondary prevention of acute myocardial infraction and ischemic stroke.
In contrary, these drugs don't seem to be as effective as LMWHs in
deep venous thrombosis prevention.
Aspirin and thienopyridines (ticlopidin and lately clopidogrel) are
administrated per os and most times in combination. They irreversibly
inhibit platelet activation and aggregation, and there is no antidote.
Aspirin, the most famous drug of this class, inhibits the platelet
activation and aggregation by irreversibly inactivating cycloxygenase,
a platelet enzyme that catalyzes arachidonic acid conversion into
thromboxane A2 (figure 2). Platelets, being anuclear, are incapable
of synthesizing new enzyme; therefore they remain inactive for the
rest of their lifetime. The time limits of hemostatic sufficiency
are not adequately determined, but it seems that they vary between
1 and 7 days, while in surgical operations they depend on the kind
of the operation. Patients who are under antiplatelet treatment need
more explicit instructions regarding preoperative management.
CONCLUSION
Although research and endless efforts on new anticoagulation agent
development go on, classic heparin and LMWHs still hold a central
position in thrombotic disorder management. Despite their two major
side effects, bleeding and thrombocytopenia, they remain the drugs
of choice for the prevention and treatment of venous thromboembolism.
Moreover, LMWHs may have additional indications: it seems that they
restrain the tumor growth, angiogenesis and metastasis, and that they
exert a favorable action upon ischemic strokes, as well as a direct
cell protective action on ischemic brain cells. These pleiotropic
properties are still under investigation.
REFERENCES
1. Μακρής Π.Ε. Αιμόσταση Ι, Θεσσαλονίκη 1998.
2. Μακρής Π.Ε. Αιμόσταση ΙΙ, Θεσσαλονίκη 1998.
3. Μακρής Π.Ε. Ηπαρίνες, Θεσσαλονίκη 1998.
4. Ioannidou-Papagiannaki E. Thrombophilic states in initial hemostasis.
Haema. 2000; Suppl., 51-55.
5. Makris P.E. Thrombophilic states. Haema 2000; Suppl., 48-50.
6. Makris P.E. Thrombophilic states due to coagulation disorders.
Haema. 2000; Suppl., 56-61.
7. Μελέτης Γ.Χ. Από το αιματολογικό εύρημα στη διάγνωση. Νηρέας 6η
έκδοση, Αθήνα 2003.
8. Katsarou O. Heparins. Haema. 2001; Suppl., 23-27.
9. Grouzi E.I. Acquired risk factors for venous thrombosis. Haema.
2001; Suppl.,33-43.
10. Interactive Anesthesia Library Ver. 2.0. Lippincott-Raven 1995.
11. HarrisonΥs Principles of Internal Medicine. 14th Edition, p.420-428,
915-928.
12. The Merck Manual, 17th Edition, sec. 11, Ch.131, Hemostasis and
Coagulation Disorders.
13. Guyton C.A. Textbook of Medical Physiology. 7th ed. Philadelphia.
WB Saunders, 1986.
14. Brenkel I.J. DVT prophylaxis in patients undergoing total hip
arthroplasty. Curr Orthop. 2001; 15, 356-363.
15. Samama M.M., Kher A. Anticoagulation: the Old and the New. Hemostaseologie.
1998; 18,S27-32.
16. Hirsh J., Levine N. M. Low molecular weight heparin. Blood. 1992;
79, 1-17.
17. Hirsh J., Warkentin T.E., Shaughnessy S. G. et al. Heparin and
Low molecular weight heparin: mechanisms of action, pharmacokinetics,
dosing considerations, monitoring, efficacy and safety. Chest. 2001;
suppl.1, 64S-94S.
18. Hyers T.M., Agnelli G., Hull R.D. et al. Antithrombotic therapy
for venous thromboembolic disease. Chest. 2001; suppl.1, 176S-193S.
19. Kakkar V.V., Gebska M., Kadziola Z. et al. Low molecular weight
heparin in the acute and long term treatment of deep vein thrombosis.
J Thromb Haemost. 2003; 89, 674-80.
20. Breddin K.H. LMWHs in the prevention of deep vein thrombosis in
general surgery. Semin Thromb Hemost. ; 25, Suppl. 3, 83-89.
21. Rosentaal R.F. Risk factors for Venus Thrombotic Disease. Thromb
Haemost. 1999; 82, 610-619.
22. Kickler T.S. Platelet biology - An Overview. TATM 2004; 6, 27-31.
23. Murphy M.F. Platelet Transfusion Thresholds. TATM 2004; 6, 32-33.
24. Anderson F.A, Spencer F.A. Risk factors for venus thromboembolism.
Circulation. 2003;107, I9-I16.
25. Kucher N., Kohler H.P., Dornhfer T. et al. Accuracy of D-Dimer/fibrinogen
ratio to predict pulmonary embolism: a prospective diagnostic study.
J Thromb Haemost. 2003; 1, 708-13.
26. Gerotziafas G.T., Samama M.M., Elalamy I. Heparin induced thrombocytopenia:
Pathogenesis, epidimiology, diagnosis and management. Haema. 2004;
7(1), 22-34.
27. Turpie G.G., Gallus A.S., Hoek J.A. A synthetic pentasaccharide
for the prevention of deep-vein thrombosis after total hip replacement.
N Engl J Med. 2001; 344, 619-625.
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