MUDr. Monika Laššánová
THROMBOSIS
= INTRAVITAL
COAGULATION OF
BLOOD IN VESSELS OR HEART

Incidence of venous
thromboembolism – 0,1%
– 0,01% among people appr. 20 years old
– 1,0% among people appr. 60 years old
Patogenesis of thrombosis =
(1856) – Wirchow´s trias
Most important
factors
activation of COAGULATION =  activity
of TXA2,  activity of anticoagulant sys. (AT
III),  levels or activation of coagulation f. ...
slow BLOOD FLOW = stasis, travelling by
airplain, heart failure, paraplegia,
immobilisation, pregnancy, varixes, operations,
fractures ...
deffect of the VESSEL WALL – by damage
of endothelium  production of PGI2 =>
proaggregatory activity

Arterial thrombi = white
– Thrombocytes
– Tight adherence => obturation = periferal
ischemia
– Prevention = antiaggregants

Venal thrombi = red
– Fibrinal tail
– Weak adherence => risk of embolisation
– Prevention = anticoagulants

Recent thrombi
– Are removed by thrombolytics = fibrinolytics
Clinical conditions increasing the
risk of thrombosis










arterial:
atherosclerosis
smoking
hypertension
diabetes mellitus
 LDL
TAG
+ family history
deffect of left
high doses of synthetic
oestrogens
polyglobulia …











venous:
general surgery
orthopedical surgery
trauma, malignities,
sepsis
immobilisation
congestive  failure
nephrotic syndrome
obesity
varixes
postphlebitic syndrome
oestrogens
pregnancy
Different!
thrombophlebitis
phlebothrombosis
THROMBOPHLEBITIS



primarily caused by mechanical, microbial or
chemical irritation  inflammation of vessel
wall  secondarily thrombosis – thrombus
firmly adhering to vessel wall  embolisation
only occasionally
clinically: local syndrome = inflammated
superficial vein, can be palpated, skin above is
red, warm, with significant pain and sensitivity,
no big oedema, no general symptoms or only
subfebrility
complications: (rarely) early – spreading of
inflammation to deep venous sys., late – sec.
chronic venous disease = postphlebitic
syndrome
Deep
Venous Thrombosis =
Phlebothrombosis
+ it´s most dangerous complication =
pulmonary embolisation (PE) – belong
(after IHD and hypertension) among the most
common CV diseases in hospitalised patients


PE - 10% of autopsial material
85% of PE is caused by deep venous
thrombosis
PHLEBOTHROMBOSIS (PT)




deep veins of lower extremities
primarily obturation of vein with thrombus
and secondarily inflammatory reaction
released thrombus = embolus
clinically: often asymptomatic – or little
symptoms = dg. only 30-50%
– oedema – asymmetric
– pain – spontaneous, compressive – mostly while hanging
down the limb, spasms, feeling of strain
– symptoms of blocked blood flow from the limb (erythemapale skin- cyanosis)
– collaterals –forming after several days of obturation
as compensatory mechanism,
– systemic symptoms – not specific (if there is no PE)
Clinical symptoms
Lower limb:
 pain
 oedema ( 1,5 cm)
 posit. palp.
maneuvers
(Homans,
Lőwenberg,...)
 enlarged superficial
collaterals
 change of skin color
and temperature
Complications of PT
1.
EMBOLUS - released thrombus, carried
by the blood flow– mainly to pulmonary
artery  pulmonary embolisation
2.
Repeated small embolisation (successive)
=>chronic pulmonary hypertension =>
cor pulmonale chronicum
3.
Chronic venous insufficiency
Diagnosis of
DVT
+
- Kontrastná venografia
- Impedančná pletysmogr.
Goals of the treatment of
PT
save the patient´s life
 avoid occurance of pulmonary
embolism
 initialise / speed-up resolution of
thrombus/embolus
 accelerate symptom regression
 prevention of recurrency

Prevention of PT
nonpharmacologic
 limb elevation
(15-20º)
 early mobilisation
after surgery
 regular exercise
with legs in bed
 elastic, special
tights
 walking
pharmacologic
 low doses of
heparin (5000 IU)
(before operation,
during
postoperation
period at risk
patients), LMWH,
fondaparinux
Antithrombotics
Antiaggregatory drugs
Anticoagulants
Thrombolytics
(inh. platelets)
(inh. coagulatory factors) (dissolve thrombus)
Antithrombotics



antiaggregants (antiplatelet drugs)
= block FORMATION of thrombus
anticoagulants = block GROWTH
of thrombus
thrombolytics (fibrinolytics) =
DISSOLUTION of already formed
thrombus
Equilibrium Between Coagulation and Fibrinolysis
Antiplatelet
drugs
Anticoagulants
Thrombolytics
Anticoagulants


DRUGS ARTIFICIALLY INDUCING
“DISTURBANCES“ OF BLOOD
COAGULATION
GOAL: TO PREVENT THROMBOSIS
OR TO PREVENT FURTHER GROWTH
OF THROMBUS
Coagulation Cascade
ANTICOAGULANTS
DIRECT

Indirect inhibitors of
thrombin and factor Xa
– Heparin (IIa : Xa)
– LMWH (IIa : Xa)

enoxa-, fraxi-, dalte-, revi-
– Fondaparinux ( Xa)

Direct inhibitors of thrombin
– Hirudin, bivalirudin, desirudin
– Dabigatran – p.o. = gatrans

Direct inhibitors of factor Xa


Rivaroxaban – p.o. = xaban
Apixaban – p.o.
INDIRECT




Warfarin
Etylbiskumacetate
Phenprocoumon
Dicumarol
Fondaparin
Idraparin
indirect
anticoag.
f. II., VII.,
IX., X
Rivaroxaban
Apixaban
Dabigatran
Hirudin, Desirudin
indirect inhibitors
of thrombin
HEPARIN






INDIRECT INHIBITOR OF THROMBIN
SUBSTANCE PRESENT ALSO IN OUR BODY (MAST
CELLS), USED FROM 1916
MW = 3 - 30 000 D (15 000 D)
produced from intestinal mucosa of porcine or cattle
lungs => quantified in IU
heterogenous mucopolysacharid, anion (´-´ charge)
ACTIVITY IS DEPENDENT FROM THE PRESENCE OF
A N T I T H R O M B I N III.
Mechanism of Action of
Heparin
-
+
1000x
H inactivates already activovated coagulation factors IIa, Xa
Effects of heparin




Anticoagulatory activity
Weak inhibition of platelet function -  adhesivity and
aggregation
Weak stimulation of fibrinolysis
releasing of lipoproteinic lipase  clearing of lipemic
plasma
anti - IIa
: anti –Xa
=
1 : 1
Advantages of heparin



acts very quickly or immediately, but
shortly
has massive effect
it has an antidote - protamine
Disadvantages of heparin






only injection (i.v., s.c.),
i.m. – no, irregular absorption and haematoma
T1/2 is variable, prolonged with  dose,
unpredictable anticoagulant effect – wide
variability (for different binding to proteins
and unpredictable absorption after s.c. admin.)
possibility of disease reactivation after stopping
administration (rebound efect)
control: aPTT (reflects effect to thrombin) –
extension to 1,5-2,5 x of norm
aPTT = 1,5-2,5 x normal
Indications of heparin





Prophylaxis of vein thrombosis
Th. of deep vein thrombosis and
pulmonary embolia
Acute coronary syndroms (Th)
Obturation of peripheral arteries
Hemodialysis, DIC
ADR of heparin


Bleeding
H. induced thrombocythopenia (HIT) –
less serious, early f.; more serious f.
after 5 and  days

Allergy

Reversible alopecia

Possible osteoporosis in case of longterm use
LOW-MOLECULARWEIGHT HEPARINS
(LMWH)

INDIRECT INHIBITORS OF
THROMBIN

smaller molecules, MR  5 000 D

INHIBIT MORE ANTI-Xa


PRODUCED BY CHEMIC OR ENZYMATIC
DEPOLARISATION OF H
ACTIVITY DEPENDS ON THE PRESENCE
OF A N T I T H R O M B I N III
Mechanism of LMWH
Action
anti - IIa : anti -Xa
1 : 2-4
Indications of LMWH




Prevention of thromboembolia
(abdominal and orthopedic surgery)
Prevention of ischemic complications
at acute coronary syndroms (unstable
angina pectoris, NSTEMI myocardial
infarction)
Therapy of phlebothrombosis and
pulmonary embolism
Hemodialysis
Advantages of LMWH




Predictable response to dose according
to weight
Longer plasmatic half-life (1-2 s.c.
injections per day)
Lower risk of thrombocytopenia,
bleeding and thrombosis
Heparin and LMWH can be
administered during pregnancy and
lactation
Fondaparin
Idraparin
indirect
anticoag.
f. II., VII.,
IX., X
Rivaroxaban
Apixaban
Dabigatran
Hirudin, Desirudin
direct inhibitors of
thrombin
FONDAPARINUX






INDIRECT INHIBITOR OF THROMBIN
SYNTHETIC PENTASACHARID SPECIFICALLY
INHIBITING FACTOR Xa
MR = 1 700 D
activity depends on the presence of
I T H R O M B I N III
ANT
doesn´t have the long chain needed for
bridging to ATIII. and f. IIa
300X  ability to inactivate f. Xa
MA of Fondaparinux
Advantages of
Fondaparinux






 of bleeding complications
administered s.c.
relatively long lasting effect
highly predictable effect
doesn´t influence aggregation of platelets
 doesn´t induce thrombocythopenia
disadvantage = price, no antidote
Fondaparin
Idraparin
Indirect
anticoag.
f. II., VII.,
IX., X
Rivaroxaban
Apixaban
Dabigatran
Hirudin, Desirudin
direct inhibitors of
thrombin
HIRUDIN, BIVALIRUDIN




PRIAMY INHIBÍTOR TROMBÍNU
 špecificky IREVERZIBILNE
INAKTIVUJE TROMBÍN BEZ potreby
prítomnosti AT III.
je prirodzený inhibítor zrážania krvi
získavaný z pijavíc (hirudo medicinalis)
vyrába sa DNA REKOMBINANTNOU
technikou
HIRUDIN, BIVALIRUDIN




DIRECT INHIBITOR OF THROMBIN
 SPECIFICALLY IRREVERSIBLY
INACTIVATES THROMBIN WITHOUT
THE NEED FOR AT III
NATURAL INHIBITOR OF BLOOD
COAGULATION GAINED FROM LEECH
(HIRUDO MEDICINALIS)
PRODUCED BY DNA RECOMBINANT
TECHNOLOGY
MA
HIRUDIN BINDS TO THROMBIN
AND irreversibly FORMS AN INACTIVE
COMPLEX
BIVALIRUDIN
- synthetic fragment of hirudin
- reversible inhibition of thrombin
- duration of action appr. 25 min.
Advantages of Hirudin








doesn´t bind to plasma proteins  predictable
anticoagulant effect
indicated for patients with thrombocythopenia
after heparin who need AC th.
bivalirudin – indicated in AMI, as an alternative
to heparin/LMWH
inactivates not binded thrombin, but also
thrombin binded to fibrin in thrombus  
anticoagulatory effectivity
inhibits formation of fibrin
inhibits activation of thrombocytes = mild
antiaggregatory effect
prevents activation of f. V, VIII, XI and XIII
peg-hirudin – 1 times per day, s.c.
Newer peroral anticoagulants
Dabigatran- direct inhibitor of thrombin; approved
for prevention of thrombosis after hip
or knee surgery; atrial fibrillation (prevention
of thr.)
Rivaroxaban- direct inhibitor of factor Xa;
approved for prevention of
thrombosis after hip or knee surgery; atrial
fibrillation (prevention of thr.)
DABIGATRAN (g a t r a n s)


Potent, competitive, direct, reversible inhibitor
of thrombin
Ximelagatran
hepatotoxicity
Inhibits:
– Free thrombin
– Thrombin binded to fibrin
– Tr. aggregation induced by thrombin






Potent, predictable anticoag. effect
!!! p.o., rapid onset + long duration
Few interactions with drugs and food
No need for regular coagulation controlls
I: primary prevention of thromboembolic dis.
!!! No antidote, high price !!!
Fondaparin
Idraparin
Indirect
anticoag.
f. II., VII.,
IX., X
Rivaroxaban
Apixaban
Dabigatran
Hirudin, Desirudin
direct inhibitors of
thrombin
RIVAROXABAN, APIXABAN
(x a b a n s)






Direct inhibitors of f. Xa
Selective, competitive, potent
Inhibits f. Xa – free, - bound with
prothrombin, - also in fibrin clot (5x)
Anticoag.effect is directly proportional to the
level in plasma and last only during this
time!!
!!! p.o., fast onset of action
No complicated metabolism => drug
Fondaparin
Idraparin
indirect
anticoag.
f. II., VII.,
IX., X
Rivaroxaban
Apixaban
Dabigatran
Hirudin, Desirudin
direct inhibitors of
thrombin
COUMARINS

INDIRECT
p.o. ANTICOAGULANTS =
„ANTAGONISTS“ OF VITAMIN K  factors
II., VII., IX., X.
DOESN´T ACT ANTICOAGULATORY IN VITRO
Warfarin – the most widely used coumarin

Other use – poison for gnawers
Mech. of Action Warfarin



inhibition of epoxidreductase, decreased
formation of active form of vitamin K 
no activation of -carboxylase and no
carboxylation of -glutamin residuums of
factors II., VII., IX., X. + inhibition
of protein C and S carboxylation

coumarins antagonise liver synthesis of f.
II, VII, IX and X =>
formed molecules are incomplete,
unfunctional, can´t get activated and
don´t participate in coagulation
Pharmacokinetics of
warfarin



EFFECT STARTS WITH LATENCY OF 1224 HOURS, MAXIMAL EFFECT AFTER
2-3 days
AFTER discontinuation the effect
REMAINS 4-5 days
100% BA, 97% binding to plasma
proteins many interactions
Interactions of Warfarin
pharmacokinetic
- high binding to plasma proteins
- metabolised by CYP 450
 pharmacodynamic
- groceries with high vitamin K content can
reduce effect
- antibiotics that suppress bacteria in GIT that
produce vitamin K can increase the effect

Amount of vit. K in selected
groceries/food
(v μg/100 g)
calabresse
celery
cabbage
dill
cole
chive
parsley
270
300
817
400
300
380
700
spinach
500
sauerkraut 1540
oliv. oil
400
soja oil
542
sunflow. oil
10
green tea
712
chicken
300
DISADVANTAGES of
warfarin



latency of effect (2-3days)  not suitable
for therapy of a c u t e conditions => used
for prophylaxis
Need for control of therapy and correct dosage
according to INR (2,0-4,5 – according to
indication)
Testing of INR every 3-4 weeks
INR

International normalised ratio
patient´s Quick time

INR =
Quick time of standard

Prophylaxis of thrombosis INR = 2,0 – 2,5

Therapy of thrombosis INR = 2,0 – 3,0

In pat. with antiphospholipid sy. INR = 3,0 –
4,5
Selfmonitoring
INR
INDICATIONS


Most commonly longterm –> after previous
heparinisation
Prevention of venous
(and sometimes arterial)
thrombosis (AF, dilatative
CMP, artificial valves,
after deep v. thr. and
pulmonary embolia,...)
Advantage: 1times per day
per os => also at home
KI



conditions with possible
bleeding
pregnancy – teratogen!
low compliance of the p.
ADR of coumarins





Bleeding
Teratogen
Bleeding at new born whose mother
takes warfarin and brest-feeds
Dyspepsia
Skin necrosis
Treatment of warfarin
induced bleeding
-
at mild bleeding – lower the dose or
stop administration
-
at more severe bleeding – vitamin K
-
at massive bleeding – frozen plasma,
prothrombin concentrate, full blood
Coumarin skin necrosis
IDEAL
ANTITHROMBOTIC:








p.o. (also parenteral at acute situations)
fast onset of action
high efficacy
withoutDoes
need of not
monitoring
exist
low interindividual
variability
low interaction potential
has an antidote
good pharmacoeconomy
Equilibrium Between Coagulation and Fibrinolysis
Schematic Illustration of
Fibrinolysis
Abbreviations: tPA – tissue plasminogen activator; PAI –
plasminogen activator inhibitor; PLG - plasminogen; AP antiplasmin; FDPs – fibrin(ogen) degradation products.
Scheme and the position of the fibrinolysis activators or
inhibitors
FIBRINOLYTICS =
thrombolytics





cause/accelerate thrombus dissolution by
degradation of fibrin
have strict indications and contraindications,
because they  risk of bleeding 4x
treatment must be combined with anticoagulant
and/or antiaggregatory th.
control: thrombin time – 2-3x extended
indications: myocardial infarction, massive
pulmonary embolism, DVT

1st generation:
– Streptokinase
– Urokinase
– Anistreplase: plasminogen-streptokinase activator
complex (APSAC)

2nd generation:
– Alteplase (tPA, tissue plasminogen activator)

3rd generation:
– Reteplase (rPA, recombinant. plasm. activator)
– Lanoteplase (nPA)
– Tenecteplase(TNK, recombinant. plasm. activator)
– Staphylokinase
Classification according to
Fibrin Specificity
not fibrin specific
not selective



Streptokinase
Antistreptase
Urokinase
fibrin specific
selective




Activation of plasmin is
systemic, are degraded
also other proteins =>
ADRs
Alteplase
Reteplase
Lanoteplase
Tenecteplase
Activate plasmin on the top of
fibrin and less in circulation
=> lower risk of systemic
bleeding
Indications
AMI (STEMI)
 massive pulmonary embolia
 acute obturation of an artery
 deep vein thrombosis (not always)
 acute thrombotic stroke



In patients with ischaemic stroke we need to apply
thrombolysis till 3 hours after beginning of ischaemia.
At pulmonary embolia, the time interval is much longer
– even several days after beginning, but the risk of
bleeding to pulmonary parenchyma is higher then.
ADRs


frequently - bleeding
including bleeding to CNS (appr. 3-4
cases /1000 treated patients)

febrile reactions

hypotension

allergic reaction after streptokinase or
anistreplase, even anaphylactic shock
Absolute
Contraindications


stroke in last 6 months, history of
bleeding to the brain
serious trauma or operation in the last
3 weeks

bleeding to GIT

dissected aneurysm of aorta

known bleeding defect
I. GENERATION: NONFIBRIN-SELECTIVE
AGENTS



STREPTOKINASE
INDIRECT activator of fibrinolytic
system
the oldest fibrinolytic /1933/, low price
Mechanism of Action of
Streptokinase
1:1
DISADVANTAGES of STK





activates also the circulating plasminogen
from -haemolytic streptococcus  antigenic  is
possible to premedicate- i.v. hydrocortisone before
administration of STK
can cause febrile reaction
effect can be reduced by streptococcal infection or
previous thrombolysis with STK
it can be risky to administer repeatedly – possible
occurence of
 allergic reaction
 doesn´t have to be effective, will react with already
formed circulating antibodies
 don´t administer from 5th day till 12th month after
previous aplication
II. GENERATION:
THROMBOLYTICS
FIBRIN-SELECTIVE







ALTEPLASE
DIRECT activator of fibrinolytic system
high selectivity for plasminogen on the top of
thrombus (on the top of thrombus activates
plasminogen 100x stronger than in circulation)
natural protease from endothelium of vessels (tPA)
produced by recombinant technology
short T1/2 => in continual infusion
not antigenic => Ø allergies, possibility of
repeated administration
III. GENERATION:
THROMBOLYTICS FIBRINSELECTIVE
- better pharmacokinetics
- fibrinolytic effect
- smaller resistency to natural inhibitors
- fibrin specificity with better safety profile
RETEPLASE





Single-chain mutant of natural tPA
Produced by cultures of E. coli
Not antigenic
Extended T1/2 => in 2 bolus doses à 30 min.
=> possibility of pre-admission treatment of
AMI
Preferably activates plasminogen binded to
fibrin => increased fibrinolytic activity
TENECTEPLASE



3-multiple mutant of tPA =>
Even longer T1/2 than reteplase +  fibrin selectivity
As one i.v. bolus during 5-10 sec.
Acute ST-Elevation Myocardial Infarction (STEMI)
Percentage of successful vessel recanalisation (A) and mortality in 30 days (B)
in clinical studies of thrombolytic therapy of acute myocardial infarction.
Guideline of Therapy of
DVT - 1

Heparin
– Bolus: 80 IU/kg
– Infusion: 18 IU/kg
 reached
faster therapeutic values of aPTT as at
- Nowadays
prevention of thromboembolic disease
fixedfor
scheme
fondaparinux
be -given
 aPTT =can
1,5also
- 2,5
3,0 x of normal values
- 1 x per
day s.c.
 aPTT every 6 hours and dose adjustment
- No need for monitoring
 control of blood count: 3. - 5. day

LMWH
– adequate replacement
– same effect, 1 – 2 x daily, s.c.
– nowadays PREFERABLY used!!!
Guideline of Therapy of
DVT - 2
After reaching effective anticoagulation
with heparin, long-term p.o.
warfarinisation is started
giving warfarin on 1st day (5mg) ~ INR
ending heparin on 5th day of warfarinisation


Goal: INR 2,0 - 3,0
Lenght of warfarinisation is questionable
– at least 3 months after the first
episode of thrombosis