MUDr. Monika Laššánová MUDr. Monika Laššánová
Dec 23, 2015
MUDr. Monika LaššánováMUDr. Monika Laššánová
THROMBOSISTHROMBOSIS
= INTRAVITAL COAGULATION OF BLOOD IN VESSELS OR HEART
Incidence of venous thromboembolism – 0,1%0,1%– 0,01% among people appr. 20 years
old– 1,0% among people appr. 60 years old
Patogenesis of Patogenesis of thrombosis =thrombosis =(1856) – Wirchow´s trias(1856) – Wirchow´s trias
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
Most
importa
nt
facto
rs
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 Clinical conditions increasing the risk of thrombosisof thrombosis
arterial:arterial: atherosclerosis smoking hypertension diabetes mellitus LDL TAG + family history deffect of left high doses of synthetic
oestrogens polyglobulia …
venous:venous: general surgery orthopedical surgery trauma, malignities,
sepsis immobilisation congestive failure nephrotic syndrome obesity varixes postphlebitic syndrome oestrogens pregnancy
Different!Different!
thrombophlebitisthrombophlebitis
phlebothrombosisphlebothrombosis
THROMBOPHLEBITISTHROMBOPHLEBITIS 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
DeepDeepVenous Thrombosis = Venous Thrombosis = PhlebothrombosisPhlebothrombosis+ 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)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
(erythema- pale skin- cyanosis) – collaterals –forming after several days of obturation as compensatory mechanism, – systemic symptoms – not specific (if there is no PE)
Clinical symptomsClinical symptoms
Lower limb:Lower limb: pain oedema ( 1,5 cm) posit. palp.
maneuvers (Homans, Lőwenberg,...)
enlarged superficial collaterals
change of skin color and temperature
Complications of PTComplications 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 Diagnosis ofofDVT DVT
+-Kontrastná venografia-Impedančná pletysmogr.
Goals of the treatment Goals of the treatment of PTof PT
save the patient´s life avoid occurance of
pulmonary embolism initialise / speed-up resolution of
thrombus/embolus accelerate symptom regression prevention of recurrency reduce long term mortality
Prevention of PTPrevention of PT
nonpharmacologinonpharmacologicc
limb elevation (15-20º) early mobilisation
after surgery regular exercise
with legs in bed elastic, special
tights walking
pharmacologicpharmacologic 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)
AntithromboticsAntithrombotics
antiaggregants (antiplatelet drugs) = block FORMATION of thrombus
anticoagulantsanticoagulants = block GROWTH of thrombus
thrombolytics thrombolytics (fibrinolytics) = DISSOLUTION of already formed thrombus
Equilibrium Between Coagulation and Fibrinolysis
Antiplatelet drugs
Anticoagulants
Thrombolytics
AnticoagulantsAnticoagulants
DRUGS ARTIFICIALLY INDUCING “DISTURBANCES“ OF BLOOD COAGULATION
GOAL: TO PREVENT THROMBOSIS OR TO PREVENT FURTHER GROWTH OF THROMBUS
Coagulation CascadeCoagulation Cascade
ANTICOAGULANTSANTICOAGULANTSDIRECTDIRECT
Indirect inhibitors of thrombin and factor Xa– Heparin Heparin (IIa : Xa)– LMWH LMWH (IIa : Xa)
enoxa-, fraxi-, dalte-, revi-enoxa-, fraxi-, dalte-, revi-
– FondaparinuxFondaparinux ( Xa)
Direct inhibitors of thrombin– Hirudin, bivalirudin, desirudinHirudin, bivalirudin, desirudin– DabigatranDabigatran – p.o. = – p.o. = gatransgatrans
Direct inhibitors of factor Xa
RivaroxabanRivaroxaban – p.o. = – p.o. = xabanxaban Apixaban Apixaban – p.o.– p.o.
INDIRECTINDIRECT WarfarinWarfarin
EtylbiskumacetateEtylbiskumacetate PhenprocoumonPhenprocoumon DicumarolDicumarol
indirect anticoa
g.f. II., VII.,
IX., X
Rivaroxaban
Apixaban
FondaparinIdraparin
indirect inhibitors of
thrombin
DabigatranHirudin, Desirudin
HEPARINHEPARIN
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 Mechanism of Action of Heparinof Heparin
1000x
H inactivates already activovated coagulation factors IIa, Xa
-
+
Effects of heparinEffects 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 : 1anti - IIa : anti –Xa = 1 : 1
Advantages of heparinAdvantages of heparin
acts very quickly or immediately, but shortly
has massive effect it has an antidote - protamine
Disadvantages of Disadvantages of heparinheparin 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 heparinIndications 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 heparinADR 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
long-term use
LOW-MOLECULAR-LOW-MOLECULAR-WEIGHT HEPARINS WEIGHT HEPARINS (LMWH)(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 Mechanism of LMWH ActionAction
anti - IIa : anti -Xa 1 : 2 - 4
anti - IIa : anti -Xa 1 : 2 - 4
Indications of LMWHIndications of LMWH
Prevention of thromboembolia Prevention of thromboembolia (abdominal and orthopedic surgery)(abdominal and orthopedic surgery)
Prevention of ischemic complications at Prevention of ischemic complications at acute coronary syndroms (unstable acute coronary syndroms (unstable angina pectoris, NSTEMI myocardial angina pectoris, NSTEMI myocardial infarction)infarction)
Therapy of phlebothrombosis and Therapy of phlebothrombosis and pulmonary embolismpulmonary embolism
HemodialysisHemodialysis
Advantages of LMWHAdvantages of LMWH
Predictable response to dose Predictable response to dose according to weightaccording to weight
Longer plasmatic half-life (1-2 s.c. Longer plasmatic half-life (1-2 s.c. injections per day)injections per day)
Lower risk of thrombocytopenia, Lower risk of thrombocytopenia, bleeding and thrombosisbleeding and thrombosis
Heparin and LMWH can be Heparin and LMWH can be administered during pregnancy and administered during pregnancy and lactationlactation
indirect anticoa
g.f. II., VII.,
IX., X
Rivaroxaban
Apixaban
FondaparinIdraparin
direct inhibitors of thrombin
DabigatranHirudin, Desirudin
FONDAPARINUXFONDAPARINUX
INDIRECT INHIBITOR OF THROMBIN SYNTHETIC PENTASACHARID
SPECIFICALLY INHIBITING FACTOR Xa MR = 1 700 D activity depends on the presence of A N
T I T H R O M B I N III doesn´t have the long chain needed for
bridging to ATIII. and f. IIa 300X ability to inactivate f. Xa
MA of FondaparinuxMA of Fondaparinux
Advantages of Advantages of FondaparinuxFondaparinux 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
Indirect anticoa
g.f. II., VII.,
IX., X
Rivaroxaban
Apixaban
FondaparinIdraparin
direct inhibitors of thrombin
DabigatranHirudin, Desirudin
HIRUDIN, BIVALIRUDINHIRUDIN, 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, BIVALIRUDINHIRUDIN, 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
MAMAHIRUDIN 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 HirudinAdvantages 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 DABIGATRAN (g a t r a n s)s) Potent, competitive, direct, reversible
inhibitor of thrombin 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 !!!
Indirect anticoa
g.f. II., VII.,
IX., X
Rivaroxaban
Apixaban
FondaparinIdraparin
direct inhibitors of thrombin
DabigatranHirudin, Desirudin
RIVAROXABAN, RIVAROXABAN, APIXABANAPIXABAN
(x a b a n s)(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
interactions
indirect anticoa
g.f. II., VII.,
IX., X
Rivaroxaban
Apixaban
FondaparinIdraparin
direct inhibitors of thrombin
DabigatranHirudin, Desirudin
COUMARINS COUMARINS
I N D I R E C T 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 - Mech. of Action - WarfarinWarfarin
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 Pharmacokinetics of warfarinwarfarin EFFECT STARTS WITH LATENCY OF
12-24 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 Amount of vit. K in selected groceries/food groceries/food (v μg/100 g)
calabressecalabresse 270270 spinachspinach 500500
celerceler yy 300300 sauerkraut sauerkraut 1540 1540
cabbagecabbage 817817 oliv. oiloliv. oil 400400
dill dill 400400 soja oilsoja oil 542542
cole cole 300 300 sunflow. oilsunflow. oil 1010
chivechive 380380 green tea green tea 712712
parsleyparsley 700700 chickenchicken 300300
DISADVANTAGES of DISADVANTAGES of warfarinwarfarin 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
INRINR
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
INDICATIONSINDICATIONS Most commonly long-
term –> after previous heparinisation
Prevention of venous (and sometimes arterial) thrombosis (AF, dilatative CMP, artificial valves, after deep v. thr. and pulmonary embolia,...)
KIKI conditions with
possible bleeding pregnancy –
teratogen! low compliance of the
p.
Advantage: 1times per day per os => also at home
ADR of coumarinsADR 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 IDEAL ANTITHROMBOTIC:ANTITHROMBOTIC: p.o. (also parenteral at acute situations) fast onset of action high efficacy without need of monitoring low interindividual variability low interaction potential has an antidote good pharmacoeconomy
Does not exist
Equilibrium Between Coagulation and Fibrinolysis
Abbreviations: tPA – tissue plasminogen activator; PAI – plasminogen activator inhibitor; PLG - plasminogen; AP - antiplasmin; FDPs – fibrin(ogen) degradation products.
Schematic Illustration of Fibrinolysis
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
Scheme and the position of the fibrinolysis activators or inhibitors
1st generation: 1st generation: – Streptokinase
– Urokinase
– Anistreplase: plasminogen-streptokinase activator complex (APSAC)
2nd generation:2nd generation: – Alteplase (tPA, tissue plasminogen activator)
3rd generation:3rd generation: – Reteplase (rPA, recombinant. plasm. activator)
– Lanoteplase (nPA)
– Tenecteplase(TNK, recombinant. plasm. activator)
– Staphylokinase
Classification according Classification according to Fibrin Specificityto Fibrin Specificitynot fibrin specific not fibrin specific
not selectivenot selective
Streptokinase Antistreptase Urokinase
Activation of Activation of plasmin is plasmin is systemicsystemic, are , are degraded also other degraded also other proteins => ADRsproteins => ADRs
fibrin specificfibrin specific
selectiveselective
AlteplaseAlteplase Reteplase Lanoteplase Tenecteplase
Activate Activate plasmin on the plasmin on the top of fibrin top of fibrin and less in and less in circulation => lower circulation => lower risk of systemic risk of systemic bleedingbleeding
IndicationsIndications 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.
ADRsADRs
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 Absolute ContraindicationsContraindications
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: I. GENERATION: NON-NON-FIBRIN-SELECTIVE FIBRIN-SELECTIVE AGENTSAGENTS
STREPTOKINASE
INDIRECT activator of fibrinolytic system
the oldest fibrinolytic /1933/, low price
Mechanism of Action Mechanism of Action of Streptokinaseof Streptokinase
1:1
DISADVANTAGES of DISADVANTAGES of STK 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: II. GENERATION: THROMBOLYTICS THROMBOLYTICS FIBRIN-SELECTIVEFIBRIN-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: III. GENERATION: THROMBOLYTICS FIBRIN-THROMBOLYTICS FIBRIN-SELECTIVESELECTIVE
- 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. Price of 1 dose appr. 1 000 €
Percentage of successful vessel recanalisation (A) and mortality in 30 days (B) in clinical studies of thrombolytic therapy of acute myocardial infarction.
Acute ST-Elevation Myocardial Infarction (STEMI)
Guideline of Therapy Guideline of Therapy of DVT - 1of DVT - 1
HeparinHeparin– Bolus: 80 IU/kg– Infusion: 18 IU/kg
reached faster therapeutic values of aPTT as at fixed scheme
aPTT = 1,5 - 2,5 - 3,0 x of normal values aPTT every 6 hours and dose adjustment control of blood count: 3. - 5. day
LMWHLMWH– adequate replacement– same effect, 1 – 2 x daily, s.c.– nowadays PREFERABLY used!!!PREFERABLY used!!!
- Nowadays for prevention of thromboembolic disease fondaparinux can also be given-1 x per day s.c.-No need for monitoring
Guideline of Therapy Guideline of Therapy of DVT - 2of DVT - 2After reaching effective anticoagulation
with heparin, long-term p.o. warfarinisation is started
giving warfarin on 1st daygiving warfarin on 1st day (5mg) (5mg) ~~ INR INR
ending heparin on 5th day ofending heparin on 5th day of warfarinisation warfarinisation
Goal: INR 2,0 - 3,0 Lenght of warfarinisation is
questionable – at least 3 months after the first episode of thrombosis