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