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PHLEBOTHROMBOSIS. 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.

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PHLEBOTHROMBOSIS

MUDr. Monika Laššánová


Thrombosis
THROMBOSIS

= INTRAVITAL

COAGULATION OF

BLOOD IN VESSELS OR HEART

  • Incidenceofvenousthromboembolism– 0,1%

    • 0,01% amongpeopleappr. 20 yearsold

    • 1,0% amongpeopleappr. 60 yearsold


Patogenesis of thrombosis 1856 wirchow s trias
Patogenesisofthrombosis=(1856) – Wirchow´strias

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 important factors


  • 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


Clinicalconditionsincreasingthe risk ofthrombosis

arterial:

  • atherosclerosis

  • smoking

  • hypertension

  • diabetes mellitus

  •  LDL

  • TAG

  • + familyhistory

  • deffectofleft

  • highdosesofsyntheticoestrogens

  • polyglobulia …

venous:

  • generalsurgery

  • orthopedicalsurgery

  • trauma, malignities, sepsis

  • immobilisation

  • congestivefailure

  • nephrotic syndrome

  • obesity

  • varixes

  • postphlebitic syndrome

  • oestrogens

  • pregnancy


Different
Different!

thrombophlebitis

phlebothrombosis


Thrombophlebitis
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
DeepVenousThrombosis= 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
PHLEBOTHROMBOSIS (PT)

  • deepveinsoflowerextremities

  • primarilyobturationofveinwiththrombus and secondarilyinflammatoryreaction

  • releasedthrombus = embolus

  • clinically:oftenasymptomatic – or littlesymptoms = dg. only 30-50%

    • oedema – asymmetric

    • pain – spontaneous, compressive – mostlywhilehangingdownthelimb, spasms, feelingofstrain

    • symptomsofblockedbloodflowfromthelimb (erythema- pale skin- cyanosis)

    • collaterals –formingafterseveraldaysofobturation

      ascompensatorymechanism,

    • systemicsymptoms – notspecific (ifthereis no PE)


Clinical symptoms
Clinicalsymptoms

Lowerlimb:

  • pain

  • oedema( 1,5 cm)

  • posit. palp. maneuvers(Homans, Lőwenberg,...)

  • enlargedsuperficialcollaterals

  • changeof skin color and temperature


Complications of pt
Complicationsof PT

  • EMBOLUS - released thrombus, carried by the blood flow– mainly to pulmonary artery pulmonary embolisation

  • Repeated small embolisation (successive) =>chronic pulmonary hypertension => cor pulmonale chronicum

  • Chronic venous insufficiency


Diagnosisof

DVT

  • +

  • Kontrastná venografia

  • Impedančná pletysmogr.


Goals of the treatment of pt
Goalsofthetreatmentof 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 pt

nonpharmacologic

limb elevation

(15-20º)

earlymobilisationaftersurgery

regularexercisewithlegs in bed

elastic, specialtights

walking

pharmacologic

lowdosesofheparin(5000 IU) (beforeoperation, duringpostoperationperiodat risk patients), LMWH, fondaparinux

Preventionof PT


Antithrombotics

Antiaggregatory drugs Anticoagulants Thrombolytics

(inh. platelets) (inh. coagulatory factors) (dissolve thrombus)


Antithrombotics
Antithrombotics

  • antiaggregants(antiplateletdrugs) = blockFORMATIONofthrombus

  • anticoagulants= blockGROWTH ofthrombus

  • thrombolytics(fibrinolytics) = DISSOLUTIONofalreadyformedthrombus


EquilibriumBetweenCoagulation and Fibrinolysis


Antiplateletdrugs

Anticoagulants

Thrombolytics


Anticoagulants
Anticoagulants

  • DRUGS ARTIFICIALLY INDUCING “DISTURBANCES“ OF BLOOD COAGULATION

  • GOAL: TO PREVENT THROMBOSIS OR TO PREVENT FURTHER GROWTH OF THROMBUS


CoagulationCascade


ANTICOAGULANTS

DIRECT

INDIRECT

  • Indirectinhibitorsofthrombin and factorXa

    • Heparin (IIa : Xa)

    • LMWH (IIa : Xa)

      • enoxa-, fraxi-, dalte-, revi-

    • Fondaparinux( Xa)

  • Directinhibitorsofthrombin

    • Hirudin, bivalirudin, desirudin

    • Dabigatran – p.o. = gatrans

  • DirectinhibitorsoffactorXa

    • Rivaroxaban – p.o. = xaban

    • Apixaban– p.o.

  • Warfarin

  • Etylbiskumacetate

  • Phenprocoumon

  • Dicumarol


Fondaparin

Idraparin

Rivaroxaban

Apixaban

indirectanticoag.

f. II., VII., IX., X

Dabigatran

Hirudin, Desirudin

indirectinhibitorsofthrombin


Heparin
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
MechanismofActionofHeparin

-

+

1000x

H inactivates already activovated coagulation factors IIa,Xa


Effects of heparin
Effectsofheparin

  • 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
Advantagesofheparin

  • acts very quickly or immediately, but shortly

  • has massive effect

  • it has an antidote -protamine


Disadvantages of heparin
Disadvantagesofheparin

  • 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
Indicationsofheparin

  • 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
ADR ofheparin

  • Bleeding

  • H. inducedthrombocythopenia(HIT) – lessserious, earlyf.; more seriousf. after5 and  days

  • Allergy

  • Reversiblealopecia

  • Possibleosteoporosis in caseoflong-termuse


Low molecular weight heparins lmwh
LOW-MOLECULAR-WEIGHT 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
Mechanismof LMWH Action

anti - IIa : anti -Xa

1 : 2 - 4


Indications of lmwh
Indicationsof LMWH

  • Preventionofthromboembolia (abdominal and orthopedicsurgery)

  • Preventionofischemiccomplicationsatacutecoronarysyndroms (unstableanginapectoris, NSTEMI myocardialinfarction)

  • Therapyofphlebothrombosis and pulmonaryembolism

  • Hemodialysis


Advantages of lmwh
Advantagesof LMWH

  • Predictableresponse to doseaccordingtoweight

  • Longerplasmatichalf-life (1-2 s.c. injections per day)

  • Lower risk ofthrombocytopenia, bleeding and thrombosis

  • Heparin and LMWH canbeadministeredduringpregnancy and lactation


Fondaparin

Idraparin

Rivaroxaban

Apixaban

indirectanticoag.

f. II., VII., IX., X

Dabigatran

Hirudin, Desirudin

directinhibitorsofthrombin


Fondaparinux
FONDAPARINUX

  • 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 fondaparinux
MA ofFondaparinux


Advantages of fondaparinux
AdvantagesofFondaparinux

  •  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

Rivaroxaban

Apixaban

Indirectanticoag.

f. II., VII., IX., X

Dabigatran

Hirudin, Desirudin

directinhibitorsofthrombin


HIRUDIN, BIVALIRUDIN

  • PRIAMY INHIBÍTOR TROMBÍNU

  •  špecificky IREVERZIBILNEINAKTIVUJE TROMBÍNBEZ potreby prítomnosti AT III.

  • je prirodzený inhibítor zrážania krvi získavaný z pijavíc (hirudo medicinalis)

  • vyrába sa DNA REKOMBINANTNOU technikou


Hirudin bivalirudin
HIRUDIN, BIVALIRUDIN

  • DIRECT INHIBITOR OF THROMBIN

  •  SPECIFICALLY IRREVERSIBLYINACTIVATES THROMBINWITHOUT THE NEED FOR AT III

  • NATURAL INHIBITOR OF BLOOD COAGULATION GAINED FROM LEECH (HIRUDO MEDICINALIS)

  • PRODUCED BY DNA RECOMBINANT TECHNOLOGY


MA

HIRUDINBINDS 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
AdvantagesofHirudin

  • 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.


DABIGATRAN (g a t r a n s)

  • Potent, competitive, direct, reversibleinhibitorofthrombin

  • Inhibits:

    • Freethrombin

    • Thrombinbinded to fibrin

    • Tr. aggregationinduced by thrombin

  • Potent, predictableanticoag. effect

  • !!! p.o., rapidonset + longduration

  • Fewinteractionswithdrugs and food

  • No needforregularcoagulationcontrolls

  • I: primarypreventionofthromboembolicdis.

  • !!! No antidote, highprice !!!

Ximelagatran

hepatotoxicity


Fondaparin

Idraparin

Rivaroxaban

Apixaban

Indirectanticoag.

f. II., VII., IX., X

Dabigatran

Hirudin, Desirudin

directinhibitorsofthrombin


RIVAROXABAN, APIXABAN(x a b a n s)

  • Directinhibitorsof f. Xa

  • Selective, competitive, potent

  • Inhibits f. Xa – free, - boundwithprothrombin, - also in fibrinclot(5x)

  • Anticoag.effectisdirectlyproportional to thelevel in plasma and lastonlyduringthistime!!

  • !!! p.o.,fastonsetofaction

  • No complicatedmetabolism => druginteractions


Fondaparin

Idraparin

Rivaroxaban

Apixaban

indirectanticoag.

f. II., VII., IX., X

Dabigatran

Hirudin, Desirudin

directinhibitorsofthrombin


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 widelyusedcoumarin

  • Otheruse– poisonforgnawers


Mech of action warfarin
Mech. ofAction - 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
Pharmacokineticsofwarfarin

  • 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
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


Amountof vit. K in selectedgroceries/food(v μg/100 g)

calabresse270 spinach 500

celer y 300 sauerkraut 1540

cabbage 817oliv. oil 400

dill 400 sojaoil 542

cole 300 sunflow. oil 10

chive 380 green tea 712

parsley 700chicken 300


DISADVANTAGES ofwarfarin

  • latency of effect (2-3days) not suitablefor 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



INDICATIONS

  • Most commonlylong-term –> afterpreviousheparinisation

  • Preventionofvenous (and sometimesarterial) thrombosis(AF, dilatative CMP, artificialvalves, afterdeep v. thr. and pulmonaryembolia,...)

KI

  • conditionswithpossiblebleeding

  • pregnancy – teratogen!

  • lowcomplianceofthe p.

Advantage: 1times per day per os => also at home


ADR ofcoumarins

  • Bleeding

  • Teratogen

  • Bleeding at new born whose mother takes warfarin and brest-feeds

  • Dyspepsia

  • Skin necrosis


Treatment of warfarin induced bleeding
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



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.)


EquilibriumBetweenCoagulation and Fibrinolysis


Schematic Illustration of Fibrinolysis

Abbreviations: tPA – tissue plasminogen activator; PAI – plasminogen activator inhibitor; PLG - plasminogen; AP - antiplasmin; FDPs – fibrin(ogen) degradation products.


Fibrinolytics thrombolytics

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-streptokinaseactivatorcomplex (APSAC)

  • 2nd generation:

    • Alteplase(tPA, tissueplasminogenactivator)

  • 3rd generation:

    • Reteplase (rPA, recombinant. plasm. activator)

    • Lanoteplase (nPA)

    • Tenecteplase(TNK, recombinant. plasm. activator)

    • Staphylokinase


Classification according to fibrin specificity
Classificationaccording to FibrinSpecificity

notfibrinspecific

notselective

fibrinspecific

selective

Alteplase

Reteplase

Lanoteplase

Tenecteplase

Activateplasmin on the top offibrinand less in circulation => lower risk ofsystemicbleeding

  • Streptokinase

  • Antistreptase

  • Urokinase

    Activationofplasminissystemic, are degradedalsootherproteins => ADRs


Indications
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
AbsoluteContraindications

  • 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 non fibrin selective agents
I. GENERATION: NON-FIBRIN-SELECTIVE AGENTS

  • STREPTOKINASE

  • INDIRECT activator of fibrinolytic system

  • the oldest fibrinolytic /1933/, low price


Mechanism of action of streptokinase
MechanismofActionofStreptokinase

1:1


Disadvantages of stk
DISADVANTAGES of STK

  • activatesalsothecirculatingplasminogen

  • from-haemolyticstreptococcusantigenicispossible to premedicate- i.v. hydrocortisonebeforeadministrationof STK

  • cancausefebrilereaction

  • effectcanbereduced by streptococcalinfection or previousthrombolysiswithSTK

  • itcanbe risky to administerrepeatedly– possibleoccurenceof

    allergicreaction

    doesn´thave to beeffective, willreactwithalreadyformedcirculatingantibodies

     don´tadministerfrom 5th daytill 12th monthafterpreviousaplication


Ii generation thrombolytics fibrin selective
II. GENERATION: THROMBOLYTICS FIBRIN-SELECTIVE

  • ALTEPLASE

  • DIRECTactivatoroffibrinolyticsystem

  • highselectivityforplasminogen on the top ofthrombus (on the top ofthrombusactivatesplasminogen100x strongerthan in circulation)

  • naturalproteasefromendotheliumofvessels (tPA)

  • produced by recombinanttechnology

  • shortT1/2 => in continualinfusion

  • notantigenic=> Øallergies, possibilityofrepeatedadministration


Iii generation thrombolytics fibrin selective
III. GENERATION: THROMBOLYTICS FIBRIN-SELECTIVE

  • 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 dosesà 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 €


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
GuidelineofTherapyof DVT - 1

  • Heparin

    • Bolus: 80 IU/kg

    • Infusion: 18 IU/kg

      • reachedfastertherapeuticvaluesofaPTTasatfixedscheme

      • aPTT = 1,5 - 2,5 - 3,0 x ofnormalvalues

      • aPTTevery6 hoursanddoseadjustment

      • controlofbloodcount: 3. - 5. day

  • LMWH

    • adequatereplacement

    • sameeffect, 1 – 2 x daily, s.c.

    • nowadaysPREFERABLY used!!!

  • - Nowadaysforpreventionofthromboembolicdiseasefondaparinuxcanalsobegiven

  • 1 x per days.c.

  • No needfor monitoring


Guideline of therapy of dvt 2
GuidelineofTherapyofDVT - 2

Afterreachingeffectiveanticoagulationwithheparin, long-termp.o. warfarinisationisstarted

givingwarfarin on 1st day(5mg) ~INR

ending heparin on 5th dayofwarfarinisation

  • Goal: INR 2,0 - 3,0

  • Lenghtofwarfarinisationisquestionable – atleast3 monthsafterthefirstepisodeofthrombosis


ad