Trattamento del tromboembolismo

Prof. Stefania Basili

Centro Aterotrombosi – Divisione di I Clinica Medica

(Direttore Prof. Francesco Violi),

tromboembolismo venoso: gestione della

anticoagulazione.

VTE is under recognized and

goes

When diagnosis is based on clinical signs and symptoms:

• <50% of all cases of No tests to

predict who will

TERZA PIU’ COMUNE CAUSA DI MORTE CARDIOVASCO

VTE is the silent killer

goes undiagnosed

• <50% of all cases of fatal PE are detected prior to death

• 80% of cases of DVT are clinically silent

predict who will have a VTE

CARDIOVASCOLARE

• PREVENTION IS KEY!!

Tromboembolia venosa

Triade di Virchow

Ipercoagulabilità

AcquisitaEreditaria

TrombosiTrombosi

1821-1902

Rudolf Virchow’s Triad

Virchow R. In Gesammelte Abhandlugen zur Wissenschaftlichen Medizin, 1856;

Frankfurt: Staatsdruckerei

Rosendaal FR. Lancet 1999; 353:1167–1173

Stasi

Lesione vascolare

Acquisita

Acquisita

Trombosivenosa

Trombosivenosa

Risk FactorsRisk Factors

�� CHFCHF

�� MalignancyMalignancy

�� ObesityObesity

�� Estrogen/OCPEstrogen/OCP

�� Venous StasisVenous Stasis

�� Prior DVTPrior DVT

�� Age > 70Age > 70

�� Prolonged Bed RestProlonged Bed Rest�� Estrogen/OCPEstrogen/OCP

�� Pregnancy (esp post Pregnancy (esp post partum)partum)

�� Lower ext injuryLower ext injury

�� CoagulopathyCoagulopathy

�� Prolonged Bed RestProlonged Bed Rest

�� Surgery requiring > Surgery requiring > 30 minutes general 30 minutes general anesthesiaanesthesia

�� Orthopedic SurgeryOrthopedic Surgery

Definizione di Tromboembolismo Venoso Definizione di Tromboembolismo Venoso

� TROMBOSI VENOSA PROFONDA A. INFERIORI

� EMBOLIA POLMONARE

PROSSIMALE:

vene iliache, vena femorale, vena poplitea

Arterioscler Thromb Vasc Biol 2009;29:298-310

DISTALE:

vene profonde del polpaccio

(peroniere e tibiali)

� TROMBOSI VENOSA PROFONDA A. SUPERIORI

Woundantithrombinsantithrombins

factor Xa

thrombin prothrombin

fibrinogen

fibrin(monomers)

Wound

platelet activation

release thrombin release ofof ADP generation thromboxane A2

aspirinaspirin

Interventi terapeutici sulla modulazione

dell’emostasi

Attivazione piastrinica ATTIVAZIONE COAGULATORIA

fibrin(monomers)

fibrin(polymer)

vitamin K-dependentγ-carboxylation ofGlu residues

coumarinscoumarins

A2

Further activation of platelets

Platelet aggregation

ADPADPreceptorreceptorantagonistsantagonists

GP IIb-IIIareceptorantagonists

CLOT

Taken from Desai UR (2004) Med. Res. Rev. 24, 151-181.

UFH

Come agiscono le eparine?

LMWH

FondaparinuxFondaparinux ::

synthetic synthetic selective inhibitors of factor selective inhibitors of factor XaXa

• Five saccharide units

• Synthetic

• Highly selective for AT3

• Factor Xa inhibition

• No binding with plasma proteins

• No effect on platelet function

• No thrombocytopenia

1941 First clinical use (short term)1944 Use of dicumarol in long-term

prophylaxis after MI1948 Synthesis of warfarin as a rat poison1954 Warfarin introduced in clinical practice

Vitamin K antagonists

Sweet clover

Melilotus alba

VKA LMWH SC UFH IV UFH Fondaparinux

MECCANISMO Antagonista

vitamina K

Inibitore

fattore Xa e

IIa

Inibitore

fattore Xa e IIa

Inibitore

fattore Xa e

IIa

Inibitore fattore

Xa

SOMMINISTRAZIONE OS 1/DIE SC 1-2/DIE SC 2/DIE IV SC 1/DIE

POSOLOGIA Secondo INR Secondo Secondo PTT Secondo PTT 7.5 mg tra 50-POSOLOGIA Secondo INR Secondo

Peso

Secondo PTT Secondo PTT 7.5 mg tra 50-

100 kg

Embricatura iniziale

con eparina

SI - - - NO

MONITORAGGIO SI (INR) NO SI (PTT) SI (PTT) NO

FUNZIONE RENALE Attento

monitoraggio

Riduzione

dose se

GFR < 30

Attento

monitoraggio

Attento

monitoraggio

No con GFR <

30, cautela < 50

CONTRO Interazioni

farmaco e dieta,

monitoraggio

Trombocito

penia da

eparina

(HIT)

HIT

Osteoporosi

monitoraggio

stretto;

ospedalizzazi

one, HIT

NO studi a

lungo termine

Antidoto Vitamina K No Protamina Protamina No

New Oral anticoagulants and their targets in the coagulation pathwaysNew Oral anticoagulants and their targets in the coagulation pathways

�� Nuovi farmaci introdotti nelle ultime linee guida CHEST 2012:Nuovi farmaci introdotti nelle ultime linee guida CHEST 2012:

VIIaXIa

XIIaTissue factor

Rivaroxaban(Xarelto) 10 mg/die

Rivaroxaban Dabigatran

Posologia 10 mg o.d. (no peso) 220 mg o.d. (no peso)

Indicazioni scheda tecnica italiana:

Rivaroxaban e Dabigatran:

Prevenzione TEV in chirurgia sostitutiva elettiva dell’anca o del

ginocchio

Xa

IXa

Fibrinogen Fibrin clot

Factor II(prothrombin) Dabigatran

(Pradaxa) 220 mg/die

Posologia 10 mg o.d. (no peso) 220 mg o.d. (no peso)

150 mg bid se FA

Monitoraggio No No

Antidoto No No

Funzione renale No in GFR < 15

(cautela < 30)

No in GFR < 30

Interazioni Antimicotici (no

fluconazolo) e

antiretrovirali

No Ketoconazolo,

itraconazolo, tacrolimus,

ciclosporina, cautela

amiodarone, chinidina o

verapamil

ginocchio

Dabigatran:

Prevenzione di ictus e embolia sistemica in FA non valvolare ad alto

rischio

TREATMENT of VENOUS THROMBOEMBOLISMTREATMENT of VENOUS THROMBOEMBOLISM

�� Both Pulmonary embolism and DVT are Both Pulmonary embolism and DVT are treated the sametreated the same

�� An adequate level of anticoagulation is An adequate level of anticoagulation is �� An adequate level of anticoagulation is An adequate level of anticoagulation is essentialessential

�� Patients will have variable effect of Patients will have variable effect of anticoagulantsanticoagulants

�� Treatment requires monitoringTreatment requires monitoring

�prevenire l’estensione locale della trombosi venosa e l’embolizzazione

� rimuovere l’ostruzione al flusso ematico polmonare e migliorare l’emodinamica

Obiettivi della terapia

� rimuovere l’ostruzione al flusso ematico polmonare e migliorare l’emodinamica

�prevenire le complicanze a distanza (sindrome post-trombotica-ipertensione polmonare )

Flow chart trattamento

embolia

2008;358:1037-52.

embolia polmonare

ANTICOAGULAZIONE ControindicazioniANTICOAGULAZIONE Controindicazioni

1.1. grave emorragia in atto, grave emorragia in atto, 2.2. recente intervento neurochirurgico o emorragia SNC,recente intervento neurochirurgico o emorragia SNC,3.3. grave diatesi emorragicagrave diatesi emorragica

Controidicazioni assolute

Heparin and LowHeparin and Low--MolecolarMolecolar--Weight Heparin. Chest 2004;126:188SWeight Heparin. Chest 2004;126:188S--203S203S

1.1. ipertensione arteriosa di grado severo non controllata, ipertensione arteriosa di grado severo non controllata, 2.2. trauma cranico recente, trauma cranico recente, 3.3. sanguinamento gastrointestinale recente,sanguinamento gastrointestinale recente,4.4. retinopatia proliferativa diabetica,retinopatia proliferativa diabetica,5.5. piastrinopenia <100.000/mm3piastrinopenia <100.000/mm3

Controidicazioni relative

General RecommendationsACCP Conference on Antithrombotic and Thrombolytic Therapy (2008)

We recommend that renal function be considered

when making decisions about the use and/or the dose

of LMWH, fondaparinux, and other antithrombotic

drugs that are cleared by the kidneys, particularly in

the elderly patients, patients with diabetes mellitus,

and those at high risk for bleeding (Grade 1A). and those at high risk for bleeding (Grade 1A).

Depending on the circumstances, we recommend one

of the following options in this situation: avoiding the

use of an anticoagulant that bioaccumulates in the

presence of renal impairment, using a lower dose of

the agent, or monitoring the drug level or its

anticoagulant effect (Grade 1B).

(The DIRECT Study (n=138) Arch Intern Med. 2008;168(16):1805The DIRECT Study (n=138) Arch Intern Med. 2008;168(16):1805--1812)1812)

Antithrombotic Therapy for Venous

Thromboembolic Diseases

-----

Antithrombotic Therapy and Prevention Antithrombotic Therapy and Prevention

of Thrombosis: ACCP Evidence-Based

Clinical Practice Guidelines, 9th ed

Copyright: American College of Chest Physicians 2012©

Terapia eparinica

Sospensione

5-7 gg

1. Come impostare la terapia iniziale?

Tp parenterale

Warfarin 5 mg INR > 2.0 (per 24 h)

Terapia anticoagulante orale

4-7 gg

Choice of Initial Anticoagulant Regimen in Patients With Proximal DVT /PE

In patients with ACUTE DVT of the leg, we suggest LMWH or

fondaparinux over IV UFH (Grade 2C) and over SC UFH

(Grade 2B for LMWH; Grade 2C for fondaparinux)..

In patients with ACUTE PE, we suggest LMWH or

fondaparinux over IV UFH (Grade 2C for LMWH; Grade 2B for

fondaparinux) and over SC UFH (Grade 2B for LMWH; Grade 2C

for fondaparinux).

Timing of Initiation of VKA and Associated Duration of

Parenteral Anticoagulant Therapy

In patients with ACUTE DVT of the leg, we recommend early

initiation of VKA (eg, same day as parenteral therapy is started)

over delayed initiation, and continuation of parenteral

anticoagulation for a minimum of 5 days and until the

international normalized ratio (INR) is 2.0 or above for at least

24 h (Grade 1B).

In patients with ACUTE PE, we recommend early initiation of

VKA (eg, same day as parenteral therapy is started) over

delayed initiation, and continuation of parenteral

anticoagulation for a minimum of 5 days and until the INR is

2.0 or above for at least 24 h (Grade 1B).

• Clinical scenario/patient risk factors

• Thrombophilia work up

Determine Recurrence Risk of VTE

• Thrombophilia work up

• Residual vein thrombosis on Ultrasound

• D-dimer testing

Risk of VTE After Cessation of Therapy

Risk of VTE Recurrence After Cessation of VTE

Risk factorRisk factor 1 st yr1 st yr Next 5 yrsNext 5 yrs

Distal DVTDistal DVT 3%3% <10%<10%

MinorMinor

TransientTransient

3%3% 10%10%

MajorMajor 55--6%6% 15%15%MajorMajor

TransientTransient

55--6%6% 15%15%

UnprovokedUnprovoked At least 10%At least 10% 30%30%

RecurrentRecurrent >10%>10% >30%>30%

Major risk factors: major surgery, major trauma, cancerMinor risk factors: OCP, HRT, pregnancy, airline travel, non-major surgery, minor traumaAssociated medical diseases- IBD, nephrotic syndrome, cancer, sickle cell, multiple myeloma, Waldentrom’s, MGUS, Bechets, P.Vera, APLS

Provoked

TERAPIA 3 MESI SEMPRE

(indipendentemente dal rischio emorragico)

TEV provocata

STOP

TEV NON provocata

Terapia a lungo

termine

Duration of AnticoagulationDuration of Anticoagulation

1)Transient risk (e.g., surgery, immobilization, estrogen use, trauma): 3 months.Shorter treatment periods are associated with a higher rate of recurrence and are not recommended.

2) Idiopathic or medical risk: 6-12 months.- Patients with documented antiphospholipid antibodies or two or more thrombophilic conditions should be treated for 12 months and considered for indefinite anticoagulation therapy.-Patients with documented deficiency of antithrombin, protein C or S, factor V -Patients with documented deficiency of antithrombin, protein C or S, factor V Leiden, prothrombin 20210 mutation, homocysteinemia, or high factor VIII conditions should be treated for 6-12 months and considered for indefinite anticoagulation therapy.

3) Recurrent disease or continued risk factors: indefinite.- Patients with cancer should be initially treated for three to six months with LWMH and anticoagulation therapy should be indefinitely or until the cancer is resolved.- Patients with two or more episodes of documented DVT should receive anticoagulation therapyindefinitely.

7th American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy

The optimal duration of oral anticoagulation in

patients with idiopathic venous thromboembolism

is uncertain.

Optimal duration of TAO

PROLONG Study

Cumulative Incidence of and Hazard Ratios (HRs) for Main Outcomes

Palareti G et al. N Engl J Med 2006;355:1780-1789

is uncertain.

Testing of D-dimerlevels may

play a role in the assessment of the need for prolonged

anticoagulation

F.C.S.A.

2009

TVP/EP idiopatica o fattori di rischio persistenti (trombofilia): 3-6 mesi

Se trombofilia grave o multipla: 1 anno/indefinitamenteSe trombofilia grave o multipla: 1 anno/indefinitamente

Se D-DIMERO +++ dopo 1 mese: ripresa trattamento

Se recidive: indefinitamente

Neoplastici: lungo termine fino alla remissione della neoplasia. Valutare utilizzo LMWH a dosi terapeutiche per almeno 6 mesi.

Choice of Anticoagulant Regimen for Long-term Therapy

In patients with DVT of the leg/PE and no cancer, we suggest

VKA therapy over LMWH for long-term therapy (Grade 2C).

For patients with DVT/PE and no cancer who are not treated

with VKA therapy, we suggest LMWH over dabigatran or

rivaroxaban for long-term therapy (Grade 2C). rivaroxaban for long-term therapy (Grade 2C).

Choice of Anticoagulant Regimen for Long-term Therapy

In patients with DVT of the leg and cancer, we suggest LMWH

over VKA therapy (Grade 2B).

In patients with DVT and cancer who are not treated with

LMWH, we suggest VKA over dabigatran or rivaroxaban for

long-term therapy (Grade 2B).

Remarks (3.3.1-3.3.2): Choice of treatment in patients with and without cancer is

sensitive to the individual patient's tolerance for daily injections, need for laboratory sensitive to the individual patient's tolerance for daily injections, need for laboratory

monitoring, and treatment costs.

LMWH, rivaroxaban, and dabigatran are retained in patients with renal impairment,

whereas this is not a concern with VKA.

Treatment of VTE with dabigatran or rivaroxaban, in addition to being less burdensome to

patients, may prove to be associated with better clinical outcomes than VKA and LMWH

therapy. When these guidelines were being prepared (October 2011), postmarketing

studies of safety were not available. Given the paucity of currently available data and that

new data are rapidly emerging, we give a weak recommendation in favor of VKA and

LMWH therapy over dabigatran and rivaroxaban, and we have not made any

recommendations in favor of one of the new agents over the other.

Long-term Treatment of Patients With PE

In patients with PE and cancer, we suggest LMWH over VKA

therapy (Grade 2B). In patients with PE and cancer who are

not treated with LMWH, we suggest VKA over dabigatran or

rivaroxaban for long-term therapy (Grade 2C).

Remarks (6.6-6.7): Choice of treatment in patients with and without cancer is

sensitive to the individual patient's tolerance for daily injections, need for sensitive to the individual patient's tolerance for daily injections, need for

laboratory monitoring, and treatment costs. Treatment of VTE with dabigatran or

rivaroxaban, in addition to being less burdensome to patients, may prove to be

associated with better clinical outcomes than VKA and LMWH therapy. When

these guidelines were being prepared (October 2011), postmarketing studies of

safety were not available. Given the paucity of currently available data and that

new data are rapidly emerging, we give a weak recommendation in favor of

VKA and LMWH therapy over dabigatran and rivaroxaban, and we have not

made any recommendation in favor of one of the new agents over the other.

Why are heparins the preferred treatmentin Trousseau’s syndrome?

Copyright ©2007 American Society of Hematology. Copyright restrictions may apply. Varki, A. Blood 2007;110:1723-1729

Heparin has several antithrombotic

mechanisms that warfarin lacks

2013

Embolizzazione rara

(estensione nel 15-25%)

N.B. Unico caso

Fattori di rischio per estensione:

- D-dimero positivo

- sede limitrofa a vena prossimale

- estensione del trombo >5 mmN.B. Unico caso

da non trattare

subito!

Ecodoppler a 2

settimane

Estensione?

- estensione del trombo >5 mm

- storia di TEV

- fattore provocativo non reversibile o neoplasia

- ospedalizzazione

NO:

no terapiaSI: terapia per

3 mesi

Centro Aterotrombosi

Divisione di Prima Clinica Medica

Direttore: Prof. Francesco Violi

Sapienza- Università di Roma

Azienda Policlinico Umberto I

Centro Aterotrombosi

Divisione di Prima Clinica Medica

Direttore: Prof. Francesco Violi

Sapienza- Università di Roma

Azienda Policlinico Umberto I

Centro AterotrombosiCentro AterotrombosiTelefoni: 06-49972249

06-49974678 Call center – 3270421933

Centro TAO 8.30-10.30 senza appuntamento

Piano Terra