inflamatia in tvp

Inflamatia in TVPInflamatia in TVP

Alexandru Andritoiu, MDSp. Militar Craiova

Tromboza venoasa profunda Tromboza venoasa profunda (TVP)(TVP)

• Provocata• Neprovocat

a• Proximal

a• DistalaCOMPLICATII

EP

Deces

Recurenta TVP/EP

Sindrom post-trombotic

Ulcer venos

Vene profunde

Flux sanguin normal

TVP Embol

Kahn S. Blood 2009; 114: 4624-4631. Kahn S. Blood review 2002. 16: 155-165.

TVP vs TromboflebitaTVP vs Tromboflebita

FlebiteleTromboflebita Tromboflebita

superficialasuperficiala• trombus endovenos +

inflamatie adiacenta in vv superficiale

TVPTVP• trombus in vv profunde • adesea nu asociaza

inflamatie (manifesta clinic)

Tromboflebita superficialaTromboflebita superficiala• Varice hidrostatice• Semne cutanate inflamatorii• Tratament cu AINS (topice)

Boala trombo-embolicaBoala trombo-embolica

Boala trombo-embolica• TVP• EP • Morbiditate

• Mortalitate• Impact economic

Subiecte propuseSubiecte propuse

1) Mecanismele inflamatorii in TVP acuta

2) Bolile inflamatorii si riscul TVP3) Cum putem combate inflamatia in

TVP?4) Inflamatia si rezolutia trombusului 5) Sdr. post-trombotic si inflamatia

??

1) Mecanismele inflamatorii in TVP acuta

2) Bolile inflamatorii si riscul TVP3) Cum putem combate inflamatia in

TVP?4) Inflamatia si rezolutia trombusului 5) Sdr. post-trombotic si inflamatia

Prakash Saha et al. Arterioscler Thromb Vasc Biol. 2011;31:506-512

(1) Activation of the endothelium (EC; red cell) generates intravascular danger signals, which guide leukocytes to areas of inflammation and induces TF production. (2) Upregulation of adhesion

molecules on endothelium mediate PMN recruitment, and TF generates thrombin, activating platelet (Plt) deposition and converting fibrinogen to cross-linked fibrin (Fb) that entraps the main RBC

mass.

Inflamatia si trombogeneza venoasa

Arterioscler Thromb Vasc Biol. 2011;31:506-512

TVP acutaTVP acuta• PMN (+++)• Rol in remodelarea peretelui venos

Cascada aderarii leucocitare Cascada aderarii leucocitare in raspunsul inflamatorin raspunsul inflamator

D. Neil Granger and Elena Senchenkovaş 2010 by Morgan & Claypool Life Sciences.

ImmediatImmediat dupa injuria dupa injuria endotelialendoteliala, celulelea, celulele endotelial endotelialee sisi plaplachetele sunt chetele sunt activate activate,, declansand declansand expresiexpresiaa molecule moleculelor de lor de

adeziune celularaadeziune celulara

Thomas W. Wakefield et al. Arterioscler Thromb Vasc Biol. 2008;28:387-391

Rolul microparticulelorRolul microparticulelor

Thomas W. Wakefield et al. Arterioscler Thromb Vasc Biol. 2008;28:387-391

Levels of P-selectin have been found to be elevated in DVT patients, and are decreased

with heparin treatmentBiomarker levels of soluble P-selectin, and D-

dimer in an algorithm to diagnose DVT: Sensitivity 73%Specificity 81%

TVP idiopatica este in relatie cu raspunsul TVP idiopatica este in relatie cu raspunsul inflamator sistemic si cresterea nivelelor inflamator sistemic si cresterea nivelelor

serice ale markerilor circulatori ai serice ale markerilor circulatori ai disfunctiei endotelialedisfunctiei endoteliale

• 49 pts. TVP primara

• Markeri de inflamatie: • high sensitive C-reactive protein (hs CRP), • IL-6, IL-8,TNF-a, • Markeri ai disfunctiei endoteliale• von Willebrand factor (vWF) • P-selectin• vascular adhesion molecule (VCAM-1)

Jezovnik M. K. , Poredos P. International Angiology 2010;29: (3):226-31

CONCLUSION: Patients with idiopathic venous thrombosis have increased levels of circulating markers of inflammation and blood markers of endothelial dysfunction. Higher levels of both groups of markers indicate that patients in the stable phase of the disease have an increased systemic inflammatory response. The interrelationship between inflammatory markers and markers of endothelial dysfunction favour the hypothesis that inflammation could be involved in the etiopathogenesis of idiopathic venous thrombosis.

J Vasc Surgery 2002;35:701-706

Clinical Chemistry 2015:61:2:3013-316

Predictori ai TVP• FR• IL-6• IL-8• CRP

Whether these markers may be useful in the diagnosis of VTE is as

yet uncertain

International Journal of General Medicine 2015:8 37–40

Relatia dintre volumul Relatia dintre volumul trombusului si testele trombusului si testele

inflamatoriiinflamatorii • TVP v. poplitee• TVP vv musculare

gambiere• Markeri inflam (+)• Risc scazut de SPT

• TVP ileo-femurala• TVP femuro-

poplitee• Markeri inflam (++

+)• Risc major de SPT

Markerii inflamatori, Markerii inflamatori, D-dimerii si riscul de TVP D-dimerii si riscul de TVP

recurentarecurentaConcluzii:• Nivelele crescute de CRP si D-dimeri

cresc riscul recurentei TVP, in timp ce nivelele crescute de citokine proinflamatorii, NU!

• Pts cu nivele crescute simultat de CRP si D-dimeri au cel mai mare risc de recutenta a TVP.

Roshani S, et al. Leiden Thrombophilia Study LETS (2012)

????

1) Mecanismele inflamatorii in TVP acuta

2) Bolile inflamatorii si riscul TVP3) Cum putem combate inflamatia in

TVP?4) Inflamatia si rezolutia trombusului 5) Sdr. post-trombotic si inflamatia

TVP si bolile inflamatorii TVP si bolile inflamatorii cronicecronice

• Boli de sistem (colagenoze): PR, LES• Neoplazii• IBD (RCUH, b. Chron)• Sepsis• Boala Behçet • Vasculite autoimune • Arterita Takayasu • Sdr. antifosfolipidic • TAO

Pts cu IBD au un risc de TVP de 2-3 x mai mare decat populatia generala

Cercul vicios inflamatie-Cercul vicios inflamatie-coagularecoagulare

??????

1) Mecanismele inflamatorii in TVP acuta

2) Bolile inflamatorii si riscul TVP3) Cum putem combate inflamatia in

TVP?4) Inflamatia si rezolutia trombusului 5) Sdr. post-trombotic si inflamatia

Putem combate inflamatia Putem combate inflamatia din TVP ?din TVP ?

• heparine• statine • sulodexid • IL-10 (in studiu)• AINS (doar in tromboflebita superficiala)

• inhiba activarea si aderarea celulelor inflamatorii (leucocite)

• reduce productia de citokine• inhiba degradarea mastocitelor si

eliberarea de histamina• protejeaza celulele endoteliale de

actiunea citotoxica • inhiba prod de heparinaza de

catre plachete• previne aderarea neutrofilelor la

cel. endoteliale

• Astm bronsic• SCA• CABPG• Chir. Cataractei• IBD

,,considering heparins as the main stay treatment of ACS, its effects are more pronounced as anticoagulating than as an anti-inflammatory agent in this

pathological condition”.

Adv Pharmacol Sci. 2015

• Mastocitele tisulare sunt singura sursa de heparina endogena care poate fi implicata in controlul raspunsului inflamator.

• Heparina inhiba influxul neutrofilelor la locul inflamatiei, cat si adeziunea leucocitelor in venulele post-capilare.

Lipidele circulante in exces:• Efect protrombotic• Cresc productia de trombina• Activare plachetara• Disfunctie endoteliala

Statinele reduc riscul de TVP independent de nivelul colesterolului seric

Rosuvastatin – 43%Rosuvastatin – 43%

• In studiul JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin), rosuvastatin 20 mg a redus rata cazurilor noi de TEV cu 43% la o populatie sanatoasa cu markeri de inflamatie cronica sistemica documentata prin cresterea concentratiei de CRP (2 mg/dL).

Kones R. Drug Design, Development and Therapy 2010

Molecula CRP

Rodriguez A et al. Thromb Thrombolysis. 2012 May ; 33(4): 371–382

Mecanisme propuse in reducerea riscului de TVP la pts tratati cu statine:

• scaderea PAI-1• cresterea expresiei tPA, • scaderea agregarii plachetare, • cresterea expresiei trombomodulinei

Efectul concret al Rosuvastatinei nu se cunoaste!

Pe langa efectul anti-trombotic/anti-inflamator, statinele nu au risc de sangerare-posibila terapie asociata in TVP

Statinele reduc riscul de Statinele reduc riscul de TVPTVP

PLOS ONE | DOI:10.1371/journal.pone.0116621 February 13, 2015

Mannello F, Medda V, Ligi D, Raffetto JD (2013) Glycosaminoglycan sulodexide inhibition of mmp-9 gelatinase secretion and activity: possible pharmacological role against collagen degradation in vascular chronic diseases. Curr Vasc Pharmacol 2013;11:354-365Mannello F. Modulation of matrix metalloproteinases and cytokines by glycosaminoglycan sulodexide in macrophage-like cells: possible role and treatment in chronic venous diseases. XVII World Meeting of the International Union of Phlebology. 2013.September 8-13, Boston, USA

SDX-proprietati anti-SDX-proprietati anti-inflamatoriiinflamatorii

SDX-PEV SDX p.o.

+/- or TRIFLUSAL

• IL-10 prezenta in exces in peretele venos ca raspuns la tromboza venoasa

• adm. de IL-10 a scazut volumul trombusului

Journal of Imunology, 1998;161:1471-1476

Circulation. 2001;103:1718-1720

????????

1) Mecanismele inflamatorii in TVP acuta

2) Bolile inflamatorii si riscul TVP3) Cum putem combate inflamatia in

TVP?4) Inflamatia si rezolutia trombusului 5) Sdr. post-trombotic si inflamatia

Rezolutia trombusuluiRezolutia trombusului

Pattern-uri diferite:• periferic• central (tunelizare)• tip cavernos

(multilocular)

• Predomina macrofagele• IL-8 rol chemotactic• MMPs 2 si 9• Urokinase activity (+++)• VEGF (+++)• IL-1alfa• IL-2• Lf-niciun rol!

Procesul de baza: NEOVASCULARIZATIE PERIADVENTICIALA HIPOXIC-INDUSA

The dynamics of recanalization are characterized by distal-to-proximal extension and in the first 6 months are significantly influenced by thrombosis etiologyPuskas A. Int Angiol 2007(26);1:53-63

• Organizarea si recanalizarea trombusului este rezultatul unui proces “outside-in” outside-in” cu celulele inflamatorii patrunzand in cu celulele inflamatorii patrunzand in interiorul trombusului via peretele venosinteriorul trombusului via peretele venos.

• Hipoxia relativa din interiorul trombusului poate repreyenta un stimul ptr formarea de vase de neoformatie deyvoltate din peretele venos inspre trombus, care, impreuna cu retractia trombusului, conduce la recanalizarea venei si reaparitia fluxului sanguin venos.

Arterioscler Thromb Vasc Biol. 2010;30:2443-2451

Rolul leucocitelor in rezolutia trombusului

Prakash Saha et al. Arterioscler Thromb Vasc Biol. 2011;31:506-512

VEGF expression in the naturally resolving mouse VEGF expression in the naturally resolving mouse thrombusthrombus

Colin Edward Evans et al. Arterioscler Thromb Vasc Biol. 2010;30:2443-2451

Etapa imediata post-tromboza se caracterizeaza prin tromboliza fiziologica dependenta de prezenta leucocitelor

(NTR) care lucreaza intr-un mediu proinflamator generat de citokine

Thomas W. Wakefield et al. Arterioscler Thromb Vasc Biol. 2008;28:387-391

• Statinele au proprietatti anti-inflamatorii, pro-angiogenice and pro-fibrinolitice care pot influenta favorabil recanalizarea si organizarea trombusului.

• Atorvastatina amplifica rata recanalizarii si inhiba inflamatia de la nivelul peretelui venos, cat si fibroza.

Int J Surg 2012;(10):8:S4

??????????

1) Mecanismele inflamatorii in TVP acuta

2) Bolile inflamatorii si riscul TVP3) Cum putem combate inflamatia in

TVP?4) Inflamatia si rezolutia trombusului 5) Sdr. post-trombotic si inflamatia

Factorii majori de prognostic ai SPT:• tromboza reziduala• reflux in v. femurala si popitee Estimate la 3 luni dupa TVP acuta

Journal of Thrombosis and Haemostasis, 11: 795–805

Sindromul post-tromboticSindromul post-trombotic

Colectia Dr. A. Andritoiu

Case-Report 1 Case-Report 1 TVP ilio-femurala TVP ilio-femurala

S. Mirel, 42 aniS. Mirel, 42 ani• TVP idiopatica stg.• Ileo-Fem-Pop• CT

• VSH 71 mm/h• CRP 7.7 mg/dL• Fibrinogen 622 mg/dL• Leuc 10.200/mmc• Fara semne de

inflamatie locala

Case-Report 2Case-Report 2 TVP v. poplitee TVP v. poplitee

N. Simona, 32 ani• TVP acuta

(idiopatica)-10 z• V poplitee stg.• CDUS

• VSH 30 mm/h• Fibrinogen 202 mg/dL • CRP 1.1 mg/dL• Leuc 8.300/mmc

In care caz riscul aparitiei SPT In care caz riscul aparitiei SPT este mai mare?este mai mare?

Raspuns corect: Cazul 1Raspuns corect: Cazul 1

Argumente:• Localizare proximala• Volum mare al trombusului• TV idiopatica• Raspuns slab la AVK (trombus masiv la INR 4.4)• Probe inflamatorii (+++)

J Thromb Haemost 2015; 13: 398–408.

Inflammation in deep vein thrombosis and the development of post-thrombotic

syndrome: A prospective study

110 pts TVP (evaluati la 12 luni pr SPT)IL-6CRP• Rezultatele acestui studiu sugereaza ca

inflamatia ar putea juca un rol in clearance-ul incomplet al trombusului, persistenta obstructiei venoase si aparitia dupa 1 an a SPT.

Klappe E et al. J of Thrombosis and Haemostasis 2009;7(4):582-587

BMC Cardiovascular Disorders 2007

• Primul studiu prospectiv care a evaluat rolul predictiv al unor biomarkeri in aparitia SPT

Triada lui Virchow…Triada lui Virchow…nu-i apartine lui nu-i apartine lui

Virchow!Virchow!

1821-1902

The elements comprising Virchow's triad were neither proposed by Virchow, nor did he ever suggest a triad to describe the pathogenesis of venous thrombosis