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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