Curs 13 - Patologia Hemostazei

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AFECTIUNI HEMORAGICE DE CAUZA VASCULARA Prof. Dr. Ana Maria Vlãdãreanu

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Hemostaza-patologie

Transcript of Curs 13 - Patologia Hemostazei

  • AFECTIUNI HEMORAGICE DE CAUZA VASCULARA Prof. Dr. Ana Maria Vldreanu

  • Afectiuni hemoragice de cauza vascularaSunt afectiuni polimorfe

    Sunt frecvent intalnite

    Anatomo-clinic se pot grupa:

    Purpure vasculare palpabile

    Purpure vasculare nepalpabile

    Leziuni hemoragice nepurpurice

  • 1. Purpure vasculare palpabilePurpura disproteinemica:CrioglobulinemiiCriofibrinogenemiiHiperglobulinemii din MM, BW, ALVasculite cutanate (purpure vasculitice)

    2. Purpure vasculare nepalpabile:

    Prin afectarea zonei subendoteliale:Purpura senilaPurpura din Boala CushingPurpura scorbuticaAnomalii de tesut conjunctiv (Sd. Ehler-Danlos)Purpura din amiloidozaPurpura simplex

  • 2. Purpure vasculare nepalpabile:2. Prin afectarea endoteliului vascular:

    Purpure infectioase:

    Infectii meningocociceFungiVirale: v. rubeolic, rujeolic, EBVPurpura alergica

    Purpura indusa medicamentos:

    AllopurinolClonidinaPeniciline

    Purpura trombotica

  • 3. Leziuni hemoragice nepurpuriceAfectiuni cu teleangiectazii:

    Ereditare: Boala Rendu-Osler

    Ataxie-Teleangiectazie

    Teleangiectazii in sarcina

    Sd. CREST

    Sarcoame: Kaposi, etc

  • BOALA RENDU-OSLERAfectiune ereditara caracterizata prin prezenta teleangiectaziilor la nivelul dermului, mucoaselor, viscerelor cavitare

    Asociaza fistule arterio-venoase la nivelul organelor parenchimatoase: ficat, pancreas, cerebral

    Teleangiectaziile apar datorita unei discontinuitati endoteliale

    Caracteristic: complicatiile hemoragice in special la nivelul mucoaselor hemoragiile pot fi reduse cantitativ, dar repetitive sau foarte abundente

    Aspect clinic particular: epistaxisul apare intotdeauna in evolutia bolii (daca apare din copilarie este un element de gravitate)

    Cel mai frecvent boala este diagnosticata la adultul tanar, cu epistaxis masiv !

  • BOALA RENDU-OSLERManifestari clinice:Epistaxis:recurentabundent anemie severa cu dezechilibre hemodinamicegreu de stapanitseveritatea sa creste cu varstaHemoragii TGI: - hematemeza / melena - abundente / reduse cantitativ, dar repetitive anemie feripriva cronica - endoscopic: elemente angiodisplaziceHemoptiziiSangerari uro-genitaleCutanat: teleangiectazii

  • BOALA RENDU-OSLERTeleangiectazii cutanateApar cu inaintarea in varstaUneori apar dupa debutul manifestarilor hemoragiceZone de electie:PerioralBaza piramidei nazaleLobul urechilorSublingualFataVarful degetelor (maini, plante)

  • Diagnosticul se formuleaza pe coroborarea clinicii + biopsie derm (endoteliu discontinuu) Prognostic global - rezervat prin:complicatii hemoragice (pot fi severe prin rapiditate, abundenta soc hemoragic)Hemoragii in organele tinta fistule arterio-venoase insuficiente de organ: IH, HTP, ICD

  • BOALA RENDU-OSLERTratament

    Urgenta: oprirea hemoragiei !Epistaxis: tamponament nazal

    Metroragii: embolizarea arterelor uterine

    HDS: sonda Blackmore

    Hemoragii genitale: agenti antifibrinolitici (acid tranexamic, acid epsilonaminocaproic)

    Anemia feripriva cronica: suplimentare fierIn complicatia hemoragica activa: antifibrinolitice: EACA, Ac tranexamic

    Masuri generale: Sustinerea functiilor vitale / reechilibrarea socului hipovolemicAnemia severa: transfuzie sange integral

  • PURPURE TROMBOCITOPENICETrombocitopenie < 100.000 - 150.000/mm

    De regula aparitia manifestarilor hemoragice este corelata cu scaderea numarului trombocitelor, dar nu e intotdeauna paralela cu trombocitopenia, ci este influentata si de gradul de trombopatie existent (*LA sindroame hemoragipare dramatice)

    Alti factori care accentueaza diateza hemoragica:HemoglobinaInfectiaUremiaInsuficienta hepatica

    Tr > 100.000/mm - nu exista de regula manifestari hemoragice

    Tr 50.000 100.000/mm - aparitia manifestarilor hemoragice dupa traumatisme, interventii, etc

  • PURPURE TROMBOCITOPENICETr 30.000 50.000/mm - manifestarile hemoragice apar spontan sau dupa trumatisme minore

    Tr < 30.000/mmc manifestari hemoragice:Cutanate: purpura trombocitopenicaMucoase: epistaxis, HDS/HDI, hematurie, metroragiiPurpura umeda bule hemoragice gingivoragii hemoragii conjunctivale, retinieneRisc major de sangerare la nivel SNC ! Tr < 10.000/mm

    Hemoragiile sunt de regula difuze, teoretic imposibil de stapanit prin manevre locale (care uneori le pot chiar amplifica)

    Controlul sistemic al hemostazei al hemoragiilor in panza

  • PURPURE TROMBOCITOPENICEI. Trombocitopenii centrale: afectarea productiei trombocitelor prin:

    - hipoplazia megakariocitelor - megakariopoieza infecienta * Componenta MK din MO e slab reprezentata II. Trombocitopenii periferice: predomina mecanismul de distructie periferica a trombocitelor* Distructie / sechestrare la nivel extramedular* Asociaza o reactie compensatorie a MK din MO (displazie MK)

  • I. Trombocitopenii CentraleMetastaze medulareLA, MM, LLC std IVMielodisplaziiPost radio / chimio- terapieAsocieri infectioase: HIV, virusuri hepatiticeMedicamente: diuretice tiazidiceAlcoolAnemii megaloblastice, aplastice

    Tratament: EtiologicSubstitutiv: masa trombocitara

  • II. Trombocitopenii PerifericeImune:PTI (purpura trombocitopenica idiopatica)Sd. PTI-like: - hepatite - boli autoimune (PR, LES) - sd. limfoproliferative (LLC, BH) - medicamente - sarcinaAlloimune: trombocitopenia neonatala (la copii din mame cu PTI, Ac antiTr trec placenta; este tranzitorie)PosttransfuzionalNon-imune:Microangiopatii trombotice complicate (CID, PTT, SHE)Prin distributie asociere hipersplenismneoplazii (LGC)boli infiltrative (AL, B. Gaucher)congestive (ciroza hepatica)infectioase (malarie, hepatita)

  • PURPURA TROMBOCITOPENICA IMUNA IDIOPATICA(PTI)Afectiune autoimuna dobandita

    Se caracterizeaza prin trombocitopenie izolata

    Exista si sindroame PTI-like

    Fiziopatologia PTI:

    Ac anti trombocitari se leaga de GP IIb IIIa din membrana trombocitului Tr devine sensibilizat este distrus mai usor in SRE (mecanism imun)

    Ac anti trombocitari se leaga si de precursorii megakariocitari din MO insuficienta productiei medulare de trombocite

    Contribuie si nivelul scazut al trombopoietinei serice

  • ITP: PathophysiologyMechanisms of Thrombocytopenia in ITPIncreased platelet destruction

    Decreased platelet production

  • Traditional Concept of ThrombocytopeniaImpaired production:CIT and aplastic anemiaDestruction:ITPSpleenAntiplatelet antibodyTPOCIT = chemotherapy-induced thrombocytopenia.

  • *Immune Thrombocytopenic Purpura Pathophysiology: Accelerated Platelet DestructionTPO- bound plateletsMacrophageSpleenAutoantibodies bind to healthy plateletGamma receptorB cell

  • *Immune Thrombocytopenic Purpura Pathophysiology: A Disease of Accelerated Platelet Destruction and Suboptimal Platelet ProductionBlue arrow represents amount of free or unbound TPO in the system.SpleenLiver

  • Antiplatelet Antibodies Impact Platelet Production in Immune Thrombocytopenic PurpuraTPOTPO-RPGPAntibodyPGP = platelet glycoprotein.

  • Triggering Factors: H pyloriaResults are expressed as the total number of patients with bacterial eradication from among the total number of treated patients.bComplete or partial response among patients with successful eradication.UK: Prevalence 47%, response rate in severe ITP
  • Gasbarrini A, et al. Lancet. 1998;352(9131):878.H pylori Infection and ITPPlatelet counts in patients with autoimmune thrombocytopenia

  • PTITablou clinic: manifestari hemoragice ample

    Cutanate: - purpura - echimoze (posttraumatice, venopunctie)

    Mucoase: - gingivoragii - epistaxis - bule hemoragice - hematemeza / melena

    Clasificare PTI

    Acut - Caz nou diagnosticat: 3 luni de evolutie

    Persistent: 3 12 luni de evolutie

    Cronic: peste 12 luni de evolutie

  • Immune Thrombocytopenic Purpura: A Chronic Disease With Potentially Serious ConsequencesSevere cutaneous bleedingMenorrhagiaGingival bleedingIntracranial hemorrhage Cines DB, Blanchette VS. N Engl J Med. 2002;346:995-1008. Reprinted with permission from: Simon Fraser/RVI, Newcastle upon Tyne/Photo Researchers, Inc.

  • PTIPTI la copil

    incidenta crescuta la cei cu suferinte hematologicepoate apare dupa infectii de cai respiratorii viraleaspect dramatic: - bule hemoragice bucale - sd hemoragipar extins - trombocitopenieevolueaza ca episod izolatraspuns bun la tratament

    PTI la adult

    usoara predominenta la femeiformele acute pot apare dupa IACRSclasic: evolutie cronica intrerupta de acutizari (pusee de trombocitopenie)

  • Diagnostic approach in suspected ITPCBC, complete blood count; Rh, rhesus; H. pylori, Helicobacter pylori; HIV, human immunodeficiency virus; HCV, hepatitis C virus; PCR, polymerase chain reaction; CMV, cytomegalovirus; TPO, thrombopoietin; ; PaIgG, platelet-associated immunoglobulin G Provan D et al. Blood, 115: 168186 (2010)

    Basic evaluationTests of potential utilityTests of unproven benefitPatient/family historyPhysical examinationCBC and reticulocyte countPeripheral blood filmQuantitative immunoglobulin level measurement*Bone marrow examination (in selected patients)Blood group (Rh)Direct antiglobulin test H. pylori**; HIV **; HCV**Glycoprotein-specific antibodyAntiphospholipid antibodies (including anticardiolipin and lupus anticoagulant)Antithyroid antibodies and thyroid functionPregnancy test in women of childbearing potentialAntinuclear antibodiesPCR for parvovirus and CMVTPOReticulated plateletsPaIgG Bleeding timePlatelet survival studySerum complement

    *Should be considered in children; Recommended in children with persistent or chronic ITP**Recommended for adult patients regardless of geographic location

  • PTIDiagnostic PTI diagnostic de excludere (PTI-like)Context clinic evocatorTrombocitopenie izolata cu MK in numar crescut, cu predominenta MK tinere in MOAc anti trombocitari se determina test Coombs anti-Tr flowcitometric Bilant negativ pentru excluderea posibilelor forme secundare

    Tratament Cresterea numarului de trombocitePrevenirea hemoragiilor / oprirea hemoragiilor

  • ITP: Treatment Goals in the 21st Century Prevention of bleedingImprovement of QOLStasi R, et al. Thromb Haemost. 2008;99(1):4-13.

  • Treatment of ITP in adults - 3 lines

  • Tratamentul PTIPrima linie terapeutica:

    (1) Corticosteroizii (pulsterapie 3 zile; i.v. doze crescande 16 - 24 - 40mg) * ~ 70% recaderi la reducerea dozelor CS !DexametazonaMetilprednisolonPrednison (2) Imunoglobuline i.v. (Ig anti-D pt pacientii Rh+): determina cresterea rapida a numarului Tr si stabila ~ 4 luni * ~ 50% din pacienti raspund la Ig i.v.

    A doua linie terapeutica pt formele persistente si cronice

    Imunosupresoare (~ 25 % raspund): - Azatioprina (Imuran) oral - Ciclofosfamida oral / i.v. - Ciclosporina (in formele ce asociaza hipoplazie medulara)

  • Tratamentul PTI(2) Splenectomia:

    Inainte de a incepe imunosupresiaDetermina raspunsuri durabileStabilizeaza numarul Tr (~ 100.000/mmc), fara oscilatii~ 30% nu raspund la splenectomie

    (3) Danazol: - androgen anabolizant cu eficienta buna la doze mari - ! Virilizare

    (4) Vincristin / Vinblastin: administrari saptamanale

    (5) Ac anti CD20: Rituximab (MabThera)

    III. A treia linie terapeutica: agonisti de receptori de trombopoietina - Eltrombopag (Revolade) - Romiplostin (NPlate)

  • *XImmune suppressionT cellTPO- bound plateletsMacrophageSpleenB cellImmune Thrombocytopenic Purpura Current Treatment Options: Immune Suppression

  • *T cellTPO- bound plateletsMacrophageSpleenB cellImmune globulinImmune Thrombocytopenic Purpura Current Treatment Options: Immune Globulin

  • *XChemotherapyT cellTPO- bound plateletsMacrophageSpleenB cellXImmune Thrombocytopenic Purpura Current Treatment Options: Targeted Chemotherapy

  • *T cellTPO- bound plateletsB cellSpleen removedImmune Thrombocytopenic Purpura Current Treatment Options: Splenectomy

  • Peptide TPO Receptor Agonist*Romiplostim (AMG531) - Nplate

    Nonpeptide TPO Receptor Agonist*Eltrombopag - RevoladeSecond Generation Thrombopoietin (TPO) Receptor Agonists in ITP*eltrombopag and romiplostim FDA / EMEA approved

  • EltrombopagTPO-R Agonist: Mechanism of ActionThrombopoietin ReceptorInactive ReceptorActive ReceptorSignal TransductionIncreased Platelet ProductionRAS/RAFMAPKKp42/44JAKSTATSHC GRB2SOSPPPPCell MembraneCytoplasmTPORomiplostimAKT?

  • BOALA von WILLEBRANDEste cea mai frecventa afectiune hemoragica ereditara (congenitala)

    Transmitere autozomal dominanta cu penetranta variabila

    Polimorfism clinic multe forme usoare, frecvent subdiagnosticate

    Afecteaza ambele sexe

    Definitie: afectare complexa a coagularii determinata de alterarea cantitativa / calitativa a factorului von Willebrand

    Factorul von Willebrand (F VIII):

    proteina plasmatica multimerica (GP) secretata de megakariocit, celule endotelialeprezent in plasma si trombocite; in sange este inclus intr-un complex cu VIII:C (proteina transportoare)dublu rol: - adeziunea trombocitelor la subendoteliu - caraus factor VIII Are situsuri diferite de legare de trombocit, factor VIII, colagen

  • BOALA von WILLEBRANDClinic:Complicatii hemoragice mucoase non purpurice la valori normale ale trombocitelor Complicatii hemoragice tip hematoame, hemartroze (fateta hemofilica in formele severe de BvW)Clinica este polimorfa si variabila interindividual precum si de-a lungul vietii pacientuluiComplicatiile hemoragice apar de regula la adult; in formele severe de boala apar din copilarieTipuri de complicatii hemoragice:EchimozeGingivoragiiMenometroragii (! Anemia feripriva severa)EpistaxisHemoragii posttraumatice, postoperatoriiHematoame (f fv)Hemartroze (doar in formele severe)

  • FORME DE BOALA von WILLEBRANDTip I - deficit cantitativ F vW moderat (trasmitere dominanta) ~ 70 80% - severitate intermediara (usoara, medie) - asociat cu nivele scazute de VIII:C (dar > 10%)Tip 2 - deficite calitative F vW (mai multe subtipuri)2 A - deficit de polimerizare: multimerii lipsesc din plasma si din Tr - 10-15% din cazuri - severitate medie/mare2 B Asociat cu Trombocitopenie deficit de polimerizare: multimerii lipsesc din plasma, dar sunt prezenti in trombocite; 5% din cazuri - severitate medie/mare2 M - deficit de legare de plachete (afinitate redusa pt GP I) - rar, severitate medie2 N - deficit de legare de VIII:C (scaderea VIII:C 2-10%) - rar, severitate medieTip 3 - defect sever de productie F vW (transmitere recesiva); rar - severitate crescuta; nivele scazute / absente VIII:C (5-10%)

  • Diagnosticul Bolii von Willebrand - Screening

    Context clinic evocator

    Numar normal de trombocite

    Timp de sangerare usor prelungit

    APTT crescut in formele severe, normal in formele atenuate (explorarea caii intrinseci a coagularii)

    Diagnostic de laborator foarte dificil pentru ca nivelul de factor von Willebrand inregistreaza fluctuatii mari

  • Diagnosticul Bolii von Willebrand Dg specific

    Dozarea Ag legat de F vW (VIIIR:Ag)

    Teste de agregare trombocitara la ristocetina (arata deficit)

    Determinarea fractiunii coagulante ce leaga VIII

    PFA -100 (Platelet Function at high shear rate) masoara capacitatea trombocitului de ocluzie/ apertura la v mariPlatelet function at low shear rate - masoara capacitatea trombocitului de ocluzie/ apertura la v mari - agregarea trombocitara specific la ristocetina raspunsul induce modificarea conformationala a Gp memebranei (IB- IX-V) in interactiunea cu FvW

    RIPA la concentrataii mici arata surplus de legare de trombocite apare in BvW tip IIB

  • Tratamentul Bolii von Willebrand Depinde de severitatea complicatiilor hemoragice Spre deosebire de hemofile, tratamentul profilactic cronic este rareori necesar

    Sangerari reduse cantitativ: - masuri locale - antifibrinolitice (acid tranexamic) 15mg.kg

    Viza sistemica: Desmopresina - 0,3 mcg/kgc pi.v. sau s.c. - elibereaza FvW din endoteliu - activa in formele usoare si intermediare de boala (tip 1, unele tipuri 2; NU 2 B) * 2 B - risc tromboze! (+ antiagregant Tr )

    In formele severe sau perioperator: tratament substitutiv Haemate P- (Aventis) preparate de F VIII ce contin si FvW (concentrate de puritate )

  • Tratamentul Bolii von Willebrand Menometroragii recurente:Antifibrinolitice - Acid tranexamic 1g la 6h/5 zile Transfuzie masa trombocitaraContraceptive hormonale pe baza de estrogeni (cresc nivelul de factor VIII, FvW) Vitaminoterapie, suplimentare FeDesmopresin

    In timpul sarcinii, creste nivelul FvW, care scade apoi foarte mult la nastere - hemoragii importante in postpartum

    De evitat AINS si Aspirina

    Exista si o forma dobandita BvW in mieloproliferari

  • HEMOFILIIAfectiuni congenitale transmise recesiv, legate de crz X

    Femeile sunt purtatoare de boala, iar barbatii dezvolta afectiunea

    Tipuri de hemofilii (tablou clinic similar, dar dg si tratament diferit): Hemofilia A deficit de F VIII (cea mai fc)

    Hemofilia B deficit de F IX

    Hemofilia C deficit de F XI (afecteaza ambele sexe)

    Severitatea fenomenelor hemoragice - strict corelata cu nivelul F VIII

    Forme severe F VIII < 1 U/dl (hemoragii spontane)

    Forme moderate F VIII 1 5 U/dl (sg. posttrauma, postoperator)

    Forme usoare F VIII 6 40 U/dl (sg. postinterventii chirurgicale laborioase, posttraumatisme majore)

  • HEMOFILII Complicatiile hemoragice in Hemofilie - caracteristici:

    Sangerari importante prin durata prelungita, posibilitatea de resangerare

    Debuteaza dupa cateva ore / o zi de la traumatism

    Primele complicatii apar cand copilul incepe sa mearga (efortul determina hemoragii intraarticulare)

    Tipic: hemartroza cotului (prin lovirea de gratiile patutului)

    Formele severe la nastere:

    Sangerare postcircumcizie (nu e tipica hemofiliei, ci deficitului de F XIII)

    Cefalhematom

  • Complicatiile hemoragice in HemofilieHemartroze: apar la traumatisme minime (mers)articulatii afectate: genunchi, cot, sold, umarfaza acuta: aspect inflamator (durere importanta, tumefactie articulara, eritem, impotenta functionala, pozitie antalgica)cronic: remanieri si modificari ale sinovialei, cartilajului articular distructii, ankiloze artropatia hemofilicului

  • Complicatiile hemoragice in Hemofilie

    2) Hematoame in spatii inchise (muscular - la simple eforturi):localizari: lingual, retrofaringian, orbitar, psoasevolueaza cu compresiii locale: asfixie, enucleere GO, fals abdomen acut, apendicitain timp --- risc de suprainfectie si de insamantare septicemica

    3) Hemoragii abundente: postoperatorii, dupa extractii dentare, amigdalectomie, apendicetomie, etc

    4) Hematurie (macroscopica, cu colica renala; poate determina blocaj renal)

    5) Hemoragii mucoase (provocate/nu): epistaxis, melena, hematemeza

    6) Hemoragii centrale: HAS, hematoame cerebrale

  • Diagnosticul HemofilieiSugerat de clinicaTeste de screeningTeste de confirmare inalt specifice (identificare tip)

    Teste de screening

    Timp Quick (PT) normal (CE)Timp coagulare global normal (sau usor crescut in f. severe)APTT crescut (sau normal in f. usoare) 35 55 sec

    Teste de confirmare inalt specifice:Determinarea nivelului F VIII / IX (tipul si severitatea deficitului)

  • Hemofilia - Complicatii Complicatii aparute in cursul evolutiei bolii:

    Secundare tratamentului trasnfuzional (conditionate genetic)

    Transmiterea unor boli: HIV, HVC, HVBSuprainfectia hematoamelor posibil cauza de septicemie

    Complicatii pe termen lung:

    aparitia de Ac inhibitori (pacientul devine refractar la transfuzie) probleme de abordare terapeutica

    LNH, Sarcom KaposiArtropatia hemofilica

  • Tratamentul in HemofilieOprirea hemoragiilor !

    Tratamentul complicatiilor

    Masuri de reinsertie socio-umane

    Stil de viata ( ! Singurul sport admis - inotul)

    Kinetoterapie (reducerea anchilozelor, invalididatii)

    Tratament substitutiv

  • Tratamentul in Hemofilia A

    Tratament substitutiv Produse recombinate tratamentul de electie Produs plasmatic inalt purificat - dublu viral inactivat 1U/kg corp creste concentratia plasmatica a factorului la 2U/dl in 6-12h

    Program profilactic: 2-3 administrari /saptamana de factor inalt purificatcat mai precoce (an 1-2 de viata)

    F VIII adm x 2-3 / saptamana (T1/2 scurt !)F IX adm 1-2 / saptamana

  • Tratamentul in HemofilieSangerari mici / interventii chirurgicale minore: Desmopresin ( F VIII x 3)

    Interventii ORL / BMF: acid epsilonaminocaproic, acid tranexamic (+ obtinerea un nivel de factor de 20 - 50%)10-25mg/kg oral pentru extractii dentare sau leziuni cutanate

    DDAVP pentru interventii minore 0,3ug/kg corp SC sau lent Iv/20min / poate fi administrat si spray nasal

  • Tratamentul in Hemofilie

    Interventii chirurgicale: se calculeaza nivelul de factor necesar pentru o desfasurare in conditii de siguranta a actului operator (* interventiile ortopedice - proteza sold necesita un nivel de 75%)

    Artropatia hemofilica echipa: ortoped + kinetoterapeut + hematolog

    Masuri generale: repaus (obligatoriu pentru orice accident hemoragic)

    Contraindicatii: AINS, injectiile intramusculare

    Registrul National al Pacientilor Hemofilici

  • HEMOFILIA CU Ac INHIBITORIImunosupresie

    Corticosteroizi

    Imuran

    Rituximab

    F VII recombinat (NOVOSEVEN)

  • COAGULAREA INTRAVASCULARA DISEMINATASindrom plurietiologic denumit generic coagulopatie de consum

    Apare ca o complicatie in diverse boli

    Asociaza anomalii complexe de:HemostazaCoagulareFibrinoliza

    3 forme clinice:

    Forma acuta

    Forma cronica

    Forma localizata

  • CIDForma acuta cauze:Obstetricale

    Infectioase: sepsis cu Gram negativi, varicela, rubeola, micoze

    Neoplazii: LAM3, carcinoame, rabdomiosarcom, etc

    Vasculare: colagenoze, malformatii vasculare

    Leziuni traumatice: arsuri, postoperator chirurgie hepatica, circulatie extracorporeala

    Alte cauze

    Forma cronica:Diateza protrombotica + trombocitopenieNeoplasmele secretante de mucina (ex. tromboflebite migratorii)

    Forma localizata: malformatii vasculare (hemangiom gigant)

  • FIZIOPATOLOGIA CID1. Initierea procesului trombotic la mai multe nivele in organism, datorita anumitor substante :

    endogene

    endotoxinice (cu rol tromboplastinic)procoagulante tumorigene

    2. Efect: aparitia unei tromboze in teritoriul micro- si macro-circulatiei, secundar formarii si activarii sistemice a trombinei

    In conditii normale formarea trombinei este limitata; in CID are loc activarea sistemica a F II

    3. micro si macro tromboze ocluzii vasculare / ischemie/ insuficiente de organe, ischemii arteriale

  • FIZIOPATOLOGIA CID

    4. Aparitia diatezei hemoragice

    Depletia factorilor de coagulare, ce se consuma in tromboza diateza hemoragica

    Consumul trombocitelor prin distrugerea lor in reteaua de fibrina sau in procesul trombozei trombocitopenie accentuarea diatezei hemoragice

    Consumul fibrinogenului accentuarea diatezei hemoragice

    Consumul factorilor anticoagulanti: antitrombina III accentuarea diatezei trombotice

  • FIZIOPATOLOGIA CID 5. Declansarea fibrinolizei reactive imediat dupa initierea formarii F Ia, ca raspuns al endoteliului la tromboza F I accentuarea diatezei hemoragice Se formeaza produsi de degradare ai fibrinei si PDF ai fibrinogenului

    6. Hemoliza microangiopatica anemie

    Mari deficiente soc Ischemii: miocardice, hepatice, IR, hipoxie cerebrala

    7. Aparitia marilor insuficiente: hepatica, cardiaca, hipoxica, renala

  • CID- patogenie -TrombozaHemoragieHemoragieHemoragieHemoragieHemoragieHemoragieHemoragieTrombozaSepsisToxineTraumeInitiereAgregareplachetaraCoagulareDepozite de fibrinaPlasminaPDFOcluzievascularaDepletiatrombocitelorDepletia factorilorde coagulareOcluzievascularaScaderea FBGInhibitia functiei plachetareInhibitia polimezarii fibrineiTrombopeniePTPTTFBGTTTSTT

  • CIDClinic 2 grupe de semne:

    Semnele diatezei hemoragice: foarte severe (purpura, echimoze, hematoame; sangerari mucoase, hemoragii interne)

    Elemente legate de tromboze si ischemii +Insuficiente de organe tinta: renala, hepatica, circulatorie cerebrala, respiratorie, cardiaca, MSOF, socAnemie severa posthemoragica microangiopatica

    Manifestarile bolii de baza

  • Diagnostic de laborator CIDAspect global modificat al timpilor de coagulare:

    T Quick (legat de o scadere masiva de F V, II, I)

    APTT (datorita deficitului multiplu de factori de coagulare)

    TT Fibrinogen (< 100 mg/dl)

    Trombocitopenie (intensitate variabila)

    Anemie hemolitica microangiopatica (eritroblasti, schizocite)

    Prezenta PDF (D dimeri) markeri moleculari polipeptizi (MMP)

  • Tratamentul CIDNu exista tratament patogenic de electie !

    Tratamentul bolii de baza:Obstetrica (resturi placentare suprainfectate): antibioterapie, chiuretajBoli infectioase: antibioterapieLAM3: acid retinoic

    Sustinerea functiilor vitale (masuri hemodinamice)

    Substitutie de factori (ME, MT):Plasma proaspataCrioprecipitatSange integral

    Restabilirea hemostazei:AT IIIAPC (activated human protein C ) pt CID din septicemiiNovoseven in diatezele hemoragice - forme severe

  • CID cronic Trombocitopenie

    Modificari de hemostaza

    Prezenta D dimerilor si PDF

    Tratament: heparina cu greutate moleculara mica (Clexane) daca trombocitopenia nu e foarte severa

  • *PTT notiuni de teorieTrombocitopenie prin distructie non-imunaMicroangiopatie trombotica

    Criterii de diagnostic:TrombocitopeniaAnemia hemoliticaFenomene neurologiceAfectare renalaFebra

  • *EtiopatogenieEndoteliul elibereaza multimeri ultralarge de FvW (ULvWF) (Disfunctia Endoteliala)Deficit de metaloproteaze ADAMTS-13FamilialNou-nascuti, gravide, varstniciCiroza, IRC, inflamatie, CID

    ULvWF afinitate foarte mare pentru trombocite agregare plachetara in arteriole si capilare

  • *Criterii diagnosticTrombocitopenia (de consum, non-imuna) posibil sub 10000/mmc.

    Anemia hemolitica microangiopatica anemie, LDH, BI, reticulocite, schizocite, haptoglobina, hemoglobinurie, hemosiderinurie

    Fenomene neurologice (afectare microcirculatiei) cefalee, paralizie nervi cranieni, disfazie/afazie, pareze, confuzie, stupor/coma, crize epileptice

    Afectare renala (afectare microcirculatiei) proteinurie, hematurie, insuficienta renala usoara

    Febra (cca 50% la prezentare / in evolutie, posibil dupa administrarea de plasma)

  • *Conditii asociate cu PTTInfectiiHuman immunodeficiency virusEscherichia coli, ShigellaPancreatitaMedicamenteCiclosporina A, Tacrolimus (FK506)AntineoplaziceTiclopidina, ClopidogrelBoli de colagenSarcina si puerperiumNeoplaziiTransplant medular

  • *TratamentTratament igieno-dietetic: evitarea traumatismelor, a frigului, contactului cu persoane bolnave, regim hidric bogat; evitarea ingestiei de alimente si lichide fierbinti, regim de crutare digestiva si regim hepato-biliarReechilibrare hidroelectroliticaTratament substitutiv: administrare MER, PPC;NU se administreaza CT in PTT!!!

    Tratamentul patogenic PTT: Plasmafereza cu plasma-exchange pana la normalizarea tabloului biologic (tr>150000 persistent 10 zile, remiterea hemolizei, normalizarea LDH) si ameliorarea clinicaCorticoterapie cu protectie gastricaTratament etiologic: antibioterapie cu spectru larg (colecistita considerata ca si posibil factor etiologic)

    ****When looking at the traditional concepts of how thrombocytopenia occurs, two main mechanisms contribute to low platelet counts: increased platelet destruction and/or impaired platelet productionITP has historically been seen as a disease of increased platelet destruction1Autoantibodies bind to healthy platelets, resulting in their sequestration and destruction in the spleenThis also results in higher eTPO clearance, as the eTPO is not recycled when the platelets are lysedAutoantibodies also bind to megakaryocytes in the bone marrow (effects to be discussed in later slides)Chemotherapy-induced thrombocytopenia (CIT) and aplastic anemia are considered conditions in which platelet production is impaired2,3Due to disease or therapy effects, the megakaryocytes in the bone marrow do not matureFewer mature megakaryocytes results in fewer platelets produced to replace naturally aging plateletsReferencesCines DB, McMillan R. Management of adult idiopathic thrombocytopenic purpura. Annu Rev Med. 2005;56:425-442.Daniel D, Crawford J. Myelotoxicity from chemotherapy. Semin Oncol. 2006;33:74-85.Marsh JC. Bone marrow failure syndromes. Clin Med. 2005;5:332-336. *In ITP, T and B cells that react with platelet autoantigens are responsible for the production of autoantibodiesThese autoantibodies recognize and bind to platelet glycoproteins (PGPs) (GPIIb-IIIa, GPIb-IX, GPIa-IIa, etc) on healthy plateletsThe autoantibody-coated platelets are recognized by macrophage Fc receptors (primarily in the spleen), causing their phagocytosis and degradationAny eTPO bound to these healthy platelets is lost with their destructionReferenceCines DB, McMillan R. Management of adult idiopathic thrombocytopenic purpura. Annu Rev Med. 2005;56:425-442.

    *ITP combines both increased platelet destruction and suboptimal platelet production, resulting in persistently low platelet counts1As seen in previous slides, ITP combines the following mechanisms:Increased platelet destruction in the spleen2Platelets are recognized by autoantibodies that bind to PGPsAutoantibody-covered platelets are recognized by macrophagesMacrophages internalize and degrade these plateletsImpaired platelet productioneTPO is constantly being bound by platelets, resulting in lower concentrations of eTPO in the bloodThere is less eTPO available to stimulate platelet production by the megakaryocytes in the bone marrowAutoantibody binding to the megakaryocytes causes some to undergo apoptosis3There are fewer megakaryocytes available to produce plateletseTPO is also lost when bound to apoptotic megakaryocytes These two mechanisms combine to result in even fewer platelets being produced to replace those lost due to destruction in the spleenThe width of the blue arrow represents the serum level of TPO, with wider arrows representing higher concentrationsReferencesCines DB, McMillan R. Management of adult idiopathic thrombocytopenic purpura. Annu Rev Med. 2005;56:425-442.Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002;346:995-1008.Houwerzijl EJ, Blom NR, van der Want JJ, et al. Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura. Blood. 2004;103:500-506.

    *Both megakaryocytes and platelets have PGPs, which are targeted by antiplatelet autoantibodies in ITP1Progenitor cells do not express PGPsAntibody binding to megakaryocytes causes apoptosis of some of the cells1This reduces the number of megakaryocytes available to produce new plateletsThis also reduces the amount of eTPO available to stimulate the remaining megakaryocytes, as whatever eTPO is bound to the dying megakaryocytes is lostAntibody binding to platelets results in their sequestration and destruction by macrophages in the spleen2This leads to a functional deficiency of plateletsThis also leads to an eTPO deficiency, as any eTPO bound to platelets is lost when the platelets are destroyedReferencesHouwerzijl EJ, Blom NR, van der Want JJ, et al. Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura. Blood. 2004;103:500-506.Chang M, Nakagawa PA, Williams SA, et al. Immune thrombocytopenic purpura (ITP) plasma and purified ITP monoclonal autoantibodies inhibit megakaryocytopoiesis in vitro. Blood. 2003;102:887-895.

    **Adult ITP is a chronic diseasePatients with low platelet counts are at risk of serious bleeding events, with an estimated rate of fatal hemorrhage of 5% per yearReferenceGeorge JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocytopenic purpura:a practice guideline developed by explicit methods for the American Society ofHematology. Blood. 1996;88:3-40. ****One treatment option for ITP targets the disease at the T- and B-cell levelImmune suppressants (eg, steroids, cyclosporine) can target the B and T cells, restricting their ability to produce the platelet-targeting autoantibodies1Steroids are FDA approved for use in ITP2Cyclosporine, while not FDA approved for use in ITP, has been reported in medical literature as a second-line treatment1This keeps macrophages from targeting the healthy platelets for removalReferences1. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002;346:995-1008. 2. Sterapred (prednisone) prescribing information; Merz Pharmaceuticals. *A second option for treating ITP is the use of IVIg1IVIg is FDA approved for use in ITP2IVIg acts by blocking the macrophage FC receptors that recognize the autoantibodies bound to platelets1This keeps the macrophages from binding the platelets and destroying them1Recent data have revealed that IVIg may also have a second function by activating an inhibitory FC receptor on macrophages3

    ReferencesCines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002;346:995-1008.Gammagard S/D prescribing information; Baxter Healthcare Corporation. Clynes R. Immune complexes as therapy for autoimmunity. J Clin Invest. 2005;115:25-27.

    *The humanized monoclonal antibody rituximab1 is used for patients with chronic ITP who are refractory to other therapies although rituximab is not FDA approved for use in ITPThe chimeric anti-CD20+ antibody rituximab can target CD20+ B cells and result in their destruction2,3Destruction of the B cells results in lower production of antiplatelet autoantibodies3Rituximab may also act by blocking the macrophage FC receptors that recognize the autoantibodies bound to platelets2,3Both of these pathways keep macrophages from targeting the healthy platelets for removalReferencesCines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002;346:995-1008.Braendstrup P, Bjerrum OW, Nielsen OJ, et al. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adult refractory idiopathic thrombocytopenic purpura. Am J Hematol. 2005;78:275-280. Tamminga RY, Bruin MC. Rituximab treatment for symptomatic chronic ITP. Pediatr Blood Cancer. 2006;47(5 suppl):714-716.

    *A third treatment option is the surgical removal of the spleenSplenectomy removes the main site of platelet destructionFewer macrophages are available to clear autoantibody-coated plateletsSplenectomy may also impair T- and B-cell synthesis of autoantibodies in some patientsReferenceCines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med.2002;346:995-1008.

    ****Anticorpi, complexe imune circulante, toxine!!!!!!!!!!!!*Antraquinona!!