ࡱ> Z\WXY5@ތbjbj22 7XX88 8l` <D  " !!!7C9C9C9C9C9C9C$8FRH]C!!!!!]C VDU9U9U9!<  7CU9!7CU9jU9:VwB@$|B `R4(B 7ClD0DB0HI7ZHIBx|HIBD!!U9!!!!!]C]CxD39"xLOKALNA FIBRINOLIZA KAO UZROK KRVARENJA U DJECE NAKON TONZILEKTOMIJE Srana uli* *Klini ka bolnica Split, Klinika za dje je bolesti, Klini ki odjel za hematologiju, onkologiju, imunologiju i medicinsku genetiku Adresa za dopisivanje: Prim.dr.sc.Srana uli, dr.med. Klini ka bolnica Split, Klinika za dje je bolesti, Klini ki odjel za hematologiju, onkologiju, imunologiju i medicinsku genetiku 21000 Split, Spin ieva 1. Tel. +385 21 556 256 Fax: +385 21 556 590 E-mail: srdjana.culic@st.htnet.hr Sa~etak: LOKALNA FIBRINOLIZA KAO UZROK KRVARENJA U DJECE NAKON TONZILEKTOMIJE Srana uli Oko 2% bolesnika mora biti lije eno zbog postoperativnog krvarenja, koje mo~e biti potencijalno letalna komplikacija tonzilektomije. Samo 6 % krvarenja dogaa se u prvih 24 sata, najviae petog i sedmog dana, a mo~e se pojaviti i kasnije osmog, petnaestog ili ak dvadesetog dana nakon tonzilektomije. Zbog velikog gubitka krvi bolesnici mogu primati i transfuzije. Rizik postoperativnog krvarenja ne mo~e se prevenirati ni koagulacijskim skriningom, niti opservacijom bolesnika u bolnici 48 do 72 sata poslije tonzilektomije. Naj eai uzrok ovakvom krvarenju je lokalna hiperfibrinoliza, koju mo~e potaknuti trauma ili upala. Koagulacijski testovi su normalni, zbog ega se ovo stanje ne mo~e otkriti niti potvrditi rutinskim laboratorijskim testovima. Kao poslijedica mo~e nastati masivno krvarenje u djece, koje mo~e ugroziti njihov ~ivot. Fibrinoliti ki sustav je fizioloaki mehanizam unutraanje obrane, koji sprije eva zgruaavanje krvi u krvnim ~ilama fibrinolizom, plazminom induciranom degradacijom fibrina. Patoloaka hiperfibrinoliza je po ~ivot opasno stanje, koje zahtijeva brzu medicinsku intervenciju. Lije enje sintetskim derivatima lizina kao ato su -aminokapronska kiselina (engl. -aminocaproic acid-EACA) i traneksemi na kiselina, koji posjeduju jaku antifibrinoliti ku ativnost, djelotvorno je, dobro podnoaljivo i smanjuje gubitak krvi. Rekombinantni faktor VIIa (rFVIIa) (NovoSeven, Novo Nordisk, Denmark) stimulira koagulaciju i inhibira fibrinolizu, pa se mo~e uspjeano primjeniti u lije enju djece s te~im krvarenjem zbog lokalne hiperfibrinolize nakon tonzilektomije. Klju ne rije i: lokalna fibrinoliza, tonzilektomija, krvarenje, dijete Summary: LOCAL FIBRINOLYSIS AS A CAUSE OF BLEEDING IN CHILDREN AFTER TONSILLECTOMY Srana uli Haemorrhage after tonsillectomy is a potentially lethal complication and approximately 2% patients have to be treated for postoperative bleeding. During the first 24 hours only 6 % bleeding episodes may occur, most of them on 5th and 7th, after 8th and 15th at the latest or even 20th day after tonsillectomy. Because of severe blood loss, patients may receive a blood transfusion. Neither the coagulation screening nor a 48 to 72 hour postoperative in hospital observation could prevent the risk of postoperative bleeding. Local hyperfibrinolysis with normal coagulation tests is most often a cause of bleeding which trauma or inflammation can induce. This condition cannot be detected by routine tests. Such condition in children can cause excessive bleeding and life threatening condition. Fibrinolytic system is one of endogenous defence mechanisms in the prevention of intravascular thrombosis and fibrinolysis is the plasmin-mediated degradation of fibrin. Patological hyperfibrinolysis is life threatening condition and needs urgent medical intervention. Synthetic derivatives of lysine, such as -aminocaproic acid (EACA) and tranexamic acid have strong antifibrinolytic activity and appears to be effective and well-tolerated agents for reduction of blood loss. Recombinant factor VIIa (rFVIIa) (NovoSeven, Novo Nordisk, Denmark) stimulates coagulation, inhibits fibrinolysis, and is a promising therapeutic option in children with massive bleeding because of local excessive hyperfibrinolysis after tonsillectomy. Key words: local fibrinolysis, tonsillectomy, bleeding, child Postoperativno krvarenje je naj ea komplikacija tonzilektomije (1). Nastaje u oko 2% bolesnika i mo~e biti letalno (2). U samo 6 % bolesnika krvarenje se dogaa u prvih 24 sata, naj ee nastaje petog ili sedmog dana, a mo~e se pojaviti i kasnije osmog, petnaestog ili ak dvadesetog dana nakon tonzilektomije (3). Prosje na dob kada se krvarenje javlja je 8.5 godina i eae je u ~enske djece (56%) (4). Ovakva krvarenja ne mo~emo predvidjeti niti pomou pozitivne anamneze, niti pomou laboratorijskih testova (5,6). Zbog teakog gubitka krvi bolesnici moraju primati transfuzije (7). U nekim slu ajevima ovakva komplikacija mo~e zavraiti letalno (8). Sustav fibrinolize Razlikujemo pet faza koagulacije: vasularnu fazu, trombocitnu fazu, koagulacijsku fazu, fazu retrakcije ugruaka i fazu razaranja ugruaka (Slika 1). Fibrinoliti ki sustav je endogeni obrambeni mehanizam koji je odgovoran za razgradnju ugruaka u svrhu prevencije intravaskularne tromboze. Fibrinoliza je fizioloaki proces odstranjivanja netopljivih depozita fibrina, pri emu nastaju topivi degradacijski produkti fibrina (9). Sredianji enzim je plazminogen, prekursor plazmina. Aktiviraju ga aktivatori plazminogena, tkivni aktivator plazminogena (tPA) i urokinaza, koji se nalaze u visokim koncentracijama u razli itim sekretima u tijelu (slina, suze, likvor) (10). Plazminogen cirkulira u mikromolarnim koncentracijama u plazmi, a primarno se sintetizira u jetri (11). Fibrinoliza ovisi o konverziji inaktivnog proenzima plazminogena u aktivni plazmin (Slika 2). Plazmin ima specifi ni afinitet za fibrin i odgovoran je za njegovu degradaciju, a mo~e razgraditi i neke druge plazmatske proteine kao ato su fibrinogen, faktor V i faktor VIII. Ekcesivna aktivacija fibrinoliti kog sustava dovodi do fibrinoliti kog stanja, koje karakterizira aktivacija plazminogena, deplecija 2-antiplazmina (2AP) i razgradnja fibrinogena. Fizioloaka fibrinoliza koja je odgovorna za uklanjanje ostataka fibrina iz krvotoka nije udru~ena s fibrinoliti kim stanjem (12). Hemostatski sustav u djece se razlikuje od odraslih. Nema dokaza da su djeca izlo~ena poveanom riziku od krvarenja, ali je rizik od tromboti kih komplikacija zna ajno ni~i zbog ega su djeca u prednosti za razliku od odraslih. Plazmatske koncentracije plazminogena i 2AP u djece ne razlikuju se od onih u odraslih bolesnika, za razliku od koncentracija tkivnog activatora plazminogena (engl. tissue plasminogen activator - tPA), koje su za 50% manje i inhibitora aktivacije plazminogena (engl. plazminogen activator inhibitors - PAI-1) koje su za 50% vee. Sveukupni kapacitet fibrinoliti kog sustava da reagira je tijekom djetinstva sni~en (13). Stabilnost fibrinskog ugruaka odreena je finom ravnote~om izmeu koagulacije i fibrinolize pri emu je iznimno va~an trombin aktivirajui inhibitor fibrinolize (engl. thrombin activatable fibrinolysis inhibitor-TAFI). TAFI cirkulira u inaktivnoj formi i aktivira se pomou trombina za vrijeme stvaranja ugruaka (Slika 2). Aktivirani TAFIa atiti fibrinski ugruaak od raspadanja inhibirajui fibrinolizu, smanjujui stvaranje plazmina. Joa uvijek do kraja nije razjaanjena uloga TAFI-a u bolestima tromboze i krvarenja (14,15). Zbog poremeaja ravnote~e izmeu koagulacije i fibrinolize nastaju bolesti krvarenja ili tromboembolijske bolesti. Usna aupljina je puna aktivatora plazminogena, koji se nalaze u slini i sluznici usne aupljine, zato su kiruraki zahvati unutar usne aupljine rizi ni i smatramo ih te~im kirurakim zahvatima. Lokalna hiperfibrinoliza mo~e nastati nakon tonzilektomije zbog infekcije ili traume nakon operativnog zahvata. Plazmin u slini neprestano otapa stvoreni ugruaak i krvarenje nakon tonzilektomije se ne mo~e zaustaviti. 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Hiperfibrinoliza mo~e biti uroena ili ste ena i nastaje naj eae zbog nedostatne aktivnosti inhibitora aktivatora plazminogena 1 (PAI-1) i 2AP (16). Jedino ispravno i uspjeano lije enje je primjena sinteti kih antifibrinolitika. Sinteti ki antifibrinolitici Sinteti ki derivati lizina kao ato su -aminokapronska kiselina (EACA) ili traneksemi na kiselina djeluju sna~no antifibrinoliti ki vrlo rijetko uzrokujui ne~eljene efekte. Primjenjuju se ve od 1960 godine uspjeano u brojnim klini kim stanjima u kontroli krvarenja uzrokovanog lokalnom ili sistemnom hiperfibrinolizom. Primjenjuju se peroralno ili intravenozno i eliminiraju se bubrezima nepromijenjene. Traneksemi na kiselina je sinteti ki derivat lizina, zna ajno smanjuje gubitak krvi djelujui antifibrinoliti ki reverzibilnim blokiranjem plazminogena (17,18). Dobro se podnosi i djelotvorna je u zaustavljanju krvarenja zbog poja ane lokalne fibrinolize nakon tonzilektomije (19,20). Deset puta je ja a u inhibiciji fibrinolize od EACA, daje se intravenozno ili peroralno 10-20 mg/kg svakih 8 sati, a mo~e se primjeniti i lokalano ispiranjem usne aupljine svakih 6 sati. EACA se primjenjuje i.v. ili per os 50-70 mg/kg svaka 4 sata (21,22). Osim inhibitora fibrinolize u zaustavljanju krvarenja, pogotovo teakih, mo~e se uspjeano primjeniti i rFVIIa koji ubrzava nastanak ugruaka i inhibira fibrinolizu aktivacijom TAFI (23,24). Zaklju ak Krvarenje nakon operativnog zahvata je potencijalno letalna komplikacija tonzilektomije u djece, uzrokovana poja anom lokalnom fibrinolizom. Ovakvo stanje treba na vrijeme prepoznati i lije iti intravenoznom primjenom antifibrinolitika kao ato su traneksemi na kiselina ili EACA, koje uspjeano smanjuju gubitak krvi i preveniraju davanje transfuzija. Zbog svojih antifibrinoliti kih i prokoagulantnih sposobnosti rFVIIa mo~e doprinijeti brzom zaustavljanju krvarenja, naro ito u bolesnika koji su ~ivotno ugro~eni, pa se u teakim slu ajevima uz derivate lizina preporu a i primjena rFVIIa. LITERATURA: Gastpar H. Complications during and following tonsillectomy. Laryngol Rhinol Otol (Stuttg) 1976;55(4):292-8. Windfuhr JP, Sesterhenn K. Hemorrhage after tonsillectomy. Analysis of 229 cases. HNO 2001;49(9):706-12. Gunzel T, Zenev E, Heinze N, Schwager K. Postoperative bleeding after tonsillectomy between 1985 and 2001 and experiences to perform laser tonsillotomy. Laryngorhinootologie 2004;83(9):579-84. Peterson J, Losek JD. Post-tonsillectomy hemorrhage and pediatric emergency care. Clin Pediatr (Phila) 2004;43(5):445-8. Howells RC 2nd, Wax MK, Ramadan HH. Value of preoperative prothrombin time/partial thromboplastin time as a predictor of postoperative hemorrhage in pediatric patients undergoing tonsillectomy. Otolaryngol Head Neck Surg 1997;117(6):628-32. Gabriel P, Mazoit X, Ecoffey C. Relationship between clinical history, coagulation tests, and perioperative bleeding during tonsillectomies in pediatrics. J Clin Anesth 2000;12(4):288-91. Mutz I, Simon H. Hemorrhagic complications after tonsillectomy and adenoidectomy. Experiences with 7,743 operations in 14 years. Wien Klin Wochenschr 1993;105(18):520-2. Windfuhr JP, Chen YS. Hemorrhage following pediatric tonsillectomy before puberty. Int J Pediatr Otorhinolaryngol 2000;58(3):197-204. Labar B, Hauptman E i sur. Sustav zgruaavanja i fibrinolize. U: Hematologija. Zagreb: `kolska knjiga, 1998:48-52. uli S. Bolesti hemostaze. U: Topi E, Primorac D, Jankovi S.. Medicinsko biokemijska dijagnostika u klini koj praksi. Zagreb: Medicinska Naklada, 2004:223-39. Raum D, Marcus D, Alper CA. Genetic polymorphism of human plasminogen. Am J Hum Genet 1980;32:681-9. Vaughan DE, Declerck PJ. Regulation of Fibrinolysis. U: Loscalzo J, Schafer AI. Thrombosis and Hemorrhage. Philadelphia: Lippincott Williams & Wilkins 2003:105-19. Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L. Maturation of the hemostatic system during childhood. Blood 1992;80(8):1998-2005. Bouma BN, Mosnier LO. Thrombin activatable fibrinolysis inhibitor (TAFI) at the interface between coagulation and fibrinolysis. Pathophysiol Haemost Thromb 2003/2004;33(5-6):375-81. Marx PF. Thrombin-activatable fibrinolysis inhibitor. Curr Med Chem 2004;11(17):2335-48. Lee MH, Vosburgh E, Anderson K, McDonagh J. Deficiency of plasma plasminogen activator inhibitor 1 results in hyperfibrinolytic bleeding. Blood 1993;81(9):2357-62. Dunn CJ, Goa KL. Tranexamic acid: a review of its use in surgery and other indications. Drugs 1999;57(6):1005-32. Verstraete M. Clinical application of inhibitors of fibrinolysis. Drugs 1985;29(3):236-61. Castelli G, Vogt E. Result of an antifibrinolytic treatment using tranexamic acid for the reduction of blood-loss during and after tonsillectomy. Schweiz Med Wochenschr 1977;107(22):780-4. Sindet-Pedersen S. Distribution of tranexamic acid to plasma and saliva after oral administration and mouth rinsing: a pharmacokinetic study. J Clin Pharmacol 1987;27(12):1005-8. Mannucci PM. Nontransfusional hemostatic agents. U: Loscalzo J, Schafer AI, ur. Thrombosis and Hemorrhage 3. izd. Philadelphia: Lippincott Williams & Wilkins, 2003:915-28. Ramstrom G, Sindet-Pedersen S, Hall G, Blomback M, Alander U. Prevention of postsurgical bleeding in oral surgery using tranexamic acid without dose modification of oral anticoagulants. J Oral Maxillofac Surg 1993;51(11):1211-6. Lisman T, Mosnier LO, Lambert T, Mauser-Bunschoten EP, Meijers JC, Nieuwenhuis HK, de Groot PG. Inhibition of fibrinolysis by recombinant factor VIIa in plasma from patients with severe hemophilia A. Blood 2002;99(1):175-9. Lisman T, de Groot PG, Lambert T, Rojkjaer R, Persson E. Enhanced in vitro procoagulant and antifibrinolytic potential of superactive variants of recombinant factor VIIa in severe hemophilia A. J Thromb Haemost 2003;1(10):2175-8. Slika 1. Koagulacija i fibrinoliza Figure 1. Coagulation and fibrilolysis  Preuzeto s web stranice:  HYPERLINK "http://www.diapharma.com/cascade/diapharma_illustrations.htm" http://www.diapharma.com/cascade/diapharma_illustrations.htm Slika 2. Mehanizam fibrinolize Figure 2. 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