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Selhání Koagulace MUDr. Tomáš Stopka Ph.D. a kolektiv Ústavu patologické fyziologie.

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Prezentace na téma: "Selhání Koagulace MUDr. Tomáš Stopka Ph.D. a kolektiv Ústavu patologické fyziologie."— Transkript prezentace:

1 Selhání Koagulace MUDr. Tomáš Stopka Ph.D. a kolektiv Ústavu patologické fyziologie

2 Plán Koagulace Koagulace Vyšetření Vyšetření DIC DIC Terapie Terapie Referát Referát

3 I. Koagulace Initiating the Clotting Process 1. Damaged cells (extrinsic pathway) display a surface protein called tissue factor (TF) that binds to activated Factor 7 (TF-7) to cleave: Factor Factor 10 binds and activates Factor 5 (prothrombinase) convertíng prothrombin (also known as Factor II) to thrombin 3. Thrombin proteolytically cleave fibrinogen (Factor I) to fibrin. 4. Factor 13 forms covalent bonds between the soluble fibrin molecules converting them into an insoluble meshwork — the clot.

4 I. Koagulace Amplifying the Clotting Process 1. The TF-7 complex also activates Factor Factor 9 binds to Factor 8, a protein that circulates in the blood stabilized by another protein, von Willebrand Factor (vWF). 3. Complex 9-8-vW activates more factors: 5,8,10,11

5 I. Koagulace LUMEN Blood clot WALL Endothelial demage Damaged endothelial cells display tissue factor (TF) that binds to activated Factor 7 (TF-7) to cleave: Factor 10 The intrinsic cascade is initiated when contact is made between blood and exposed endothelial cell surfaces.

6 I. Koagulace Controlling Clotting Antithrombin III inactivates: prothrombin, factor 9, factor 10 Protein C and its cofactor Protein S together inhibit thrombin formation by inactivating Factor 5 and by inactivating Factor 8. Inherited deficiency (mutations) of Protein C or Protein S (or FV, Leiden)= thrombophilia Vitamin K is a cofactor needed for the synthesis (in the liver) of factors 2 (prothrombin), 7, 9, and 10, proteins C and S Deficiency of Vitamin K predisposes to bleeding. Conversely, blocking the action of vitamin K helps to prevent inappropriate clotting. Heparin binds to and enhances antithrombin III. Warfarin (aka coumadin) is an effective vitamin K antagonist.antagonist

7 I. Koagulace Dissolving clots Plasma plasminogen to the fibrin molecules in a clot. Nearby healthy cells release tissue plasminogen activator (TPA), which also binds to fibrin and, activates plasminogen forming plasmin. Plasmin (serine protease) proceeds to digest fibrin, thus dissolving the clot.serine protease

8 I. Koagulace HEMOKOAGULAČNÍ ROVNOVÁHA JE INTEGRÁLNÍ SOUČÁSTÍ ZÁNĚTOVÉ ODPOVĚDI. KREVNÍ DESTIČKY PLAZMATICKÝ KOAGULAČNÍ SYSTÉM KOAGULAČNÍ, FIBRINOLYTICKÝ, KALIKREIN-KININOVÝ CÉVNÍ STĚNA ENDOTEL

9 I. Koagulace PORUCHY HEMOKOAGULAČNÍ ROVNOVÁHY = TROMBÓZY A EMBOLIE TROMBÓZA V MIKROCIRKULACI ARTERIÁLNÍ ŽILNÍ EMBOLIE PLICNÍSYSTÉMOVÁ OBECNÉ PŘÍZNAKY - ISCHEMIE TKÁNÍ - OBĚHOVÉ SELHÁNÍ

10 I. Koagulace Časná hluboká žilní trombóza (DVT) A) asymptomatická : způsobuje > 50% PE. B) symptomatická: otok, pasivní bolest nebo palpační bolestivost, změny zbarvení a teploty kůže, Homansův příznak. Posttrombotický syndrom Příznaky chronické DVT, někdy s latencí let po inzultu následkem rozvoje zpočátku asymptomatické DVT, náplň povrchových kolaterálních žil, lipodermatoskleróza, varixy, ulcerace - 50% v důsledku DVT. Plicní embolie (PE) Dle závažnosti: dyspnoe, tachypnoe, tachykardie, pleuritická bolest na hrudi, zvýšená náplň krčních žil, hemoptýza, oběhová nestabilita, oběhové selhání až náhlá smrt.

11 I. Koagulace KRVÁCENÍ CHIRURGICKÉ Z MALÝCH TRAUMAT - sc., im.vpichy - eroze na sliznicích DIFUZNÍ MIKROVASKULÁRNÍ - purpury - petechie, ekchymozy (>3 mm) - orgánové apoplexie A) trombocytopenie B) desintegrace mikrovaskulární intimy selhání posttraumatické hemostázy - dysfunkce D, PKS, E nadhraniční trauma i při funkční hemostáze

12 II. Vyšetření Stanovení času krvácení (Duke, 1910) Měří se čas potřebný pro spontánní zastavení krvácení ze standardního vpichu do ušního lalůčku (Duke, 1910) nebo ze standardního řezu na předloktí (Ivy, 1941). Normální čas krvácení je min. nebo min., dle metody. Prodloužený čas signalizuje poruchu primární hemostázy - nejčastěji poruchu funkce destiček, těžkou trombocytopenii (<20 000/uL) nebo vonWillebrandovu chorobu (kvant. nebo kval. změny vWf). Stanovení rezistence kapilár ( Rumpel, Leede) Zjisťuje se počet petechií, které se vytvoří na určité ploše předloktí (4x4 cm) po stlačení známou silou (manžeta 10,5 kPa/10 min) nebo po aplikaci podtlaku (Brown, 1949). V klasickém uspořádání počet petechií > 5 signalizuje zvýšení fragility kapilár. Test slouží především k diagnotice hereditárních purpur (Weber-Rendu-Osler). STANOVENÍ ČASU KRVÁCENÍ A REZISTENCE KAPILÁR

13 II. Vyšetření Lee-Whiteův test - koagulační čas plné krve odebrané bez antikoagulancí v polystyrenové nebo skleněné zkumavce při 37oC. Normální hodnoty min., dle uspořádání. Hrubý orientační test funkce PKS v akutních stavech. Trombinový čas plné krve - koagulační čas plné krve odebrané bez antikoagulancií ve zkumavce se standardním množstvím trombinu. Slouží pro rychlou orientační kontrolu přítomnosti fibrinogenu (+/-) v krvi při dekompenzaci akutní DIC. Aktivovaný koagulační čas (ACT) - krev odebraná bez antikoagulancia se aplikuje do zkumavky s kontaktním aktivátorem (silika, kaolin) a v přístroji je při 37oC míchána do odečtení času koagulace. Rutinní použití pro kontrolu heparinizace při mimotělním oběhu a hemodialýze. ACT normální krve je cca 150 s, při heparinizaci pro dlouhodobý MO nebo hemodialýzu s, při MO v kardiochirurgii > 600 s. Metody vyšetření srážlivosti plné krve u lůžka

14 II. Vyšetření Počet krevních destiček (PLT) - normál /uL, pro chirurgii optimum > /uL. Těžké trombocytopenie PLT < / uL - spontánní krvácení a purpury. Střední objem destiček (MPV) - normál fL, velké destičky - některé hereditární trombocytopatie. Agregometrie - fotometrickým nebo impedančním měřením se v kyvetě agregometru stanoví agregace destiček v citrátové plazmě bohaté na destičky nebo v plné citrátové krvi po přidání aktivátoru - ADP, trombinu, kolagenu. Diagnostika především hereditárních trombocytopatií. Průtoková cytometrie - imunologické stanovení receptorů na destičkách. Protilátky proti destičkám - diagnostika imunitních trombocytopenií Stanovení vWf - imunologicky nebo funkčně jako ristocetin kofaktor agregometricky. Laboratorní metody diagnostiky poruch krevních destiček a vWf

15 II. Vyšetření Základní vyšetření PT - protrombinový čas PT (Quickův test) APTT - aktivovaný parciální tromboplastinový čas Další statimově dostupná vyšetření v ČR FBG - stanovení concentrace fibrinogenu v plazmě (normál :2 - 4 g/L). Funkční (klotabilní FBG) nebo imunologická metoda. Diagnostika hypofibrinogenemie (např. při akutní DIC) nebo hyperfibrinogenemie ( při zánětu, FBG je protein akutní fáze) FDP - imunologické stanovení celkových degradačních produktů fibri(noge)nu (normál: < 1000 ug/L), ELISA nebo aglutinační semikvant. metody. Diagnostika hemokoagulačního rozvratu. Vysoké FDP při hyperfibrino(geno)lýze. Laboratorní metody diagnostiky poruch PKS Krev odebraná do citrátu sodného se odstředí a získá se tak citrátová plazma chudá na destičky, která se použije k testu.

16 II. Vyšetření D-dimer - imunologické stanovení FDP specifických pro stabilizovaný fibrin (normál < 500 ug/L). Zvýšení D-dimeru je vysoce senzitivní pro diagnostiku DVT/PE, avšak málo specifické. AT - funkční test stanovení aktivity antitrombinu v plazmě (normál % aktivity kontrolní plazmy ). Při dysregulaci trombinu se AT spotřebovává v inhibičním komplexu TAT, kofaktorem je heparin. Primární nebo sekundární deficience AT (< 75%) představuje riziko trombofilie až rozvoje DIC. TT - trombinový čas plazmy (normál s). Přímé vyšetření konverze FBG na fibrin, TT je prodloužen při dysfibrinogenemii, těžké hypo- nebo afibrinogenemii, vysoké hladině FDP (působí antipolymeračně), při heparinové terapii. Statimově dostupná vyšetření PKS (II)

17 II. Vyšetření Testy běžné v ČR, avšak stále méně používané ve světě - nízká specificita senzitivita Etanolový test - orientační test na přítombost FDP a fibrinových monomerů v plazmě. V přítomnosti etanolu disociují antipolymeračně působící FDP z přítomných fibrinových monomerů a dochází k tvorbě fibrinového polymeru - vlákna. Normálně je test negativní, pozitivní je při dysregulaci trombinu a plazminu (DIC). Euglobulinová metoda stanovení fibrinolytické aktivity Z plazmy se vysráží v izoelektrickém bodě kys. octovou euglobulinová frakce obsahující plazminogen, frakce se oddělí, rozpustí a znovu vysráží CaCl2. Přítomný plazmin, precipitací zbavený účinku alfa2 antiplazminu lyzuje vzniklou sraženinu. Při aktivaci fibrinolytického systému je přítomno více aktivovaného volného plazminu a lýza sraženiny je rychlejší. Normální čas lýzy je min. Kratší časy signalizují zvýšenou aktivaci fibrinolytického systému. Statimově dostupná vyšetření PKS (III)

18 II. Vyšetření Vyšetření systému proteinu C- stanovení proteinu C, Akt. Protein C rezistence (mutace FV), proteinu S Vyšetření fibrinolytického systému- stanovení aktivátorů plazminogenu tPA, uPA, jejich inhibitoru PAI-1, stanovení plazminogenu, jeho inhibitoru alfa2AP, stanovení lipoproteinu Lp (a) Vyšetření antifosfolipidových protilátek - lupus antikoagulans (LA) : modif. APTT a spec. koag. Testy na LA, antikardiolipinové protilátky - imunologicky Vyšetření aktivity jednotlivých faktorů PKS pomocí APTT testu s použitím selektivně deficitní plazmy - diagnostika hemofilie A (FVIII), B(FIX), C (FXI) a dalších deficiencí Speciální vyšetření PKS

19 II. Vyšetření Princip metody: test simuluje hlavní cestu aktivace PKS - cestu tkáňového faktoru (historicky: vnější cesta aktivace). Do citrátové plazmy se přidá přebytek tkáňového tromboplastinu (tkáňový faktor v negativně nabitých fosfolipidech) a CaCl2. V koagulometru se měří čas vzniku fibrinového vlákna. Normální hodnoty: PTN= s Prodloužení PT:, deficit FV nebo vit. K dep. FII, VII, X těžký deficit FBG, vysoké FDP, porucha konverze FBG, v určitém uspořádání není ovlivněn heparinem (do 1 U/mL) Využití testu: screeningový test, řízení orální antikoagulační terapie antagonisty vit. K, test jaterní proteosyntézy (FVII) Vyjadřování výsledků: a) % protrombinového komplexu, b) poměr PTP/ PTN, c) mezinárodní normalizovaný poměr INR= (PTP/ PTN)ISI kde ISI = mezinárodní index senzitivity užitého tromboplastinu (většinou > 1). INR je oficiálně určen pouze pro řízení orální antikoagulační terapie (max. terapeut. INR = 4,5), používá se však často všeobecně. Protrombinový čas PT (Quickův test)

20 II. Vyšetření Princip metody: test simuluje kontaktní cestu aktivace PKS (vnitřní cestu). Do citrátové plazmy se aplikuje kontaktní aktivátor (např.kaolin) pro aktivaci kontaktního systému a negativně nabité fosfolipidy pro umožnění tvorby FX- a FII- aktivačních komplexů. Plazma se rekalcifikuje CaCl2 a v koagulometru se měří čas do vzniku fibrinového vlákna. Normální hodnoty: APTTN = s Využití testu: screeningový test, diagnostika deficitu faktorů “vnitřního“ systému, lupus antikoagulans, řízení heparinové terapie. Prodloužení APTT: deficit FII,V, X, deficit kontaktních faktorů - F XII, PK, HMWK, deficit FXI, FIX, FVIII (hemofilie C, B,A), lupus antikoagulans, těžkýdeficit FBG, vysoké FDP, porucha konverze FBG. Zkrácení APTT: protrombotický stav Vyjadřování výsledků: APTT pacienta, APTT kontroly (normálu), při heparinové terapii řízené APTT požadováno 1,5x - 2,5 x prodloužení. Aktivovaný parciální tromboplastinový čas APTT

21 II. Vyšetření Pravděpodobné výsledky laboratorních testů při různých poruchách hemostázy (I) Porucha PLT BT APTT PT TT FBG Trombocytopenie L P N N N N Hemofilie A N N P N N N Hemofilie B N N P N N N Hemofilie C N N P N N N vW-choroba N P N/P N N N LA N N P N/P N N

22 II. Vyšetření Pravděpodobné výsledky laboratorních testů při různých poruchách hemostázy (II) PoruchaPLTBT APTTPTTTFBG FV-def. FII-def. FVII-def. Vit.Kdef./OA FBG-def. Heparin NP/NPN/PN N NNPPPLNNPPPL NNPPN N NNNPNNNNNPNN NNPPNNNNPPNN NNPPNNNNPPNN

23 III. DIC Definice Definice Narušení rovnováhy mezi jednotlivými složkami hemostatických mechanismů. Vždy doprovází jinou chorobu DIFF (diseminovaná intravaskulární formace fibrinu)

24 III. DIC Etiopatogeneze Etiopatogeneze Průnik substancí aktivujících srážení krve do oběhu tkáňový faktor (vnější systém F X, VII, V, Ca) krevní tromboplastin, trombokináza (vnitřní systém F XII, XI, IX, X, VII, V, K) Přímá intravaskulární aktivace koagulace Selhání inhibičních mechanismů koagulace a monocyto- makrofágového systému

25 III. DIC Rozdělení DIC Rozdělení DIC Akutní (dekompenzovaný, high-grade) život ohrožující stav Chronický (kompenzovaný, low-grade) prolongovaná alterace hemostatických mechanismů nevýrazná klinická symptomatologie

26 Conditions Associated with DIC Heat stroke Heat stroke Sepsis Sepsis Viremia Viremia Pancreatitis Pancreatitis Neoplasia (Diffuse and local) Neoplasia (Diffuse and local) Parasitic Infections Parasitic Infections Intravascular Hemolysis Intravascular Hemolysis Immune-mediated Diseases Immune-mediated Diseases Exposure to venom/toxins Exposure to venom/toxins Massive tissue injury (including burns, crush trauma, and surgical procedures) Massive tissue injury (including burns, crush trauma, and surgical procedures) Obstetric Complications Insufficiency of major organs (Liver, Kidney) Diabetes mellitus Acidosis Polycythemia Severe prolonged hypotension (including shock) Severe volume depletion Impaired blood flow to a major organ

27 What are FDPs and D-dimers and how do they relate to DIC? Activation of the coagulation cascade results in increased levels of circulating thrombin and plasmin. Activation of the coagulation cascade results in increased levels of circulating thrombin and plasmin. Thrombin cleaves fibrinopeptides A and B from fibrinogen, leaving soluble fibrin monomers as the end product (Figure 1). Thrombin cleaves fibrinopeptides A and B from fibrinogen, leaving soluble fibrin monomers as the end product (Figure 1). Activation of factor XIII results in polymerization of these fibrin monomers into insoluble cross- linked fibrin clots. Activation of factor XIII results in polymerization of these fibrin monomers into insoluble cross- linked fibrin clots. Increased levels of circulating plasmin causes clot lysis and degradation of fibrinogen and the soluble fibrin monomers.Increased levels of circulating plasmin causes clot lysis and degradation of fibrinogen and the soluble fibrin monomers. Plasmin cleaves fibrinogen into fragments X,Y,D, and E, known as fibrinogen degradation products (FDPs).Plasmin cleaves fibrinogen into fragments X,Y,D, and E, known as fibrinogen degradation products (FDPs). Plasmin also cleaves insoluble cross- linked fibrin polymers into x-oligomers. The main x-oligomers are known as d-dimers.Plasmin also cleaves insoluble cross- linked fibrin polymers into x-oligomers. The main x-oligomers are known as d-dimers. DIC

28 What are FDPs and D-dimers and how do they relate to DIC? FIBRIN Monoclonal antibodies have been generated which recognize the cross-linked domain of d-dimers as an antigenic target. These antibodies are used in all available d- dimer assays. Monoclonal antibodies have been generated which recognize the cross-linked domain of d-dimers as an antigenic target. These antibodies are used in all available d- dimer assays. Quantitative tests for d-dimers are available, including enzymatic immunoassays (ELISA) and immunoturbidometric systems. Quantitative tests for d-dimers are available, including enzymatic immunoassays (ELISA) and immunoturbidometric systems.

29 III. DIC Klinické příznaky Klinické příznaky 1Makro- a mikrotrombóza + selhání cílových orgánů 2Krvácení Kombinace těchto projevů 3Modifikace základním onemocněním Rychlost aktivace koagulace

30 III. DIC Diagnóza Anamnéza Objektivní nález základní onemocnění klinická symptomatologie Laboratorní diagnóza Negativní laboratoř nevylučuje DIC !!!

31 III. DIC Laboratorní diagnóza NORMA Laboratorní diagnóza NORMA PLT x 10 exp9 /l PLT x 10 exp9 /l APTT s APTT s AT % AT % TT s TT s FBG g/l FBG g/l FM (etanol test) FM (etanol test) DD < 500 ng/ml DD < 500 ng/ml FDP FDP

32 III. DIC Laboratorní diagnóza DIC Laboratorní diagnóza DIC PLT sníženy PLT sníženy APTT zkrácený nebo prodloužený APTT zkrácený nebo prodloužený AT snížený AT snížený TT prodloužený TT prodloužený FBG snížený FBG snížený FM (etanol test) pozitivní FM (etanol test) pozitivní plazminogen snížený plazminogen snížený DD pozitivní DD pozitivní FDP pozitivní FDP pozitivní euglobulinová lýza norm. - prodloužená euglobulinová lýza norm. - prodloužená

33 III. DIC Laboratorní diagnóza “SUMMARY” Laboratorní diagnóza “SUMMARY” PLT PLT FBG FBG DD DD AT AT opakovat v intervalech 3-4h opakovat v intervalech 3-4h

34 III. DIC Stadia DIC Stadia DIC 1Hyperkoagulační klinicky němé 2Přechod do hypokoagulace krvácení z vpichů, chabá koagulace, trombózy v mikrocirkulaci 3Hypokoagulace s masívní fibrinolýzou masívní krvácení, nesrážlivá krev, orgánové selhání (MOF) - mikrotrombózy 4Laboratorně neměřitelné hodnoty

35 III. DIC Diferenciální diagnóza Diferenciální diagnóza 1Masívní krevní převody či hemodiluce 2Stavy se zvýšeným FDP a DD operace, porod, trauma, embolizace 3HIT/HITT heparinem indukovaná trombocytopenie /+ trombóza 4DIC like sy (TTP, HUS) 5Lupus anticoagulans katastrofická forma (pozitivní APA)

36 Thrombotic Thrombocytopenic Purpura von Willebrand factor protein multimer analysis on agarose gel electrophoresis. Lane 1. - normal plasma. Lane 2. - patient plasma when symptomatic. Multimer pattern is similar to the control plasma. Lane 3. - patient plasma after response to pheresis. Note the presence of ultra- large high molecular weight multimers. Peripheral smear showing microangiopathic hemolytic features with numerous RBC fragments (helmet cells/schistocytes). Marked thrombocytopenia is evident. Renal biopsy showing hyaline thrombi in the glomerulus and small arterioles.

37 Researchers Pinpoint Cause of Deadly Blood-Clotting Disorder Several earlier studies had implicated a clotting-related protein known as Several earlier studies had implicated a clotting-related protein known as von Willebrand factor (VWF) in the disorder. These studies found that the blood of patients with TTP showed an abnormally large form of the VWF protein that had not been cleaved into two smaller sizes, as is normally the case. Thus, said Ginsburg, many scientists believed that a defect in a protein- clipping enzyme known as a protease might be responsible for the disorder. One of the keys to identifying the gene mutations that underlie TTP was the development of a precise assay for detecting VWF protease activity. Han-Mou Tsai, a senior author of the Nature paper, and colleagues at Montefiore Medical Center and Albert Einstein College of Medicine developed the assay and applied it to blood samples that were provided by members of four families that had an inherited form of TTP. The assays clearly revealed that within these families, those who had TTP showed low VWF protease activity, while carriers of the disease showed medium levels of protease activity, and unaffected individuals showed normal levels. One of the keys to identifying the gene mutations that underlie TTP was the development of a precise assay for detecting VWF protease activity. Han-Mou Tsai, a senior author of the Nature paper, and colleagues at Montefiore Medical Center and Albert Einstein College of Medicine developed the assay and applied it to blood samples that were provided by members of four families that had an inherited form of TTP. The assays clearly revealed that within these families, those who had TTP showed low VWF protease activity, while carriers of the disease showed medium levels of protease activity, and unaffected individuals showed normal levels. Using results from the assay as a guide, Gallia G. Levy, lead author of the Nature article, performed linkage analyses of the family members and determined which of known genomic markers were inherited with the disease gene. These studies enabled her to narrow down the region containing the disease gene to a specific region of chromosome 9. Using results from the assay as a guide, Gallia G. Levy, lead author of the Nature article, performed linkage analyses of the family members and determined which of known genomic markers were inherited with the disease gene. These studies enabled her to narrow down the region containing the disease gene to a specific region of chromosome 9. Levy then obtained the full gene sequence and proceeded to test the other patients for mutations in the gene, which they named ADAMTS13. Levy subsequently identified a dozen mutations in the gene among the patients, accounting for nearly all the cases of TTP. According to Ginsburg, Levy’s findings open the way to understanding how and why the ADAMTS13 protease cleaves VWF and how the failure to cleave the protein causes disease. Levy then obtained the full gene sequence and proceeded to test the other patients for mutations in the gene, which they named ADAMTS13. Levy subsequently identified a dozen mutations in the gene among the patients, accounting for nearly all the cases of TTP. According to Ginsburg, Levy’s findings open the way to understanding how and why the ADAMTS13 protease cleaves VWF and how the failure to cleave the protein causes disease.

38 III. DIC Terapie 1: Terapie 1: Přerušení aktivace koagulace Přerušení aktivace koagulace 1 Heparin nefrakcionovaný 1 Heparin nefrakcionovaný 5-10 IU/kg/h 5-10 IU/kg/h bolus 2500 IU, poté inf. do IU/24h bolus 2500 IU, poté inf. do IU/24h LMWH LMWH

39 III. DIC Terapie 2: Terapie 2: Přerušení aktivace koagulace Přerušení aktivace koagulace 2 AT (Antitrombin III, Kybernin P) 2 AT (Antitrombin III, Kybernin P) při méně než 60%, cílem % při méně než 60%, cílem % IU jako bolus IU jako bolus KI nejsou známy KI nejsou známy biologický poločas 3-4 dny, u sepse několik hodin biologický poločas 3-4 dny, u sepse několik hodin

40 III. DIC Terapie 3 Terapie 3 Substituční léčba Substituční léčba 3 Čerstvě zmražená plazma 3 Čerstvě zmražená plazma 15 ml/kg při APTT více než 1.5 R 15 ml/kg při APTT více než 1.5 R 4 Fibrinogen 4 Fibrinogen při poklesu 1.0 g/l (maximálně 2g/24h) při poklesu 1.0 g/l (maximálně 2g/24h) obavy z podnícení konzumpce obavy z podnícení konzumpce g v infúzi g v infúzi

41 III. DIC Terapie 4 Terapie 4 Substituční léčba Substituční léčba 5 Čerstvá krev 5 Čerstvá krev 6 Krevní destičky 6 Krevní destičky 1 jednotka/10kg 1 jednotka/10kg Antifibrinolytika ne !!! Antifibrinolytika ne !!! pouze po konzultaci s hematologem pouze po konzultaci s hematologem

42 III. DIC Terapie 5 Terapie 5 Obecná léčba Obecná léčba 1 Léčba šoku 1 Léčba šoku 2 Doplnění objemu 2 Doplnění objemu 3 Úprava vnitřního prostředí 3 Úprava vnitřního prostředí 4 Širokospektrá ATB 4 Širokospektrá ATB 5 Operační výkony k zástavě krvácení 5 Operační výkony k zástavě krvácení

43 Prevence - miniheparinizace 1 eklampsie, preeklampsie 1 eklampsie, preeklampsie 2 tromboflebitis anamn. 2 tromboflebitis anamn. 3 poruchy srážlivosti krve (protein C, AT III) 3 poruchy srážlivosti krve (protein C, AT III) 4 mrtvý plod 4 mrtvý plod 5 opakované revize dutiny děložní 5 opakované revize dutiny děložní 6 septický porod (potrat) 6 septický porod (potrat) 7 transplacent. průnik 7 transplacent. průnik 8 placenta praevia 8 placenta praevia 9 atonie dělohy 9 atonie dělohy 10 placenta accreta 10 placenta accreta 11 větší krevní ztráta 11 větší krevní ztráta 12 abrupce placenty 12 abrupce placenty 13 SC iterativa 13 SC iterativa 14 obezita 14 obezita 15 vyšší věk (33 let) 15 vyšší věk (33 let) 16 rozsáhlejší porodní poranění 16 rozsáhlejší porodní poranění 17 mola hydatidosa 17 mola hydatidosa 18 DM 18 DM

44 III. DIC

45 Acute DIC DIAGNOSIS Clinical findings Clinical findings Multiple bleeding sites Ecchymoses of skin, mucous membranes Visceral hemorrhage Ischemic tissue Laboratory abnormalities Laboratory abnormalities Coagulation abnormalities: prolonged prothrombin time, activated partial thromboplastin time, thrombin time; decreased fibrinogen levels; increased levels of FDP (eg, on testing for FDP, D dimer) Platelet count decreased as a rule but may be falling from a higher level yet still be normal Schistocytes on peripheral smear

46 Chronic DIC DIAGNOSIS Clinical findings Clinical findings Signs of deep venous or arterial thrombosis or embolism Superficial venous thrombosis, especially without varicose veins Multiple thrombotic sites at the same time Serial thrombotic episodes

47 Chronic DIC Laboratory abnormalities Laboratory abnormalities Modestly increased prothrombin time in some patients Shortened or lengthened partial thromboplastin time Normal thrombin time in most patients High, normal, or low fibrinogen level High, normal, or low platelet count Increased levels of FDP (eg, on testing for FDP, D dimer) Evidence of molecular markers* (eg, thrombin-antithrombin complexes, activation markers on platelet membranes, prothrombin fragment F1+2)

48 Current Management of DIC At present, diagnosis requires a set of blood tests; therapy focuses on reversing the underlying disorder and providing supportive treatment. At present, diagnosis requires a set of blood tests; therapy focuses on reversing the underlying disorder and providing supportive treatment.

49 Case 1 Presentation A 56-year-old man was admitted to the emergency department after a car accident. A 56-year-old man was admitted to the emergency department after a car accident. He had several bone fractures, a cerebral contusion, and hemodynamic instability caused by a ruptured spleen.He had several bone fractures, a cerebral contusion, and hemodynamic instability caused by a ruptured spleen. Emergency splenectomy and aggressive administration of fluids restored hemodynamic stability, and the patient was transferred to the intensive care unit (ICU).Emergency splenectomy and aggressive administration of fluids restored hemodynamic stability, and the patient was transferred to the intensive care unit (ICU). A few hours later, profuse extravasation was noted from the abdominal drains, endotracheal tube, and puncture sites of all intravascular lines.

50 Case 1 Presentation Laboratory tests showed a rapidly falling hemoglobin level and a platelet count of 25,000/µL. Laboratory tests showed a rapidly falling hemoglobin level and a platelet count of 25,000/µL. The activated partial thromboplastin time (aPTT) was 44 sec (normal, <28) and the prothrombin time (PT) was 29 sec (normal, <12.5). The activated partial thromboplastin time (aPTT) was 44 sec (normal, <28) and the prothrombin time (PT) was 29 sec (normal, <12.5). The level of fibrinogen degradation products was g/L (normal, <40) and the plasma antithrombin III level was 28% (normal, ). The level of fibrinogen degradation products was g/L (normal, <40) and the plasma antithrombin III level was 28% (normal, ).

51 Case 1 Presentation Based on these findings, the diagnosis was DIC secondary to severe trauma. Surgical exploration revealed diffuse oozing of blood at the site of the operation, but only partial surgical hemostasis could be achieved. Based on these findings, the diagnosis was DIC secondary to severe trauma. Surgical exploration revealed diffuse oozing of blood at the site of the operation, but only partial surgical hemostasis could be achieved. The patient was given supportive treatment with: The patient was given supportive treatment with: large infusions of fresh frozen plasma large infusions of fresh frozen plasma platelet concentrates. platelet concentrates. The bleeding stopped 48 hours later. Coagulation parameters eventually returned to normal and the subsequent clinical course was uneventful.

52 The pathogenesis of DIC

53 Selected Disorders That May Be Associated with DIC Malignancy (solid tumors, myeloproliferative, lymphoproliferative) Obstetric emergencies (amniotic fluid embolism, abruptio placentae) Malignancy (solid tumors, myeloproliferative, lymphoproliferative) Obstetric emergencies (amniotic fluid embolism, abruptio placentae) Organ destruction (severe pancreatitis) Organ destruction (severe pancreatitis) Sepsis/severe infection (any microorganism) Sepsis/severe infection (any microorganism) Severe hepatic failure Severe hepatic failure Severe toxic or immunologic reactions (snake bites, recreational drugs, transfusion reactions, transplant rejection) Severe toxic or immunologic reactions (snake bites, recreational drugs, transfusion reactions, transplant rejection) Trauma (polytrauma, neurotrauma, trauma resulting in fat embolism) Trauma (polytrauma, neurotrauma, trauma resulting in fat embolism) Vascular abnormalities (Kasabach-Merritt syndrome, large vascular aneurysms) Vascular abnormalities (Kasabach-Merritt syndrome, large vascular aneurysms)

54 Infection. Bacterial infection, in particular septicemia, is commonly associated with DIC. However, systemic infections with other microorganisms, such as viruses and parasites, also may lead to DIC. Bacterial infection, in particular septicemia, is commonly associated with DIC. However, systemic infections with other microorganisms, such as viruses and parasites, also may lead to DIC. Components of the microorganism's cell membrane (lipopolysaccharide, or endotoxin) or bacterial exotoxins (e.g. staphylococcal alpha-toxin) may cause a generalized inflammatory response characterized by systemic production of cytokines, mainly by activated mononuclear cells and endothelial cells. Components of the microorganism's cell membrane (lipopolysaccharide, or endotoxin) or bacterial exotoxins (e.g. staphylococcal alpha-toxin) may cause a generalized inflammatory response characterized by systemic production of cytokines, mainly by activated mononuclear cells and endothelial cells. The cytokines are responsible for the derangement of the coagulation system in DIC. The cytokines are responsible for the derangement of the coagulation system in DIC.

55 Trauma Head trauma in particular is strongly associated with DIC; both local and systemic activation of coagulation may be detected after such an event. Head trauma in particular is strongly associated with DIC; both local and systemic activation of coagulation may be detected after such an event. The increased risk of DIC after head trauma is understandable in view of the relatively large amount of tissue factor in the cerebral compartment. The increased risk of DIC after head trauma is understandable in view of the relatively large amount of tissue factor in the cerebral compartment.

56 Cancer Both solid tumors and hematologic malignancies may be complicated by DIC. Both solid tumors and hematologic malignancies may be complicated by DIC. The mechanism by which the coagulation system becomes deranged is poorly understood. However, most studies implicate tissue factor, perhaps expressed on the surface of tumor cells. The mechanism by which the coagulation system becomes deranged is poorly understood. However, most studies implicate tissue factor, perhaps expressed on the surface of tumor cells. A distinct form of DIC is frequently encountered in patients with acute promyelocytic leukemia; it is characterized by a severe hyperfibrinolysis superimposed on an activated coagulation system. A distinct form of DIC is frequently encountered in patients with acute promyelocytic leukemia; it is characterized by a severe hyperfibrinolysis superimposed on an activated coagulation system. Although clinical bleeding predominates in such cases, disseminated thrombosis is found at autopsy in a considerable number of patients. Although clinical bleeding predominates in such cases, disseminated thrombosis is found at autopsy in a considerable number of patients.

57 Obstetric Emergencies Acute DIC occurs in obstetric complications such as amniotic fluid embolism and abruptio placentae. Acute DIC occurs in obstetric complications such as amniotic fluid embolism and abruptio placentae. Amniotic fluid can activate coagulation in vitro, and in abruptio placentae, the degree of placental separation correlates with the severity of DIC, suggesting that leakage of thromboplastinlike material from the placental system triggers DIC in these patients. Amniotic fluid can activate coagulation in vitro, and in abruptio placentae, the degree of placental separation correlates with the severity of DIC, suggesting that leakage of thromboplastinlike material from the placental system triggers DIC in these patients. The most common obstetric complication associated with activation of coagulation is preeclampsia. Severe preeclampsia may also be complicated by : The most common obstetric complication associated with activation of coagulation is preeclampsia. Severe preeclampsia may also be complicated by : HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets). The latter, however, is characterized by a microangiopathic hemolytic anemia with secondary changes in the coagulation system. It is related to, but clearly distinct from, DIC. HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets). The latter, however, is characterized by a microangiopathic hemolytic anemia with secondary changes in the coagulation system. It is related to, but clearly distinct from, DIC.

58 Vascular Disorders Large aortic aneurysms or giant hemangiomas (Kasabach-Merritt syndrome) may result in local activation of coagulation factors. Large aortic aneurysms or giant hemangiomas (Kasabach-Merritt syndrome) may result in local activation of coagulation factors. The activated local factors can ultimately overflow to the systemic circulation and cause DIC; more commonly, systemic depletion of coagulation factors and platelets results from local consumption. The activated local factors can ultimately overflow to the systemic circulation and cause DIC; more commonly, systemic depletion of coagulation factors and platelets results from local consumption. The ensuing clinical condition may be difficult to distinguish from DIC. The ensuing clinical condition may be difficult to distinguish from DIC.

59 Microangiopathic hemolytic anemia Microangiopathic hemolytic anemia is a group of disorders that includes: Microangiopathic hemolytic anemia is a group of disorders that includes: thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, chemotherapy-induced microangiopathic hemolytic anemia, malignant hypertension, and HELLP syndrome. thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, chemotherapy-induced microangiopathic hemolytic anemia, malignant hypertension, and HELLP syndrome. A common pathogenetic feature appears to be endothelial damage, which promotes platelet adhesion and aggregation, thrombin formation, and impaired fibrinolysis. A common pathogenetic feature appears to be endothelial damage, which promotes platelet adhesion and aggregation, thrombin formation, and impaired fibrinolysis. Although some characteristics of microangiopathic hemolytic anemia and the resulting thrombotic occlusion of small and mid-size vessels (leading to organ failure) may mimic the clinical presentation of DIC, these disorders in fact represent a distinct group of diseases. Although some characteristics of microangiopathic hemolytic anemia and the resulting thrombotic occlusion of small and mid-size vessels (leading to organ failure) may mimic the clinical presentation of DIC, these disorders in fact represent a distinct group of diseases.

60 Early events in sepsis 1) The intital toxic stimuli, such as endotoxin (LPS), triggers production of proinflammatory cytokines (TNF, IL-1) and monocyte adherence to endothelial cells. 2) TNF and IL-1 also activates neutrophils and endothelial cells for increased adherence. All activated cells release secondary inflammatory mediators, including cytokines. 3) Activation of platelets and increased production of procoagulants by endothelial cells may trigger microthrombosis. In some cases, disseminated intravascular coagulation (DIC) may occur with life-threatening tissue ischemia. 4) Vessel dilation caused by free radicals, histamine, prostaglandins, prostacyclin, and the kinin and tachykinin family of molecules, combined with the effects of cytokines on the endothelial cells, contribute to increased vascular permeability for fluids and low- molecular weight substances, causing oedema. If the process is wide-spread, a capillary leak syndrome may result.

61 Case 2 Presentation A 71-year-old woman was admitted to the ICU with sepsis complicated by hemodynamic and respiratory instability. A 71-year-old woman was admitted to the ICU with sepsis complicated by hemodynamic and respiratory instability. Four days earlier, she had undergone a duodenopancreatectomy for pancreatic carcinoma. Four days earlier, she had undergone a duodenopancreatectomy for pancreatic carcinoma. Fever, chills, and abdominal pain developed on the fourth day, and a computed tomographic scan showed an intra-abdominal abscess. Fever, chills, and abdominal pain developed on the fourth day, and a computed tomographic scan showed an intra-abdominal abscess. The diagnosis was septic shock complicated by respiratory failure, which was caused by adult respiratory distress syndrome. The diagnosis was septic shock complicated by respiratory failure, which was caused by adult respiratory distress syndrome.

62 Case 2 Presentation The patient was treated with intravenous fluids and vasopressors, intubation and mechanical ventilation, surgical drainage of the abscess, and intravenous antibiotics. The patient was treated with intravenous fluids and vasopressors, intubation and mechanical ventilation, surgical drainage of the abscess, and intravenous antibiotics. Acute renal failure and hepatic insufficiency supervened during the next several days. Moreover, the patient's respiratory status deteriorated; the cause was determined to be a large pulmonary embolism. Acute renal failure and hepatic insufficiency supervened during the next several days. Moreover, the patient's respiratory status deteriorated; the cause was determined to be a large pulmonary embolism. Laboratory tests showed persistent thrombocytopenia (platelet count, 30,000-40,000/µL) and prolonged global clotting times: aPTT, sec; PT, sec. Fibrin degradation product levels were very high (>1600 µg/L; normal 1600 µg/L; normal <40), and the antithrombin III level was 30%.

63 Case 2 Presentation Based on those findings, DIC secondary to sepsis was diagnosed. Based on those findings, DIC secondary to sepsis was diagnosed. The patient received supportive treatment with intravenous heparin and antithrombin III concentrate (50-70 U/kg), with a goal of producing greater than normal plasma concentrations. The patient received supportive treatment with intravenous heparin and antithrombin III concentrate (50-70 U/kg), with a goal of producing greater than normal plasma concentrations. After 10 days in the ICU, the patient gradually recovered and all organ function normalized. One month after her operation, she was discharged from the hospital in good condition. After 10 days in the ICU, the patient gradually recovered and all organ function normalized. One month after her operation, she was discharged from the hospital in good condition.

64 Diagnosis of DIC Test Result Platelet count Markedly decreased Prothrombin time Increased Activated partial thromboplastin time Increased Fibrin degradation products Markedly increased Fibrinogen Normal or decreased Antithrombin III Markedly decreased Protein C Markedly decreased

65 Specific Therapies Platelet and Coagulation Factor Infusion Platelet and Coagulation Factor Infusion Heparin Heparin

66 Platelet and Coagulation Factor Infusion Although low levels of platelets and coagulation factors may increase the risk of bleeding in patients with DIC, plasma or platelet transfusions should not be given on the basis of laboratory test results alone; they are indicated only in patients with active bleeding and in those who require an invasive procedure or are otherwise at risk for bleeding. Although low levels of platelets and coagulation factors may increase the risk of bleeding in patients with DIC, plasma or platelet transfusions should not be given on the basis of laboratory test results alone; they are indicated only in patients with active bleeding and in those who require an invasive procedure or are otherwise at risk for bleeding. The suggestion that administration of blood components might exacerbate DIC has never been proved in clinical or experimental studies. The efficacy of treatment with plasma or platelets has not been confirmed in randomized controlled trials; however, it appears to be a rational therapy in patients who are bleeding or at risk for bleeding because of significant depletion of these elements. The suggestion that administration of blood components might exacerbate DIC has never been proved in clinical or experimental studies. The efficacy of treatment with plasma or platelets has not been confirmed in randomized controlled trials; however, it appears to be a rational therapy in patients who are bleeding or at risk for bleeding because of significant depletion of these elements.

67 Heparin Experimental studies have shown that heparin can at least partly inhibit the activation of coagulation in DIC secondary to sepsis and other causes. Experimental studies have shown that heparin can at least partly inhibit the activation of coagulation in DIC secondary to sepsis and other causes. In addition, patients with DIC need prophylaxis against venous thromboembolism. In addition, patients with DIC need prophylaxis against venous thromboembolism. The benefit of heparin has been shown in a small, uncontrolled series of patients with DIC but has never been demonstrated in controlled clinical trials. The safety of heparin in patients with DIC who are prone to bleeding is often debated, but clinical studies have not shown that heparin significantly worsens bleeding complications in this group. The benefit of heparin has been shown in a small, uncontrolled series of patients with DIC but has never been demonstrated in controlled clinical trials. The safety of heparin in patients with DIC who are prone to bleeding is often debated, but clinical studies have not shown that heparin significantly worsens bleeding complications in this group. Altogether, heparin is probably useful in patients with DIC, particularly in those with clinically overt thromboembolism or extensive fibrin deposition, such as purpura fulminans or ischemia in the extremities. Altogether, heparin is probably useful in patients with DIC, particularly in those with clinically overt thromboembolism or extensive fibrin deposition, such as purpura fulminans or ischemia in the extremities. Heparin is usually given in a relatively low-dose, continuous infusion ( U/hr). Heparin is usually given in a relatively low-dose, continuous infusion ( U/hr). Recent studies show that low-molecular-weight heparin can be used as an alternative to unfractionated heparin. Recent studies show that low-molecular-weight heparin can be used as an alternative to unfractionated heparin.

68 Experimental Therapies Theoretically, the most logical anticoagulation therapy in patients with DIC is an agent that is directed against tissue factor activity. Theoretically, the most logical anticoagulation therapy in patients with DIC is an agent that is directed against tissue factor activity. Indeed, inhibitors of the tissue factor pathway have been developed and ongoing clinical studies are evaluating their efficacy and safety in DIC. Indeed, inhibitors of the tissue factor pathway have been developed and ongoing clinical studies are evaluating their efficacy and safety in DIC.

69 Experimental Therapies Restoration of physiologic anticoagulation pathways might be an appropriate therapeutic option in DIC. Antithrombin III is one of the most important natural inhibitors of coagulation; patients with DIC almost invariably have an acquired deficiency of the substance. Restoration of physiologic anticoagulation pathways might be an appropriate therapeutic option in DIC. Antithrombin III is one of the most important natural inhibitors of coagulation; patients with DIC almost invariably have an acquired deficiency of the substance. Administration of supraphysiologic concentrations of antithrombin III has produced promising results in clinical trials involving patients with sepsis or septic shock, with or without DIC. Some trials showed a modestly (but statistically insignificant) reduced mortality in patients treated with antithrombin III. A metaanalysis of the trials showed that mortality decreased from 56% to 44% (odds ratio, 0.63; 95% confidence interval, 0.39 to 1.0). A large, randomized, controlled multicenter trial of supraphysiologic doses of antithrombin III in patients with sepsis is currently under way, and its outcome will more definitively determine the place of antithrombin III treatment in sepsis and DIC. Administration of supraphysiologic concentrations of antithrombin III has produced promising results in clinical trials involving patients with sepsis or septic shock, with or without DIC. Some trials showed a modestly (but statistically insignificant) reduced mortality in patients treated with antithrombin III. A metaanalysis of the trials showed that mortality decreased from 56% to 44% (odds ratio, 0.63; 95% confidence interval, 0.39 to 1.0). A large, randomized, controlled multicenter trial of supraphysiologic doses of antithrombin III in patients with sepsis is currently under way, and its outcome will more definitively determine the place of antithrombin III treatment in sepsis and DIC.

70 Experimental Therapies Another promising treatment is recombinant activated protein C. Another promising treatment is recombinant activated protein C. This compound is now being evaluated in large multicenter trials in patients with sepsis, DIC, or both. In view of the pivotal role of protein C as inhibitor of the coagulation cascade and its postulated role as an important mediator of inflammation, activated protein C may be a good candidate for supportive treatment of patients with DIC. This compound is now being evaluated in large multicenter trials in patients with sepsis, DIC, or both. In view of the pivotal role of protein C as inhibitor of the coagulation cascade and its postulated role as an important mediator of inflammation, activated protein C may be a good candidate for supportive treatment of patients with DIC.

71 Treatment options for DIC Acute DIC Without bleeding or evidence of ischemia No treatment With bleeding Blood components as needed Fresh frozen plasma Cryoprecipitate Platelet transfusions With ischemia Anticoagulants (see "with thromboembolism" below) after bleeding risk is corrected with blood products Acute DIC Without bleeding or evidence of ischemia No treatment With bleeding Blood components as needed Fresh frozen plasma Cryoprecipitate Platelet transfusions With ischemia Anticoagulants (see "with thromboembolism" below) after bleeding risk is corrected with blood products

72 Treatment options for DIC Chronic DIC Without thromboembolism No specific therapy needed but prophylactic drugs (eg, low-dose heparin, low-molecular-weight heparin) may be used for patients at high risk of thrombosis With thromboembolism Heparin or low-molecular-weight heparin, trial of warfarin sodium (Coumadin). (If warfarin is unsuccessful, long-term use of low-molecular-weight heparin may be helpful.)* Chronic DIC Without thromboembolism No specific therapy needed but prophylactic drugs (eg, low-dose heparin, low-molecular-weight heparin) may be used for patients at high risk of thrombosis With thromboembolism Heparin or low-molecular-weight heparin, trial of warfarin sodium (Coumadin). (If warfarin is unsuccessful, long-term use of low-molecular-weight heparin may be helpful.)*

73 DIC DIC - Gangrene in patient with meningococcal sepsis Schistocytes on the Peripheral Blood Smear

74 DIC Subdermal bleeding at IV site following a bite by Hoplocephalus stephensi

75 Disseminated intravascular coagulation (DIC). Patient with Postvaricella purpura fulminans showing extent of necrotic lesions Leg after skin grafting 14 year old otherwise healthy male who three weeks after primary varicella infection developed large painful lesions on his leg. (Fig 1). Laboratories evaluation showed evidence of disseminated intravascular coagulation (DIC). Plasma free protein S level was below 5% with other factors only mildly decreased (consistent with his DIC). Patient was treated with heparin and plasma infusion which resulted in stabilization of his lesions. For his presumed autoimmune protein S deficiency he received immunoglobulin. Over the course of the next several months his protein S levels increased back into the normal range but his skin lesions required extensive grafting (fig 2 and 3).

76 konec


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