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Crit Care Med 2006 March Vol.34 p871-877 Ri 陳凱翔

Pulmonary coagulopathy as a new target in therapeutic studies of acute lung injury or pneumonia – A review. Crit Care Med 2006 March Vol.34 p871-877 Ri 陳凱翔. Coagulopathy in sepsis study in recent 10 years Coagulopathy in different kinds of lung injury

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Crit Care Med 2006 March Vol.34 p871-877 Ri 陳凱翔

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  1. Pulmonary coagulopathy as a new target in therapeutic studies of acute lung injury or pneumonia– A review Crit Care Med 2006 March Vol.34 p871-877Ri 陳凱翔

  2. Coagulopathy in sepsis study in recent 10 years • Coagulopathy in different kinds of lung injury • New target in ALI/ARDS, Ventilator induced lung injury(VILI) therapy

  3. What is the relationship between inflammation and coagulation in sepsis?

  4. The relation between systemic inflammation and coagulation • During the initial phase of the inflammatory response, high levels of proinflammatory cytokines, such as TNF-α, IL-1 and IL-6. They activate coagulation via tissue factor and attenuate fibrinolysis by stimulating the release of inhibitors of plasminogen activatorsNEJM 1999;341:586-592

  5. The relation between systemic inflammation and coagulation • APC, AT(Antithrombin) and tissue factor pathway inhibitor(TFPI) decline in sepsis ethier decreased production or enhanced breakdown Chest 1992;101:816-823

  6. The relation between systemic inflammation and coagulation • Monocytes and endothelial cells can express TF on their surface (Blood Coagul Fibrinolysis 1998) • Endotoxin and proinflammatory cytokines can stimulate TF expression (Semin Thromb Hemost 2001) • Thrombomodulin, the pivotal mediator of thrombin-induced protein C activation, is down-regulated at the endothelial surface by TNF and IL-1, result in dysfunction of protein C(NEJM 2001; 345)

  7. Inhibition of Fibrinolysis • PAI-1 is present during the septic response, the main inhibitor of tissue-type and urokinase-type plasminogen activator, which activate the fibrinolytic system • TNF and IL-1 stimulated the release of PAI-1 and reduced the release of tissue-type plasminogen activator(Thromb Haemost 1995; 73:223-230)

  8. Inflammation and Coagulation have reciprocal amplifying effects • Protease-activated receptors ( transmembrane proteins that are expressed on the surface of monocytes, endothelial cells, and leukocytes) seem to play a key role in translating coagulation products into infammatory signals

  9. Inflammation and Coagulation have reciprocal amplifying effects • Activation of these receptors by thrombin and other coagulation proteases has a strong proinflammatory effect, with additional generation of proinflammatory cytokines and increased expression of cell-surface proteins that enhance binding and extravasation of leukocytes(Nature 2000; 407:258-264) (Circulation 2004; 109:2698-2704) (Blood 2001; 97:3109-3116)

  10. Anticoagulant therapy in sepsis • Immunomodulatory therapy has largely failed to demonstrate any beneficial effects in human sepsis although with encouraging results from preclinical studies (Lancet Infect Dis 2001; 1:165-174) • AT or TFPI infusions in septic patient were both failed in phase III study, only APC was proved to be effective in sepsis (Crit Care Med 2001; 29:2081-2089)

  11. Sepsis pathophysiology Infection Sepsis injury coagulation activationInflammation (amplifying) DICMulti-Organ Failure Tissue perfusion decrease

  12. Disturbed fibrin turnover in ALI • ALI/ARDS and pneumonia are associated with local production of proinflammatory mediators with low cytokines level in serum. (Intensive Care Med 2004; 30:68-74) • Alveolar thrombin generation in ALI/ARDS and pneumonia seems to be mediated by the TF-factor VIIa pathway. TF levels are low in the normal lung and elevated in disease (Am J Respi Crit Care Med 1996; 153:336-342)

  13. Disturbed fibrin turnover in ALI • In experimental models of low-dose endotoxemia, markers of thrombin generation are increased in bronchoalveolar lavage fluid(Am J Respir Crit Care Med 1998; 158:92-98) • In ARDS, inhibition of the TF-factor VIIa pathway completely abrogated intrapulmonary fibrin deposition(Am J Respir Cell Mol Biol 2002; 26:650-658)

  14. Disturbed fibrin turnover in ALI • Protein C system suppressed in VILI and pneumonia patients • Oxidation of thrombomodulin and shedding of TM from the cell surface, result in coagulopathy. High plasma thrombomodulin associated with worse clinical outcomes (Crit Care 2004; 8(Suppl 1):111)

  15. Attenuated fibrin breakdown • Fibrinolytic activity is depressed in bronchoalveolar lavage fluids of patients with ALI/ARDS or pneumonia related to high pulmonary concentrations of PAI-1, which probably secreted by lung epithelial cells, fibroblast, and endothelial cells(Crit Care Med 2002; 30:S274-S280) • Alveolar PAI-1 levels are associated with mortality rate in patients with ALI/ARDS(Am J Physiol LungCell Mol Physiol 2003;285)

  16. Ventilator-induced coagulopathy • Similar changes in coagulation and fibrinolysis may occur in Ventilator induced lung injury (VILI) • Healthy lung randomized with large tidal volume(12ml/kg) and protective strategy(6ml/kg) for 5 hrs ventilator use. Large increase in alveolar TF-mediated coagulation were found in large tidal volume group (EK Wlthuis, unpublished data) • In rats model, mechanical ventilation with larger tidal volumes attenuated the fibrinolytic activity

  17. Treatment of ARDS • Low tidal volume (6ml/kg) can decrease 22% than with raditional ventilation(NEJM 2000; 342: 1301~8) • PEEP Improved oxygenation and recruit of the collapsed alveoliHigh PEEP(13.2+/-3.5) and Low PEEP(8.3+/-3.2) didn’t have significant difference in clinical outcome (NEJM 2004; 351: 327~336)

  18. Treatment of ARDS • Fluid restriction(Chest 1990; 97: 1176 Am ReV Respi Dis 1992) • Prone position: improve oxygenation temporarily • Surfactant inhalation therapy, or Recombinant surfactant protein C therapy:Not effect on outcome or survival rate(NEJM 1996;334:1417~21 NEJM 2004; 351:884~92) • Inhaled NO and other vasodilators:Didn’t reduce morality or improve oxygenation(Crit Care Med 1998;26:15-23 Intensive Care Med 1999;25)

  19. Treatment of ARDS • Short curse of high-dose glucocorticoids • Removal of pulmona edema inhaled and systemic beta agonist: increase surfactan and anti-inflammatory effect(J Appl Physiol 1999;87:30-5) • Keratinocyte growth factors Can stimulate alveolar type II cells, experimentally (Am J Respir Crit Care Med 1999;159)

  20. Study on treatment of ALI/ARDS • ALI/ARDS, pneumonia and VILI have both activation of coagulation and attenuation of fibrinolysis although lesser extent in pneumonia and VILI • APC exerts an anticoagulant effect in the human lung challenged with endotoxin(Am J Respi Crit Care Med 2005; 171:1125-1128) • Elevated PAI-1 activity and pulmonary coagulation were diminished by APC infusion

  21. Study on treatment of ALI/ARDS • No studies on inhibitors of natural inhibitors of coagulation have been performed in ALI/ARDS • Neubulization of heparin has been found to be beneficial in preclinical and clinical studies in patients with inhalation trauma(Shock 2002; 18:236-241)

  22. Study on treatment of ALI/ARDS • Since the most common cause of death in ALI/ARDS is not respiratory failure but multiple-organ system failure, the systemic abnormalities of coagulation and fibrinolysis may be an important therapeutic target over and above the local pulmonary abnormalities

  23. Treatment concept • Anticoagulant therapy might be either harmful(atenuating the host response) or beneficial(attenuating the destructive effects of the inflammatory response)

  24. Thanks for your attention!

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