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

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

What is the relationship between inflammation and coagulation in sepsis?

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 activators NEJM 1999;341: 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 activators NEJM 1999;341:

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: APC, AT(Antithrombin) and tissue factor pathway inhibitor(TFPI) decline in sepsis ethier decreased production or enhanced breakdown Chest 1992;101:

The relation between systemic inflammation and coagulation Monocytes and endothelial cells can express TF on their surface (Blood Coagul Fibrinolysis 1998) 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) 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) 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)

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 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: ) TNF and IL-1 stimulated the release of PAI-1 and reduced the release of tissue- type plasminogen activator (Thromb Haemost 1995; 73: )

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 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

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: ) (Circulation 2004; 109: ) (Blood 2001; 97: ) 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: ) (Circulation 2004; 109: ) (Blood 2001; 97: )

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: ) 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: ) 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: ) 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: )

Sepsis pathophysiology Infection Infection Sepsis injury coagulation activation Inflammation (amplifying) DIC Multi-Organ Failure Tissue perfusion decrease Sepsis injury coagulation activation Inflammation (amplifying) DIC Multi-Organ Failure Tissue perfusion decrease

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) 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: ) 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: )

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 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: ) In ARDS, inhibition of the TF-factor VIIa pathway completely abrogated intrapulmonary fibrin deposition (Am J Respir Cell Mol Biol 2002; 26: )

Disturbed fibrin turnover in ALI Protein C system suppressed in VILI and pneumonia patients 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) 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)

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) 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) Alveolar PAI-1 levels are associated with mortality rate in patients with ALI/ARDS (Am J Physiol LungCell Mol Physiol 2003;285)

Ventilator-induced coagulopathy Similar changes in coagulation and fibrinolysis may occur in Ventilator induced lung injury (VILI) 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) 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 In rats model, mechanical ventilation with larger tidal volumes attenuated the fibrinolytic activity

Treatment of ARDS Low tidal volume (6ml/kg) can decrease 22% than with raditional ventilation (NEJM 2000; 342: 1301~8) 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 alveoli High 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) PEEP  Improved oxygenation and recruit of the collapsed alveoli High 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)

Treatment of ARDS Fluid restriction (Chest 1990; 97: 1176 Am ReV Respi Dis 1992) Fluid restriction (Chest 1990; 97: 1176 Am ReV Respi Dis 1992) Prone position: improve oxygenation temporarily 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) 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) Inhaled NO and other vasodilators:  Didn ’ t reduce morality or improve oxygenation (Crit Care Med 1998;26:15-23 Intensive Care Med 1999;25)

Treatment of ARDS Short curse of high-dose glucocorticoids 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) 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) Keratinocyte growth factors  Can stimulate alveolar type II cells, experimentally (Am J Respir Crit Care Med 1999;159)

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 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: ) APC exerts an anticoagulant effect in the human lung challenged with endotoxin (Am J Respi Crit Care Med 2005; 171: ) Elevated PAI-1 activity and pulmonary coagulation were diminished by APC infusion Elevated PAI-1 activity and pulmonary coagulation were diminished by APC infusion

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

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 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

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

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