C protein concentrates in paediatric septic

patientsGiacomo Monti MD

University Vita ndash Salute S Raffaele MilanoDepartment of

Anesthesia and Intensive Care

2

montigiacomohsrit

3

C- protein concentrate

C proteinbull Virtually side ndash effect free drugbull No bleeding riskbull Few papers but very often used in clinical

practice expecially in Italybull Active in a disease that causes severe

mortality and morbidity

4

Protein C

bull CEPROTIN(Human)BAXTER

bull PC

bull Zymogen

bull (human) protein C concentrate(s)

bull Protein C zymogen (concentrate)

bull XIGRIS(Recombinant)LILLY

bull APC rhAPC

bull Enzyme

bull Activated protein C

bull Drotrecogin alfa activated

4

55

6

PC in literature

bull Extensive literature scan by PubMed Embase Google Scholar

bull Contact with expertbull Update to January 2009

7

Sepsis in children US

bull In the United States there were 42000 cases of severe sepsis in children in 1995 in 1997 the total number of cases increased to 47700

bull Hospital mortality among US children with severe sepsis was 103

7

8

Sepsis in children US - 2

bull Sepsis is the 2nd cause of death among children 4th among infants

bull Children who develop severe sepsis consume substantial healthcare resources with an average length of stay of 31 days and cost of $40600

8

9

Sepsis in children Italy

bull In 2004-2005 lower overall incidence of sepsis severe sepsis and septic shock (79 16 and 21 of PICU admission)

bull Severe sepsis and septic shock had a mortality rate of 177 and 508 respectively

Incidence of and mortality due to sepsis severe sepsis and septic shock in Italian Pediatric Intensive Care Units a prospective national survey Wolfler A et al Intensive Care Med 2008 341690-7

9

1010

ldquoProtein C concentrations in children reach adult values at the age of 3 yrs Thismight indicate that the importance of protein C supplementation either as proteinC concentrate or as rhAPC is greater in young children than in adultsrdquo

11

The ldquoRESOLVErdquo study

Drotrecogin alfa (activated) in children with severe sepsis a multicentre phase III randomised controlled trial Nadel S et al Lancet 2007 369 836ndash43

Our results showed no significantdifference between groups in CTCOFR score

(p=0middot72) or in 28-day mortality (placebo 17middot5 DrotAA 17middot2 p=0middot93)

11

12

Author Year Journal NGerson 1993 Pediatrics 1Rivard 1995 J Pediatr 4Smith 1997 Lancet 12Rintala 1998 Crit Care Med 3Ettingshausen 1999 Semin Thromb Hemost 8Clarke 2000 Intensive Care Med 1Leclerc 2000 Crit Care Med 2White 2000 Blood 36De Kleijn 2003 Crit Care Med 30Fourrier 2003 Intensive Care Med 15Pettenazzo 2004 Minerva Anestesiol 8Silvani 2005 Minerva Anestesiol 11De Carolis 2008 Turk J Pediatr 1TOTAL 131

Summary of all published papers reporting on children patients

receiving protein C concentrates

12

13

Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive

meningococcemia33

De Kleijn 30 Severe sepsis or meningococcal disease 23

Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103

(79)

13

Summary of all published papers reporting on children patients

receiving protein C concentrates

14

bull Few papers account for more than half of published ndash treated patients

bull 3 ldquomajorrdquo papers 78 children (59)

14

15

Smith Lancet 1997

bull 12 patientsbull Meningoccemia and

septic shockbull GMSPS score predicted

mortality 80bull PRISM predicted

mortality 57bull Dose titrate to

concentration of 08-12 IUml (normal)

bull 100 survivalbull 2 (17) lower limb

amputation

bull No drug ndash related adverse event

15

2

montigiacomohsrit

3

C- protein concentrate

C proteinbull Virtually side ndash effect free drugbull No bleeding riskbull Few papers but very often used in clinical

practice expecially in Italybull Active in a disease that causes severe

mortality and morbidity

4

Protein C

bull CEPROTIN(Human)BAXTER

bull PC

bull Zymogen

bull (human) protein C concentrate(s)

bull Protein C zymogen (concentrate)

bull XIGRIS(Recombinant)LILLY

bull APC rhAPC

bull Enzyme

bull Activated protein C

bull Drotrecogin alfa activated

4

55

6

PC in literature

bull Extensive literature scan by PubMed Embase Google Scholar

bull Contact with expertbull Update to January 2009

7

Sepsis in children US

bull In the United States there were 42000 cases of severe sepsis in children in 1995 in 1997 the total number of cases increased to 47700

bull Hospital mortality among US children with severe sepsis was 103

7

8

Sepsis in children US - 2

bull Sepsis is the 2nd cause of death among children 4th among infants

bull Children who develop severe sepsis consume substantial healthcare resources with an average length of stay of 31 days and cost of $40600

8

9

Sepsis in children Italy

bull In 2004-2005 lower overall incidence of sepsis severe sepsis and septic shock (79 16 and 21 of PICU admission)

bull Severe sepsis and septic shock had a mortality rate of 177 and 508 respectively

Incidence of and mortality due to sepsis severe sepsis and septic shock in Italian Pediatric Intensive Care Units a prospective national survey Wolfler A et al Intensive Care Med 2008 341690-7

9

1010

ldquoProtein C concentrations in children reach adult values at the age of 3 yrs Thismight indicate that the importance of protein C supplementation either as proteinC concentrate or as rhAPC is greater in young children than in adultsrdquo

11

The ldquoRESOLVErdquo study

Drotrecogin alfa (activated) in children with severe sepsis a multicentre phase III randomised controlled trial Nadel S et al Lancet 2007 369 836ndash43

Our results showed no significantdifference between groups in CTCOFR score

(p=0middot72) or in 28-day mortality (placebo 17middot5 DrotAA 17middot2 p=0middot93)

11

12

Author Year Journal NGerson 1993 Pediatrics 1Rivard 1995 J Pediatr 4Smith 1997 Lancet 12Rintala 1998 Crit Care Med 3Ettingshausen 1999 Semin Thromb Hemost 8Clarke 2000 Intensive Care Med 1Leclerc 2000 Crit Care Med 2White 2000 Blood 36De Kleijn 2003 Crit Care Med 30Fourrier 2003 Intensive Care Med 15Pettenazzo 2004 Minerva Anestesiol 8Silvani 2005 Minerva Anestesiol 11De Carolis 2008 Turk J Pediatr 1TOTAL 131

Summary of all published papers reporting on children patients

receiving protein C concentrates

12

13

Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive

meningococcemia33

De Kleijn 30 Severe sepsis or meningococcal disease 23

Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103

(79)

13

Summary of all published papers reporting on children patients

receiving protein C concentrates

14

bull Few papers account for more than half of published ndash treated patients

bull 3 ldquomajorrdquo papers 78 children (59)

14

15

Smith Lancet 1997

bull 12 patientsbull Meningoccemia and

septic shockbull GMSPS score predicted

mortality 80bull PRISM predicted

mortality 57bull Dose titrate to

concentration of 08-12 IUml (normal)

bull 100 survivalbull 2 (17) lower limb

amputation

bull No drug ndash related adverse event

15

3

C- protein concentrate

C proteinbull Virtually side ndash effect free drugbull No bleeding riskbull Few papers but very often used in clinical

practice expecially in Italybull Active in a disease that causes severe

mortality and morbidity

4

Protein C

bull CEPROTIN(Human)BAXTER

bull PC

bull Zymogen

bull (human) protein C concentrate(s)

bull Protein C zymogen (concentrate)

bull XIGRIS(Recombinant)LILLY

bull APC rhAPC

bull Enzyme

bull Activated protein C

bull Drotrecogin alfa activated

4

55

6

PC in literature

bull Extensive literature scan by PubMed Embase Google Scholar

bull Contact with expertbull Update to January 2009

7

Sepsis in children US

bull In the United States there were 42000 cases of severe sepsis in children in 1995 in 1997 the total number of cases increased to 47700

bull Hospital mortality among US children with severe sepsis was 103

7

8

Sepsis in children US - 2

bull Sepsis is the 2nd cause of death among children 4th among infants

bull Children who develop severe sepsis consume substantial healthcare resources with an average length of stay of 31 days and cost of $40600

8

9

Sepsis in children Italy

bull In 2004-2005 lower overall incidence of sepsis severe sepsis and septic shock (79 16 and 21 of PICU admission)

bull Severe sepsis and septic shock had a mortality rate of 177 and 508 respectively

Incidence of and mortality due to sepsis severe sepsis and septic shock in Italian Pediatric Intensive Care Units a prospective national survey Wolfler A et al Intensive Care Med 2008 341690-7

9

1010

ldquoProtein C concentrations in children reach adult values at the age of 3 yrs Thismight indicate that the importance of protein C supplementation either as proteinC concentrate or as rhAPC is greater in young children than in adultsrdquo

11

The ldquoRESOLVErdquo study

Drotrecogin alfa (activated) in children with severe sepsis a multicentre phase III randomised controlled trial Nadel S et al Lancet 2007 369 836ndash43

Our results showed no significantdifference between groups in CTCOFR score

(p=0middot72) or in 28-day mortality (placebo 17middot5 DrotAA 17middot2 p=0middot93)

11

12

Author Year Journal NGerson 1993 Pediatrics 1Rivard 1995 J Pediatr 4Smith 1997 Lancet 12Rintala 1998 Crit Care Med 3Ettingshausen 1999 Semin Thromb Hemost 8Clarke 2000 Intensive Care Med 1Leclerc 2000 Crit Care Med 2White 2000 Blood 36De Kleijn 2003 Crit Care Med 30Fourrier 2003 Intensive Care Med 15Pettenazzo 2004 Minerva Anestesiol 8Silvani 2005 Minerva Anestesiol 11De Carolis 2008 Turk J Pediatr 1TOTAL 131

Summary of all published papers reporting on children patients

receiving protein C concentrates

12

13

Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive

meningococcemia33

De Kleijn 30 Severe sepsis or meningococcal disease 23

Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103

(79)

13

Summary of all published papers reporting on children patients

receiving protein C concentrates

14

bull Few papers account for more than half of published ndash treated patients

bull 3 ldquomajorrdquo papers 78 children (59)

14

15

Smith Lancet 1997

bull 12 patientsbull Meningoccemia and

septic shockbull GMSPS score predicted

mortality 80bull PRISM predicted

mortality 57bull Dose titrate to

concentration of 08-12 IUml (normal)

bull 100 survivalbull 2 (17) lower limb

amputation

bull No drug ndash related adverse event

15

4

Protein C

bull CEPROTIN(Human)BAXTER

bull PC

bull Zymogen

bull (human) protein C concentrate(s)

bull Protein C zymogen (concentrate)

bull XIGRIS(Recombinant)LILLY

bull APC rhAPC

bull Enzyme

bull Activated protein C

bull Drotrecogin alfa activated

4

55

6

PC in literature

bull Extensive literature scan by PubMed Embase Google Scholar

bull Contact with expertbull Update to January 2009

7

Sepsis in children US

bull In the United States there were 42000 cases of severe sepsis in children in 1995 in 1997 the total number of cases increased to 47700

bull Hospital mortality among US children with severe sepsis was 103

7

8

Sepsis in children US - 2

bull Sepsis is the 2nd cause of death among children 4th among infants

bull Children who develop severe sepsis consume substantial healthcare resources with an average length of stay of 31 days and cost of $40600

8

9

Sepsis in children Italy

bull In 2004-2005 lower overall incidence of sepsis severe sepsis and septic shock (79 16 and 21 of PICU admission)

bull Severe sepsis and septic shock had a mortality rate of 177 and 508 respectively

Incidence of and mortality due to sepsis severe sepsis and septic shock in Italian Pediatric Intensive Care Units a prospective national survey Wolfler A et al Intensive Care Med 2008 341690-7

9

1010

ldquoProtein C concentrations in children reach adult values at the age of 3 yrs Thismight indicate that the importance of protein C supplementation either as proteinC concentrate or as rhAPC is greater in young children than in adultsrdquo

11

The ldquoRESOLVErdquo study

Drotrecogin alfa (activated) in children with severe sepsis a multicentre phase III randomised controlled trial Nadel S et al Lancet 2007 369 836ndash43

Our results showed no significantdifference between groups in CTCOFR score

(p=0middot72) or in 28-day mortality (placebo 17middot5 DrotAA 17middot2 p=0middot93)

11

12

Author Year Journal NGerson 1993 Pediatrics 1Rivard 1995 J Pediatr 4Smith 1997 Lancet 12Rintala 1998 Crit Care Med 3Ettingshausen 1999 Semin Thromb Hemost 8Clarke 2000 Intensive Care Med 1Leclerc 2000 Crit Care Med 2White 2000 Blood 36De Kleijn 2003 Crit Care Med 30Fourrier 2003 Intensive Care Med 15Pettenazzo 2004 Minerva Anestesiol 8Silvani 2005 Minerva Anestesiol 11De Carolis 2008 Turk J Pediatr 1TOTAL 131

Summary of all published papers reporting on children patients

receiving protein C concentrates

12

13

Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive

meningococcemia33

De Kleijn 30 Severe sepsis or meningococcal disease 23

Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103

(79)

13

Summary of all published papers reporting on children patients

receiving protein C concentrates

14

bull Few papers account for more than half of published ndash treated patients

bull 3 ldquomajorrdquo papers 78 children (59)

14

15

Smith Lancet 1997

bull 12 patientsbull Meningoccemia and

septic shockbull GMSPS score predicted

mortality 80bull PRISM predicted

mortality 57bull Dose titrate to

concentration of 08-12 IUml (normal)

bull 100 survivalbull 2 (17) lower limb

amputation

bull No drug ndash related adverse event

15

55

6

PC in literature

bull Extensive literature scan by PubMed Embase Google Scholar

bull Contact with expertbull Update to January 2009

7

Sepsis in children US

bull In the United States there were 42000 cases of severe sepsis in children in 1995 in 1997 the total number of cases increased to 47700

bull Hospital mortality among US children with severe sepsis was 103

7

8

Sepsis in children US - 2

bull Sepsis is the 2nd cause of death among children 4th among infants

bull Children who develop severe sepsis consume substantial healthcare resources with an average length of stay of 31 days and cost of $40600

8

9

Sepsis in children Italy

bull In 2004-2005 lower overall incidence of sepsis severe sepsis and septic shock (79 16 and 21 of PICU admission)

bull Severe sepsis and septic shock had a mortality rate of 177 and 508 respectively

Incidence of and mortality due to sepsis severe sepsis and septic shock in Italian Pediatric Intensive Care Units a prospective national survey Wolfler A et al Intensive Care Med 2008 341690-7

9

1010

ldquoProtein C concentrations in children reach adult values at the age of 3 yrs Thismight indicate that the importance of protein C supplementation either as proteinC concentrate or as rhAPC is greater in young children than in adultsrdquo

11

The ldquoRESOLVErdquo study

Drotrecogin alfa (activated) in children with severe sepsis a multicentre phase III randomised controlled trial Nadel S et al Lancet 2007 369 836ndash43

Our results showed no significantdifference between groups in CTCOFR score

(p=0middot72) or in 28-day mortality (placebo 17middot5 DrotAA 17middot2 p=0middot93)

11

12

Author Year Journal NGerson 1993 Pediatrics 1Rivard 1995 J Pediatr 4Smith 1997 Lancet 12Rintala 1998 Crit Care Med 3Ettingshausen 1999 Semin Thromb Hemost 8Clarke 2000 Intensive Care Med 1Leclerc 2000 Crit Care Med 2White 2000 Blood 36De Kleijn 2003 Crit Care Med 30Fourrier 2003 Intensive Care Med 15Pettenazzo 2004 Minerva Anestesiol 8Silvani 2005 Minerva Anestesiol 11De Carolis 2008 Turk J Pediatr 1TOTAL 131

Summary of all published papers reporting on children patients

receiving protein C concentrates

12

13

Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive

meningococcemia33

De Kleijn 30 Severe sepsis or meningococcal disease 23

Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103

(79)

13

Summary of all published papers reporting on children patients

receiving protein C concentrates

14

bull Few papers account for more than half of published ndash treated patients

bull 3 ldquomajorrdquo papers 78 children (59)

14

15

Smith Lancet 1997

bull 12 patientsbull Meningoccemia and

septic shockbull GMSPS score predicted

mortality 80bull PRISM predicted

mortality 57bull Dose titrate to

concentration of 08-12 IUml (normal)

bull 100 survivalbull 2 (17) lower limb

amputation

bull No drug ndash related adverse event

15

6

PC in literature

bull Extensive literature scan by PubMed Embase Google Scholar

bull Contact with expertbull Update to January 2009

7

Sepsis in children US

bull In the United States there were 42000 cases of severe sepsis in children in 1995 in 1997 the total number of cases increased to 47700

bull Hospital mortality among US children with severe sepsis was 103

7

8

Sepsis in children US - 2

bull Sepsis is the 2nd cause of death among children 4th among infants

bull Children who develop severe sepsis consume substantial healthcare resources with an average length of stay of 31 days and cost of $40600

8

9

Sepsis in children Italy

bull In 2004-2005 lower overall incidence of sepsis severe sepsis and septic shock (79 16 and 21 of PICU admission)

bull Severe sepsis and septic shock had a mortality rate of 177 and 508 respectively

Incidence of and mortality due to sepsis severe sepsis and septic shock in Italian Pediatric Intensive Care Units a prospective national survey Wolfler A et al Intensive Care Med 2008 341690-7

9

1010

ldquoProtein C concentrations in children reach adult values at the age of 3 yrs Thismight indicate that the importance of protein C supplementation either as proteinC concentrate or as rhAPC is greater in young children than in adultsrdquo

11

The ldquoRESOLVErdquo study

Drotrecogin alfa (activated) in children with severe sepsis a multicentre phase III randomised controlled trial Nadel S et al Lancet 2007 369 836ndash43

Our results showed no significantdifference between groups in CTCOFR score

(p=0middot72) or in 28-day mortality (placebo 17middot5 DrotAA 17middot2 p=0middot93)

11

12

Author Year Journal NGerson 1993 Pediatrics 1Rivard 1995 J Pediatr 4Smith 1997 Lancet 12Rintala 1998 Crit Care Med 3Ettingshausen 1999 Semin Thromb Hemost 8Clarke 2000 Intensive Care Med 1Leclerc 2000 Crit Care Med 2White 2000 Blood 36De Kleijn 2003 Crit Care Med 30Fourrier 2003 Intensive Care Med 15Pettenazzo 2004 Minerva Anestesiol 8Silvani 2005 Minerva Anestesiol 11De Carolis 2008 Turk J Pediatr 1TOTAL 131

Summary of all published papers reporting on children patients

receiving protein C concentrates

12

13

Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive

meningococcemia33

De Kleijn 30 Severe sepsis or meningococcal disease 23

Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103

(79)

13

Summary of all published papers reporting on children patients

receiving protein C concentrates

14

bull Few papers account for more than half of published ndash treated patients

bull 3 ldquomajorrdquo papers 78 children (59)

14

15

Smith Lancet 1997

bull 12 patientsbull Meningoccemia and

septic shockbull GMSPS score predicted

mortality 80bull PRISM predicted

mortality 57bull Dose titrate to

concentration of 08-12 IUml (normal)

bull 100 survivalbull 2 (17) lower limb

amputation

bull No drug ndash related adverse event

15

7

Sepsis in children US

bull In the United States there were 42000 cases of severe sepsis in children in 1995 in 1997 the total number of cases increased to 47700

bull Hospital mortality among US children with severe sepsis was 103

7

8

Sepsis in children US - 2

bull Sepsis is the 2nd cause of death among children 4th among infants

bull Children who develop severe sepsis consume substantial healthcare resources with an average length of stay of 31 days and cost of $40600

8

9

Sepsis in children Italy

bull In 2004-2005 lower overall incidence of sepsis severe sepsis and septic shock (79 16 and 21 of PICU admission)

bull Severe sepsis and septic shock had a mortality rate of 177 and 508 respectively

Incidence of and mortality due to sepsis severe sepsis and septic shock in Italian Pediatric Intensive Care Units a prospective national survey Wolfler A et al Intensive Care Med 2008 341690-7

9

1010

ldquoProtein C concentrations in children reach adult values at the age of 3 yrs Thismight indicate that the importance of protein C supplementation either as proteinC concentrate or as rhAPC is greater in young children than in adultsrdquo

11

The ldquoRESOLVErdquo study

Drotrecogin alfa (activated) in children with severe sepsis a multicentre phase III randomised controlled trial Nadel S et al Lancet 2007 369 836ndash43

Our results showed no significantdifference between groups in CTCOFR score

(p=0middot72) or in 28-day mortality (placebo 17middot5 DrotAA 17middot2 p=0middot93)

11

12

Author Year Journal NGerson 1993 Pediatrics 1Rivard 1995 J Pediatr 4Smith 1997 Lancet 12Rintala 1998 Crit Care Med 3Ettingshausen 1999 Semin Thromb Hemost 8Clarke 2000 Intensive Care Med 1Leclerc 2000 Crit Care Med 2White 2000 Blood 36De Kleijn 2003 Crit Care Med 30Fourrier 2003 Intensive Care Med 15Pettenazzo 2004 Minerva Anestesiol 8Silvani 2005 Minerva Anestesiol 11De Carolis 2008 Turk J Pediatr 1TOTAL 131

Summary of all published papers reporting on children patients

receiving protein C concentrates

12

13

Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive

meningococcemia33

De Kleijn 30 Severe sepsis or meningococcal disease 23

Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103

(79)

13

Summary of all published papers reporting on children patients

receiving protein C concentrates

14

bull Few papers account for more than half of published ndash treated patients

bull 3 ldquomajorrdquo papers 78 children (59)

14

15

Smith Lancet 1997

bull 12 patientsbull Meningoccemia and

septic shockbull GMSPS score predicted

mortality 80bull PRISM predicted

mortality 57bull Dose titrate to

concentration of 08-12 IUml (normal)

bull 100 survivalbull 2 (17) lower limb

amputation

bull No drug ndash related adverse event

15

8

Sepsis in children US - 2

bull Sepsis is the 2nd cause of death among children 4th among infants

bull Children who develop severe sepsis consume substantial healthcare resources with an average length of stay of 31 days and cost of $40600

8

9

Sepsis in children Italy

bull In 2004-2005 lower overall incidence of sepsis severe sepsis and septic shock (79 16 and 21 of PICU admission)

bull Severe sepsis and septic shock had a mortality rate of 177 and 508 respectively

Incidence of and mortality due to sepsis severe sepsis and septic shock in Italian Pediatric Intensive Care Units a prospective national survey Wolfler A et al Intensive Care Med 2008 341690-7

9

1010

ldquoProtein C concentrations in children reach adult values at the age of 3 yrs Thismight indicate that the importance of protein C supplementation either as proteinC concentrate or as rhAPC is greater in young children than in adultsrdquo

11

The ldquoRESOLVErdquo study

Drotrecogin alfa (activated) in children with severe sepsis a multicentre phase III randomised controlled trial Nadel S et al Lancet 2007 369 836ndash43

Our results showed no significantdifference between groups in CTCOFR score

(p=0middot72) or in 28-day mortality (placebo 17middot5 DrotAA 17middot2 p=0middot93)

11

12

Author Year Journal NGerson 1993 Pediatrics 1Rivard 1995 J Pediatr 4Smith 1997 Lancet 12Rintala 1998 Crit Care Med 3Ettingshausen 1999 Semin Thromb Hemost 8Clarke 2000 Intensive Care Med 1Leclerc 2000 Crit Care Med 2White 2000 Blood 36De Kleijn 2003 Crit Care Med 30Fourrier 2003 Intensive Care Med 15Pettenazzo 2004 Minerva Anestesiol 8Silvani 2005 Minerva Anestesiol 11De Carolis 2008 Turk J Pediatr 1TOTAL 131

Summary of all published papers reporting on children patients

receiving protein C concentrates

12

13

Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive

meningococcemia33

De Kleijn 30 Severe sepsis or meningococcal disease 23

Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103

(79)

13

Summary of all published papers reporting on children patients

receiving protein C concentrates

14

bull Few papers account for more than half of published ndash treated patients

bull 3 ldquomajorrdquo papers 78 children (59)

14

15

Smith Lancet 1997

bull 12 patientsbull Meningoccemia and

septic shockbull GMSPS score predicted

mortality 80bull PRISM predicted

mortality 57bull Dose titrate to

concentration of 08-12 IUml (normal)

bull 100 survivalbull 2 (17) lower limb

amputation

bull No drug ndash related adverse event

15

9

Sepsis in children Italy

bull In 2004-2005 lower overall incidence of sepsis severe sepsis and septic shock (79 16 and 21 of PICU admission)

bull Severe sepsis and septic shock had a mortality rate of 177 and 508 respectively

Incidence of and mortality due to sepsis severe sepsis and septic shock in Italian Pediatric Intensive Care Units a prospective national survey Wolfler A et al Intensive Care Med 2008 341690-7

9

1010

ldquoProtein C concentrations in children reach adult values at the age of 3 yrs Thismight indicate that the importance of protein C supplementation either as proteinC concentrate or as rhAPC is greater in young children than in adultsrdquo

11

The ldquoRESOLVErdquo study

Drotrecogin alfa (activated) in children with severe sepsis a multicentre phase III randomised controlled trial Nadel S et al Lancet 2007 369 836ndash43

Our results showed no significantdifference between groups in CTCOFR score

(p=0middot72) or in 28-day mortality (placebo 17middot5 DrotAA 17middot2 p=0middot93)

11

12

Author Year Journal NGerson 1993 Pediatrics 1Rivard 1995 J Pediatr 4Smith 1997 Lancet 12Rintala 1998 Crit Care Med 3Ettingshausen 1999 Semin Thromb Hemost 8Clarke 2000 Intensive Care Med 1Leclerc 2000 Crit Care Med 2White 2000 Blood 36De Kleijn 2003 Crit Care Med 30Fourrier 2003 Intensive Care Med 15Pettenazzo 2004 Minerva Anestesiol 8Silvani 2005 Minerva Anestesiol 11De Carolis 2008 Turk J Pediatr 1TOTAL 131

Summary of all published papers reporting on children patients

receiving protein C concentrates

12

13

Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive

meningococcemia33

De Kleijn 30 Severe sepsis or meningococcal disease 23

Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103

(79)

13

Summary of all published papers reporting on children patients

receiving protein C concentrates

14

bull Few papers account for more than half of published ndash treated patients

bull 3 ldquomajorrdquo papers 78 children (59)

14

15

Smith Lancet 1997

bull 12 patientsbull Meningoccemia and

septic shockbull GMSPS score predicted

mortality 80bull PRISM predicted

mortality 57bull Dose titrate to

concentration of 08-12 IUml (normal)

bull 100 survivalbull 2 (17) lower limb

amputation

bull No drug ndash related adverse event

15

1010

ldquoProtein C concentrations in children reach adult values at the age of 3 yrs Thismight indicate that the importance of protein C supplementation either as proteinC concentrate or as rhAPC is greater in young children than in adultsrdquo

11

The ldquoRESOLVErdquo study

Drotrecogin alfa (activated) in children with severe sepsis a multicentre phase III randomised controlled trial Nadel S et al Lancet 2007 369 836ndash43

Our results showed no significantdifference between groups in CTCOFR score

(p=0middot72) or in 28-day mortality (placebo 17middot5 DrotAA 17middot2 p=0middot93)

11

12

Author Year Journal NGerson 1993 Pediatrics 1Rivard 1995 J Pediatr 4Smith 1997 Lancet 12Rintala 1998 Crit Care Med 3Ettingshausen 1999 Semin Thromb Hemost 8Clarke 2000 Intensive Care Med 1Leclerc 2000 Crit Care Med 2White 2000 Blood 36De Kleijn 2003 Crit Care Med 30Fourrier 2003 Intensive Care Med 15Pettenazzo 2004 Minerva Anestesiol 8Silvani 2005 Minerva Anestesiol 11De Carolis 2008 Turk J Pediatr 1TOTAL 131

Summary of all published papers reporting on children patients

receiving protein C concentrates

12

13

Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive

meningococcemia33

De Kleijn 30 Severe sepsis or meningococcal disease 23

Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103

(79)

13

Summary of all published papers reporting on children patients

receiving protein C concentrates

14

bull Few papers account for more than half of published ndash treated patients

bull 3 ldquomajorrdquo papers 78 children (59)

14

15

Smith Lancet 1997

bull 12 patientsbull Meningoccemia and

septic shockbull GMSPS score predicted

mortality 80bull PRISM predicted

mortality 57bull Dose titrate to

concentration of 08-12 IUml (normal)

bull 100 survivalbull 2 (17) lower limb

amputation

bull No drug ndash related adverse event

15

11

The ldquoRESOLVErdquo study

Drotrecogin alfa (activated) in children with severe sepsis a multicentre phase III randomised controlled trial Nadel S et al Lancet 2007 369 836ndash43

Our results showed no significantdifference between groups in CTCOFR score

(p=0middot72) or in 28-day mortality (placebo 17middot5 DrotAA 17middot2 p=0middot93)

11

12

Author Year Journal NGerson 1993 Pediatrics 1Rivard 1995 J Pediatr 4Smith 1997 Lancet 12Rintala 1998 Crit Care Med 3Ettingshausen 1999 Semin Thromb Hemost 8Clarke 2000 Intensive Care Med 1Leclerc 2000 Crit Care Med 2White 2000 Blood 36De Kleijn 2003 Crit Care Med 30Fourrier 2003 Intensive Care Med 15Pettenazzo 2004 Minerva Anestesiol 8Silvani 2005 Minerva Anestesiol 11De Carolis 2008 Turk J Pediatr 1TOTAL 131

Summary of all published papers reporting on children patients

receiving protein C concentrates

12

13

Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive

meningococcemia33

De Kleijn 30 Severe sepsis or meningococcal disease 23

Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103

(79)

13

Summary of all published papers reporting on children patients

receiving protein C concentrates

14

bull Few papers account for more than half of published ndash treated patients

bull 3 ldquomajorrdquo papers 78 children (59)

14

15

Smith Lancet 1997

bull 12 patientsbull Meningoccemia and

septic shockbull GMSPS score predicted

mortality 80bull PRISM predicted

mortality 57bull Dose titrate to

concentration of 08-12 IUml (normal)

bull 100 survivalbull 2 (17) lower limb

amputation

bull No drug ndash related adverse event

15

12

Author Year Journal NGerson 1993 Pediatrics 1Rivard 1995 J Pediatr 4Smith 1997 Lancet 12Rintala 1998 Crit Care Med 3Ettingshausen 1999 Semin Thromb Hemost 8Clarke 2000 Intensive Care Med 1Leclerc 2000 Crit Care Med 2White 2000 Blood 36De Kleijn 2003 Crit Care Med 30Fourrier 2003 Intensive Care Med 15Pettenazzo 2004 Minerva Anestesiol 8Silvani 2005 Minerva Anestesiol 11De Carolis 2008 Turk J Pediatr 1TOTAL 131

Summary of all published papers reporting on children patients

receiving protein C concentrates

12

13

Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive

meningococcemia33

De Kleijn 30 Severe sepsis or meningococcal disease 23

Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103

(79)

13

Summary of all published papers reporting on children patients

receiving protein C concentrates

14

bull Few papers account for more than half of published ndash treated patients

bull 3 ldquomajorrdquo papers 78 children (59)

14

15

Smith Lancet 1997

bull 12 patientsbull Meningoccemia and

septic shockbull GMSPS score predicted

mortality 80bull PRISM predicted

mortality 57bull Dose titrate to

concentration of 08-12 IUml (normal)

bull 100 survivalbull 2 (17) lower limb

amputation

bull No drug ndash related adverse event

15

13

Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive

meningococcemia33

De Kleijn 30 Severe sepsis or meningococcal disease 23

Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103

(79)

13

Summary of all published papers reporting on children patients

receiving protein C concentrates

14

bull Few papers account for more than half of published ndash treated patients

bull 3 ldquomajorrdquo papers 78 children (59)

14

15

Smith Lancet 1997

bull 12 patientsbull Meningoccemia and

septic shockbull GMSPS score predicted

mortality 80bull PRISM predicted

mortality 57bull Dose titrate to

concentration of 08-12 IUml (normal)

bull 100 survivalbull 2 (17) lower limb

amputation

bull No drug ndash related adverse event

15

14

bull Few papers account for more than half of published ndash treated patients

bull 3 ldquomajorrdquo papers 78 children (59)

14

15

Smith Lancet 1997

bull 12 patientsbull Meningoccemia and

septic shockbull GMSPS score predicted

mortality 80bull PRISM predicted

mortality 57bull Dose titrate to

concentration of 08-12 IUml (normal)

bull 100 survivalbull 2 (17) lower limb

amputation

bull No drug ndash related adverse event

15

15

Smith Lancet 1997

bull 12 patientsbull Meningoccemia and

septic shockbull GMSPS score predicted

mortality 80bull PRISM predicted

mortality 57bull Dose titrate to

concentration of 08-12 IUml (normal)

bull 100 survivalbull 2 (17) lower limb

amputation

bull No drug ndash related adverse event

15

16

Mean time to PC infusion begin in non amputated 12 (31) hMean time to PC infusion begin in amputated 60 (170) h

plt001

Use of protein-C concentrate heparin and haemodiafiltration in meningococcus-induced purpura fulminans Smith OP et al Lancet 1997 350 1590ndash93 16

17

White Blood 2000

bull 36 patients (some adults mean age 12)

bull Meningococcemia and septic shock

bull GMSPS score predicted mortality 50

bull Dose bolus 100 IUkg and infusion 10 IUkgh

bull 92 survivalbull 4 (12) amputation

bull No drug ndash related adverse event

17

18

Four amputation 2 patients received PC after 24 hours to admission

An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia White B et al Blood 2000 96 3719-3724 18

19

De Kleijn Crit Care Med 2003

bull Only RCT double blinde PC vs placebo

bull 40 patients (10 placebo 30 treatment)

bull Meningoccemia and septic shock

bull Fase two study (dose findings safety)

bull 1 placebo groupbull 3 treatment groups

incremental doses (50 100 150 IUkg6h

19

20

Main findings

MortalityNot powered to achieve a

significant result

No linear trend comparing predicted versus observed mortality

Fascinating result compared to predicted mortality

Group PRISM predicted mortality

Actual mortality

placebo 67 20

50 IUkg 35 9

100 IUkg 26 11

150 IUkg 60 50

Overall (drug)

40 23

Adapted from De Kleijn et al Crit Care Med 2003 311839-47

20

21

Main findings - 2

bull Supplementation of PC is effective

bull Concentration is dose ndash dependant

21

bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value

bull Effect on concentration is stable in the 6 hours beetwen doses

Dose response - PC

22

Main findings - 3

Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash

dependant

bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher

bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo

22

23

Main findings - 4

Safetybull 4 amputations (not

attributed to study drugs)

bull 1 not serious bleeding event in a patient with severe DIC

23

24

Lessons from literature - 1

bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor

bull Safety is high

bull We need a RCT trial

24

25

Lessons from literature - 2

bull If you decide to use PC do use preferably within 24 hours from admission

bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative

dose of 400-600 IUkg or use bolus at least every 6 hours

25

26

Hot topics

bull From 131 patients published just 8 children were not affected by meningococcal disease

bull PC is always activated Should we really need activation

26

27

PC pathways

DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27

28

A-PC effect

282007

29

A-PC anticoagulative properties

bull The A-PC PS complex binds to VIIIa and Va and inactivate them

bull Decreased Thrombin Generationbull Decreased Fibrin Formation and

reduced amplification of inflammatory pathway

A-PC Side effects

29

3030

31

PC and endothelium

Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to

ndash Activated PCndash Not-activated PC

31

32

Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92

Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9

Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964

Lack of PC ndash EPCR interaction

32

17

White Blood 2000

bull 36 patients (some adults mean age 12)

bull Meningococcemia and septic shock

bull GMSPS score predicted mortality 50

bull Dose bolus 100 IUkg and infusion 10 IUkgh

bull 92 survivalbull 4 (12) amputation

bull No drug ndash related adverse event

17

18

Four amputation 2 patients received PC after 24 hours to admission

An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia White B et al Blood 2000 96 3719-3724 18

19

De Kleijn Crit Care Med 2003

bull Only RCT double blinde PC vs placebo

bull 40 patients (10 placebo 30 treatment)

bull Meningoccemia and septic shock

bull Fase two study (dose findings safety)

bull 1 placebo groupbull 3 treatment groups

incremental doses (50 100 150 IUkg6h

19

20

Main findings

MortalityNot powered to achieve a

significant result

No linear trend comparing predicted versus observed mortality

Fascinating result compared to predicted mortality

Group PRISM predicted mortality

Actual mortality

placebo 67 20

50 IUkg 35 9

100 IUkg 26 11

150 IUkg 60 50

Overall (drug)

40 23

Adapted from De Kleijn et al Crit Care Med 2003 311839-47

20

21

Main findings - 2

bull Supplementation of PC is effective

bull Concentration is dose ndash dependant

21

bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value

bull Effect on concentration is stable in the 6 hours beetwen doses

Dose response - PC

22

Main findings - 3

Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash

dependant

bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher

bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo

22

23

Main findings - 4

Safetybull 4 amputations (not

attributed to study drugs)

bull 1 not serious bleeding event in a patient with severe DIC

23

24

Lessons from literature - 1

bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor

bull Safety is high

bull We need a RCT trial

24

25

Lessons from literature - 2

bull If you decide to use PC do use preferably within 24 hours from admission

bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative

dose of 400-600 IUkg or use bolus at least every 6 hours

25

26

Hot topics

bull From 131 patients published just 8 children were not affected by meningococcal disease

bull PC is always activated Should we really need activation

26

27

PC pathways

DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27

28

A-PC effect

282007

29

A-PC anticoagulative properties

bull The A-PC PS complex binds to VIIIa and Va and inactivate them

bull Decreased Thrombin Generationbull Decreased Fibrin Formation and

reduced amplification of inflammatory pathway

A-PC Side effects

29

3030

31

PC and endothelium

Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to

ndash Activated PCndash Not-activated PC

31

32

Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92

Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9

Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964

Lack of PC ndash EPCR interaction

32

18

Four amputation 2 patients received PC after 24 hours to admission

An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia White B et al Blood 2000 96 3719-3724 18

19

De Kleijn Crit Care Med 2003

bull Only RCT double blinde PC vs placebo

bull 40 patients (10 placebo 30 treatment)

bull Meningoccemia and septic shock

bull Fase two study (dose findings safety)

bull 1 placebo groupbull 3 treatment groups

incremental doses (50 100 150 IUkg6h

19

20

Main findings

MortalityNot powered to achieve a

significant result

No linear trend comparing predicted versus observed mortality

Fascinating result compared to predicted mortality

Group PRISM predicted mortality

Actual mortality

placebo 67 20

50 IUkg 35 9

100 IUkg 26 11

150 IUkg 60 50

Overall (drug)

40 23

Adapted from De Kleijn et al Crit Care Med 2003 311839-47

20

21

Main findings - 2

bull Supplementation of PC is effective

bull Concentration is dose ndash dependant

21

bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value

bull Effect on concentration is stable in the 6 hours beetwen doses

Dose response - PC

22

Main findings - 3

Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash

dependant

bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher

bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo

22

23

Main findings - 4

Safetybull 4 amputations (not

attributed to study drugs)

bull 1 not serious bleeding event in a patient with severe DIC

23

24

Lessons from literature - 1

bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor

bull Safety is high

bull We need a RCT trial

24

25

Lessons from literature - 2

bull If you decide to use PC do use preferably within 24 hours from admission

bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative

dose of 400-600 IUkg or use bolus at least every 6 hours

25

26

Hot topics

bull From 131 patients published just 8 children were not affected by meningococcal disease

bull PC is always activated Should we really need activation

26

27

PC pathways

DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27

28

A-PC effect

282007

29

A-PC anticoagulative properties

bull The A-PC PS complex binds to VIIIa and Va and inactivate them

bull Decreased Thrombin Generationbull Decreased Fibrin Formation and

reduced amplification of inflammatory pathway

A-PC Side effects

29

3030

31

PC and endothelium

Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to

ndash Activated PCndash Not-activated PC

31

32

Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92

Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9

Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964

Lack of PC ndash EPCR interaction

32

19

De Kleijn Crit Care Med 2003

bull Only RCT double blinde PC vs placebo

bull 40 patients (10 placebo 30 treatment)

bull Meningoccemia and septic shock

bull Fase two study (dose findings safety)

bull 1 placebo groupbull 3 treatment groups

incremental doses (50 100 150 IUkg6h

19

20

Main findings

MortalityNot powered to achieve a

significant result

No linear trend comparing predicted versus observed mortality

Fascinating result compared to predicted mortality

Group PRISM predicted mortality

Actual mortality

placebo 67 20

50 IUkg 35 9

100 IUkg 26 11

150 IUkg 60 50

Overall (drug)

40 23

Adapted from De Kleijn et al Crit Care Med 2003 311839-47

20

21

Main findings - 2

bull Supplementation of PC is effective

bull Concentration is dose ndash dependant

21

bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value

bull Effect on concentration is stable in the 6 hours beetwen doses

Dose response - PC

22

Main findings - 3

Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash

dependant

bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher

bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo

22

23

Main findings - 4

Safetybull 4 amputations (not

attributed to study drugs)

bull 1 not serious bleeding event in a patient with severe DIC

23

24

Lessons from literature - 1

bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor

bull Safety is high

bull We need a RCT trial

24

25

Lessons from literature - 2

bull If you decide to use PC do use preferably within 24 hours from admission

bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative

dose of 400-600 IUkg or use bolus at least every 6 hours

25

26

Hot topics

bull From 131 patients published just 8 children were not affected by meningococcal disease

bull PC is always activated Should we really need activation

26

27

PC pathways

DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27

28

A-PC effect

282007

29

A-PC anticoagulative properties

bull The A-PC PS complex binds to VIIIa and Va and inactivate them

bull Decreased Thrombin Generationbull Decreased Fibrin Formation and

reduced amplification of inflammatory pathway

A-PC Side effects

29

3030

31

PC and endothelium

Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to

ndash Activated PCndash Not-activated PC

31

32

Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92

Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9

Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964

Lack of PC ndash EPCR interaction

32

20

Main findings

MortalityNot powered to achieve a

significant result

No linear trend comparing predicted versus observed mortality

Fascinating result compared to predicted mortality

Group PRISM predicted mortality

Actual mortality

placebo 67 20

50 IUkg 35 9

100 IUkg 26 11

150 IUkg 60 50

Overall (drug)

40 23

Adapted from De Kleijn et al Crit Care Med 2003 311839-47

20

21

Main findings - 2

bull Supplementation of PC is effective

bull Concentration is dose ndash dependant

21

bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value

bull Effect on concentration is stable in the 6 hours beetwen doses

Dose response - PC

22

Main findings - 3

Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash

dependant

bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher

bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo

22

23

Main findings - 4

Safetybull 4 amputations (not

attributed to study drugs)

bull 1 not serious bleeding event in a patient with severe DIC

23

24

Lessons from literature - 1

bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor

bull Safety is high

bull We need a RCT trial

24

25

Lessons from literature - 2

bull If you decide to use PC do use preferably within 24 hours from admission

bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative

dose of 400-600 IUkg or use bolus at least every 6 hours

25

26

Hot topics

bull From 131 patients published just 8 children were not affected by meningococcal disease

bull PC is always activated Should we really need activation

26

27

PC pathways

DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27

28

A-PC effect

282007

29

A-PC anticoagulative properties

bull The A-PC PS complex binds to VIIIa and Va and inactivate them

bull Decreased Thrombin Generationbull Decreased Fibrin Formation and

reduced amplification of inflammatory pathway

A-PC Side effects

29

3030

31

PC and endothelium

Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to

ndash Activated PCndash Not-activated PC

31

32

Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92

Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9

Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964

Lack of PC ndash EPCR interaction

32

21

Main findings - 2

bull Supplementation of PC is effective

bull Concentration is dose ndash dependant

21

bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value

bull Effect on concentration is stable in the 6 hours beetwen doses

Dose response - PC

22

Main findings - 3

Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash

dependant

bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher

bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo

22

23

Main findings - 4

Safetybull 4 amputations (not

attributed to study drugs)

bull 1 not serious bleeding event in a patient with severe DIC

23

24

Lessons from literature - 1

bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor

bull Safety is high

bull We need a RCT trial

24

25

Lessons from literature - 2

bull If you decide to use PC do use preferably within 24 hours from admission

bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative

dose of 400-600 IUkg or use bolus at least every 6 hours

25

26

Hot topics

bull From 131 patients published just 8 children were not affected by meningococcal disease

bull PC is always activated Should we really need activation

26

27

PC pathways

DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27

28

A-PC effect

282007

29

A-PC anticoagulative properties

bull The A-PC PS complex binds to VIIIa and Va and inactivate them

bull Decreased Thrombin Generationbull Decreased Fibrin Formation and

reduced amplification of inflammatory pathway

A-PC Side effects

29

3030

31

PC and endothelium

Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to

ndash Activated PCndash Not-activated PC

31

32

Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92

Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9

Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964

Lack of PC ndash EPCR interaction

32

22

Main findings - 3

Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash

dependant

bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher

bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo

22

23

Main findings - 4

Safetybull 4 amputations (not

attributed to study drugs)

bull 1 not serious bleeding event in a patient with severe DIC

23

24

Lessons from literature - 1

bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor

bull Safety is high

bull We need a RCT trial

24

25

Lessons from literature - 2

bull If you decide to use PC do use preferably within 24 hours from admission

bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative

dose of 400-600 IUkg or use bolus at least every 6 hours

25

26

Hot topics

bull From 131 patients published just 8 children were not affected by meningococcal disease

bull PC is always activated Should we really need activation

26

27

PC pathways

DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27

28

A-PC effect

282007

29

A-PC anticoagulative properties

bull The A-PC PS complex binds to VIIIa and Va and inactivate them

bull Decreased Thrombin Generationbull Decreased Fibrin Formation and

reduced amplification of inflammatory pathway

A-PC Side effects

29

3030

31

PC and endothelium

Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to

ndash Activated PCndash Not-activated PC

31

32

Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92

Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9

Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964

Lack of PC ndash EPCR interaction

32

23

Main findings - 4

Safetybull 4 amputations (not

attributed to study drugs)

bull 1 not serious bleeding event in a patient with severe DIC

23

24

Lessons from literature - 1

bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor

bull Safety is high

bull We need a RCT trial

24

25

Lessons from literature - 2

bull If you decide to use PC do use preferably within 24 hours from admission

bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative

dose of 400-600 IUkg or use bolus at least every 6 hours

25

26

Hot topics

bull From 131 patients published just 8 children were not affected by meningococcal disease

bull PC is always activated Should we really need activation

26

27

PC pathways

DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27

28

A-PC effect

282007

29

A-PC anticoagulative properties

bull The A-PC PS complex binds to VIIIa and Va and inactivate them

bull Decreased Thrombin Generationbull Decreased Fibrin Formation and

reduced amplification of inflammatory pathway

A-PC Side effects

29

3030

31

PC and endothelium

Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to

ndash Activated PCndash Not-activated PC

31

32

Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92

Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9

Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964

Lack of PC ndash EPCR interaction

32

24

Lessons from literature - 1

bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor

bull Safety is high

bull We need a RCT trial

24

25

Lessons from literature - 2

bull If you decide to use PC do use preferably within 24 hours from admission

bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative

dose of 400-600 IUkg or use bolus at least every 6 hours

25

26

Hot topics

bull From 131 patients published just 8 children were not affected by meningococcal disease

bull PC is always activated Should we really need activation

26

27

PC pathways

DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27

28

A-PC effect

282007

29

A-PC anticoagulative properties

bull The A-PC PS complex binds to VIIIa and Va and inactivate them

bull Decreased Thrombin Generationbull Decreased Fibrin Formation and

reduced amplification of inflammatory pathway

A-PC Side effects

29

3030

31

PC and endothelium

Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to

ndash Activated PCndash Not-activated PC

31

32

Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92

Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9

Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964

Lack of PC ndash EPCR interaction

32

25

Lessons from literature - 2

bull If you decide to use PC do use preferably within 24 hours from admission

bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative

dose of 400-600 IUkg or use bolus at least every 6 hours

25

26

Hot topics

bull From 131 patients published just 8 children were not affected by meningococcal disease

bull PC is always activated Should we really need activation

26

27

PC pathways

DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27

28

A-PC effect

282007

29

A-PC anticoagulative properties

bull The A-PC PS complex binds to VIIIa and Va and inactivate them

bull Decreased Thrombin Generationbull Decreased Fibrin Formation and

reduced amplification of inflammatory pathway

A-PC Side effects

29

3030

31

PC and endothelium

Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to

ndash Activated PCndash Not-activated PC

31

32

Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92

Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9

Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964

Lack of PC ndash EPCR interaction

32

26

Hot topics

bull From 131 patients published just 8 children were not affected by meningococcal disease

bull PC is always activated Should we really need activation

26

27

PC pathways

DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27

28

A-PC effect

282007

29

A-PC anticoagulative properties

bull The A-PC PS complex binds to VIIIa and Va and inactivate them

bull Decreased Thrombin Generationbull Decreased Fibrin Formation and

reduced amplification of inflammatory pathway

A-PC Side effects

29

3030

31

PC and endothelium

Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to

ndash Activated PCndash Not-activated PC

31

32

Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92

Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9

Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964

Lack of PC ndash EPCR interaction

32

27

PC pathways

DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27

28

A-PC effect

282007

29

A-PC anticoagulative properties

bull The A-PC PS complex binds to VIIIa and Va and inactivate them

bull Decreased Thrombin Generationbull Decreased Fibrin Formation and

reduced amplification of inflammatory pathway

A-PC Side effects

29

3030

31

PC and endothelium

Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to

ndash Activated PCndash Not-activated PC

31

32

Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92

Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9

Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964

Lack of PC ndash EPCR interaction

32

28

A-PC effect

282007

29

A-PC anticoagulative properties

bull The A-PC PS complex binds to VIIIa and Va and inactivate them

bull Decreased Thrombin Generationbull Decreased Fibrin Formation and

reduced amplification of inflammatory pathway

A-PC Side effects

29

3030

31

PC and endothelium

Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to

ndash Activated PCndash Not-activated PC

31

32

Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92

Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9

Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964

Lack of PC ndash EPCR interaction

32

29

A-PC anticoagulative properties

bull The A-PC PS complex binds to VIIIa and Va and inactivate them

bull Decreased Thrombin Generationbull Decreased Fibrin Formation and

reduced amplification of inflammatory pathway

A-PC Side effects

29

3030

31

PC and endothelium

Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to

ndash Activated PCndash Not-activated PC

31

32

Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92

Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9

Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964

Lack of PC ndash EPCR interaction

32

3030

31

PC and endothelium

Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to

ndash Activated PCndash Not-activated PC

31

32

Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92

Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9

Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964

Lack of PC ndash EPCR interaction

32

31

PC and endothelium

Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to

ndash Activated PCndash Not-activated PC

31

32

Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92

Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9

Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964

Lack of PC ndash EPCR interaction

32

32

Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92

Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9

Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964

Lack of PC ndash EPCR interaction

32

33

PC and endothelium

Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to

ndash Activated PCndash Not-activated PC

33

34

APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization

Mediated by a Gi protein intracellular pathway

EPCR binds to a-PC

34

35

PC and endothelium

Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to

ndash Activated PCndash Not-activated PC

35

36

Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109

The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916

EPCR binds to PC (and thrombin)

36

37

wild type PC

Modified non anticoagulant PC

Unfortunately up to now just in mice 37

38

montigiacomohsrit

Thanks

3939

For these and further slides on these topics please feel free to visit the

metcardioorg website

httpwwwmetcardioorgslideshtml

34

APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization

Mediated by a Gi protein intracellular pathway

EPCR binds to a-PC

34

35

PC and endothelium

Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to

ndash Activated PCndash Not-activated PC

35

36

Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109

The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916

EPCR binds to PC (and thrombin)

36

37

wild type PC

Modified non anticoagulant PC

Unfortunately up to now just in mice 37

38

montigiacomohsrit

Thanks

3939

For these and further slides on these topics please feel free to visit the

metcardioorg website

httpwwwmetcardioorgslideshtml

35

PC and endothelium

Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to

ndash Activated PCndash Not-activated PC

35

36

Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109

The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916

EPCR binds to PC (and thrombin)

36

37

wild type PC

Modified non anticoagulant PC

Unfortunately up to now just in mice 37

38

montigiacomohsrit

Thanks

3939

For these and further slides on these topics please feel free to visit the

metcardioorg website

httpwwwmetcardioorgslideshtml

36

Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109

The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916

EPCR binds to PC (and thrombin)

36

37

wild type PC

Modified non anticoagulant PC

Unfortunately up to now just in mice 37

38

montigiacomohsrit

Thanks

3939

For these and further slides on these topics please feel free to visit the

metcardioorg website

httpwwwmetcardioorgslideshtml

37

wild type PC

Modified non anticoagulant PC

Unfortunately up to now just in mice 37

38

montigiacomohsrit

Thanks

3939

For these and further slides on these topics please feel free to visit the

metcardioorg website

httpwwwmetcardioorgslideshtml

38

montigiacomohsrit

Thanks

3939

For these and further slides on these topics please feel free to visit the

metcardioorg website

httpwwwmetcardioorgslideshtml

3939

For these and further slides on these topics please feel free to visit the

metcardioorg website

httpwwwmetcardioorgslideshtml

For these and further slides on these topics please feel free to visit the

metcardioorg website

httpwwwmetcardioorgslideshtml