Severe congenital protein C deficiency

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Severe congenital protein C deficiency

• Charles Eby MD
• May 19, 2006

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Case History

• 33 year old woman G3 P2 A0, 16 weeks gestation,
  referred to hematology
• Previous pregnancies
• 1 1998 uncomplicated, term, vaginal delivery,
  neonatal death at 10 days intracranial
  hemorrhage and sepsis
• 2 2001 C section at 36 weeks, neonatal death at
  11 days autopsy severe hydrocephalus and
  neonatal purpura fulminans

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• Same father
• No personal history of venous thromboembolic
  events for either parent
• Protein C activities (chromogenic 70-150)
• Mother 54
• Father 57
• No knowledge of consanguinity
• Maternal uncle with DVT
• Working diagnosis neonatal deaths due to severe
  protein C deficiency

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• Protein C regulation of Thrombin Generation

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Neonatal purpura fulminans due to severe protein
C deficiency

• Rare!
• Severe protein S deficiency even rarer
• Usually no detectable Protein C activity
• Parents obligate partial protein C deficient and
  usually asymptomatic
• Consanguinity common
• Both antenatal and postnatal thrombotic
  complications
• Prompt diagnosis and treatment can prevent death
  from DIC-multiorgan failure

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First reported kindred 1984
12 heterozygous relatives
Seligsohn et al NEJM 1984310559
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Thrombotic Complications

• CNS ischemic and hemorrhagic injuries,
  hydrocephalus
• Retinal vein thrombosis, neovascularization,
  hemorrhage, retinal detachment,and blindness
• Placental infarctions
• Full thickness skin infarctions
• Multiple organ microthrombi
• Adrenal
• Kidney
• Lungs
• Macrothrombi PE, IVC and renal vein thromboses

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Diagnosis

• First sign gt1 purpuric lesion appears within
  hours to days of birth
• Laboratory findings classic DIC
• Presumed DIC 20 sepsis
• Delay in diagnosis of severe protein C or S
  deficiency unless sensitized by previous infant
  with neonatal purpura fulminans

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Primagravida, nl US at 26.5 weeks, dilated
ventricles, orbital mass at 33 weeks. C-section
at 36 wk (fetal distress) first purpuric lesion
48 hr. pro C act 2.
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Treatment options

• Premature delivery
• Protein C replacement
• FFP
• Protein C concentrate
• Anticoagulation
• Oral vitamin K antagonist
• LMWH?
• Direct thrombin inhibitor?
• Factor Xa inhibitor?
• Liver transplant

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Protein C concentrate

• 1989 monoclonal purified from plasma
• 2001 European Union approves protein C
  concentrate for patients with severe congenital
  protein C deficiency and
• Neonatal purpura fulminans
• Coumadin skin necrosis
• surgery, invasive procedures, initiation of OAT
• OAT failure (thrombotic or hemorrhagic)
• Two manufacturers
• Baxter Ceprotin
• LFB (France)
• Baxter to seek FDA approval in 2006

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Ceprotin

• 500 IU and 1000 IU vials
• T1/2 8hrs
• Neonatal purpura fulminans dosing
• 50-150 IU/kg q 6 hr trough gt 80
• Maintenance dosing
• IV QD, QOD, trough detectable to 25
• SC pump QOD

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Potential indications acquired protein C
deficiency

• Meningicoccal sepsis
• Sepsis in general

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• N 12 (3m-27 yr) mean Pro C 20
• 100IU/kg load, 15IU/kg/hr continuous infusion
  until DIC resolved 5.7 d (4-8)
• Protein C started lt 18 hr in 10/12 pts
• 11 concurrent heparin, 9 hemodialysis
• Predicted mortality 57-80

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• Hypothesis could severity of thrombotic
  complications in meningcoccal sepsis be due to
  impaired endothelial activation of protein C?
• Design compare skin biopsies and plasma from
  patients with meningococcal sepsis and purpura
  fulminans to controls and to patients following
  recovery

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Endothelial protein C receptor antibody
Thrombomodulin antibody
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Thrombomodulin immunostaining
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Plasma activated protein C undetectable in 14/14
patients on days 2-4. Two patients pro C conc,
obtained normal pro C activities but no
detectable activated protein C.
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• 40 children 1m-18 yr
• Eligibility criteria presumed meningococcal
  infection, petechial or purpuric rash,
  andhypotensive or oliguric or acidotic or mental
  status changes
• Diagnosis of shock ,lt 6 hr before entry
• Q 6 hr placebo, 50, 100, 150 IU/kg/hr

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Plasma protein C Activities baseline, 24, 48,
and 72 hrs
most patients had elevated aPC at baseline
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Sustained aPC 3-4x baseline
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Change in mean natural log D-dimer during
infusions
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Outcome Mortality 23. Median 12 hr after
admission (7.5-42 hr)
Sustained increased aPC was obtained with 150
IU/kg q 6 hr Larger trial of this dose vs placebo
to assess impact on mortality
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Returning to case

• Current management plan
• Week 29 uncomplicated pregnancy, Lovenox sc 40
  mg/d
• Week 28 ultrasound normal
• Begin weekly OB visits and US at week 30
• Steroids for fetal lung maturity
• C-section at week 34
• Infuse 500IU Ceprotin at birth prior to
  obtaining umbilical cord blood protein C activity

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