Pediatric Stroke Team Inaugurated February 2002

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Pediatric Stroke TeamInaugurated February 2002
Co-Directors F.S. Buonanno and E.F.Grabowski

• Purposes
• 1. Rapid, coordinated response to the
  management of pediatric stroke cases.
• Long-term follow-up care for these patients.
• Evaluation of selected children with complex
  cerebrovascular disease

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Team Members

• Ferdinando Buonanno, adult stroke service
• Eric Grabowski, pediatric hematology/oncology
• K. Krishnamoorthy, neonatal pediatric neurology
  
• Robin Jones, outpatient pediatric neurology
  Elizabeth Van Cott, coagulation lab
• P. Ellen Grant, neuroradiology
• J. Pryor, interventional neuroradiology
• W. Butler, C.S. Ogilvy, neurosurgery

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Overall Concerns Addressed by Our
Multidisciplinary Team

• 1. Clinical diagnosis, stabilization
• (O2 seizure control), and triage
• 2. Diagnostic imaging
• 3. Studies for thrombophilia
• 4. Anticoagulation
• 5. Follow-up

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Clinical Case Illustrating How We Approach These
Concerns

• J.C., a seven-year old boy with nephrotic
  syndrome, presented to our EW on a Saturday
  evening with 3 day history of headache and
  vomiting. Exam revealed left-beating nystagmus
  and left hyper-reflexia, but no ataxia.

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JCs MRI- DWI

• MRI revealed multiple foci of increased signal on
  DWI (shown).
• ADC maps showed restricted diffusion in several
  of these areas others appeared ADC isointense.
• Findings suggested infarcts in early and later
  subacute stages

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Studies for Thrombophilia

• 1. Factor V Leiden (stroke risk)
• 2. Factor II G20210A (stroke risk)
• 3. Lipoprotein (a) (stroke risk)
• 4. Hyperhomocysteinemia
• 5. Protein C
• 6. Protein S
• ATIII
• 8. Vascular anomalies

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Nephrotic Syndrome An Acquired Hypercoagulable
State

• 1. Low ATIII increased clearance
• 2. Low functional protein S decreased
  clearance of C4BP increased clearance of free
  protein S
• 3. Increased levels of factors V, VII, VIII,
  vWf, and fibrinogen
• Increased lipoprotein (a)
• Our patient had both 1 and 4

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Antithrombin III

• Inhibits serine esterase activity, which accounts
  for its effects on activated forms of coagulation
  factors XII, XI, X, and IX. MW 150,000.
• Requires a cofactor to be active heparin, low MW
  heparin, or, in vivo, heparan sulfate.

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Lipoprotein (a)

• A low density lipoprotein which shares a high
  degree of sequence identity with plasminogen.
  Therefore, antifibrinolytic via competition with
  plasminogen for binding sites on a specific
  endothelial cell receptor.
• Also binds and inactivates tissue factor pathway
  inhibitor.

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Anticoagulation Challenges in JCs Case

• 1. Low serum albumin made a therapeutic window
  for heparin virtually non-existent.
• 2. Lack of assays on weekend for anti-Xa levels
  made it impossible to judge efficacy of low MW
  heparin, given unknown level of ATIII.
• 3. Inability to use concomitant heparin or low
  MW heparin (to prevent augmentation of a
  transient hypercoagulable state) made use of
  warfarin unacceptably risky.

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Heparin

• 1. Anticoagulant derived from porcine
  intestine or beef lung. MW 12,000- 15,000.
  Cofactor for ATIII.
• 2. Potentially very effective inhibits
  activation of factors XI, X, IX, and II.
• Follow PTT.
• 3. Fails to penetrate deep into thrombi, 80-
• 90 bound to cell membranes and
• proteins, and associated with HIT.

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Low MW Heparin (e.g., dalteparin)

• 1. Anticoagulant derived from standard,
• unfractionated heparin. MW 4000-6000.
• Co-factor for ATIII.
• 2. Inhibits activation of factor X gt factor
  II.
• Follow anti-factor Xa level.
• 3. Lower bleeding risk.
• 4. Does not bind significantly to cell
• membranes or proteins.
• 5. Long half-life (5 to 15 hrs).

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Argatroban

• 1. An arginine derivative which is a selective
  and competitive antithrombin agent.
  Specifically and reversibly inactivates thrombin.
  Follow PTT.
• 2. ATIII independent.
• 3. Liver metabolized. Excreted normally even in
  renal failure.
• 4. Used in a) HIT, b) studies at MGH to prevent
  post-angioplasty heparin rebound, and c) ECMO
  (Japan).

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Why Argatroban?

• 1. Only 55 plasma protein bound, vs 80-90 for
  heparin
• 2. Monitored via PTT
• 3. ATIII independent
• 4. Liver metabolized not dependent upon renal
  function

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But, Argatroban Challenges

• 1. Unknown whether we could achieve a
  therapeutic window in nephrotic syndrome (with a
  low serum albumin).
• We found that we could!
• 2. Lack of pediatric experience and
  non-existence of pediatric dosing.
• We made up a dose by assuming a) negligible
  protein buffering, and b) the presence of a
  mild coagulopathy!

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Argatroban Challenges, Contd

• 3. Argatroban itself increases the PT and INR,
  complicating coumadinization.
• We followed an existing protocol which calls for
  monitoring (chromogenic assay) factor X levels
  (vitamin K-dependent). Argatroban was d/cd when
  factor X was lt 40.

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Follow-up

• Our patient has had no recurrence of cerebral
  ischemia or stroke, although he continues to be
  dependent upon hemodialysis.

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How to reach us

• For ACUTE cerebro-vascular referrals
• call 617-724-6400,
• or call 617-726-2000 and page
• the pediatric neurology resident on
  call.
• For OUTPATIENT evaluations and follow-up
• call 617-726-2737