ANTICOAGULATION

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ANTICOAGULATION

• STOP THE CLOT
• January 14, 2008

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HEPARIN(HEPARAN SULFATE)

• Introduction
• Naturally occurring sulfated polysaccharide
• Discovered in 1916 (McLean)
• Clinical use porcine/bovine tissue
• Preparation UF or depolymerized LMW

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Main Complication

• Life threatening bleeding
• Lab monitoring w/adjustment dose regimens improve
  antithrombotic efficacy

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UF Heparin

• Activity usually monitored by APTT
• APTT most widely used global assay
• APTT-simple test, allows for automation
• Draw back if prolonged past normal range a more
  specific assay is required.

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Biochemistry of Heparin

• Sulfated glycosaminoglycan (GAG)
• Found in mammalian/non mast cells
• Located tissue/organs (lung, skin, intest.)
• Found extravascularly
• Heparan Sulfate GAG AA

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Anticoagulant Activity of (Heparan Sulfate)

• Plasma Binds to AT
• Conformational Change
• Accelerates AT INH
• FIXa, Xa, XIa, XIIa, kallikrein
• Heparin-accelerated INH of FIIa

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Mw

• Two Forms UF/LMWH
• UF Avg. Mw 15,000
• LMWH Avg Mw 4,000-6,000
• LMW FXa
• UF FIIa FXa

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Catalytic MechanismHeparin

• Template AT Protease bind
• Accelerating function depends unique AT-binding
  pentasaccharide sequence in Heparin GAG chain.
• Facilitates react. w/target protease
• INH predominately works conformational change of
  AT-Heparin
• Has Higher affinity for unreacted AT

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UF Heparin

• Activity usually monitored by APTT
• APTT most widely used global assay
• APTT-simple test, allows for automation
• Draw back if prolonged past normal range a more
  specific assay is required.

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UFHTwo Forms

• High affinity Anticoagulant Activity (AA)
• Low affinity Low AA

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LMWH

• Depolymerized UF
• Chain length lowers affinity for plasma proteins,
  endo. cells, macro, platelets
• Leads higher Bioavailability, half-life
• More predictable therapeutic response
• Reduced platelet associated side-effects.

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Clinical Use of Heparin

• Goal to reduce, delay, prevent presence of
  Thrombin
• Low dose (-) thrombin generation
• Acute cases Neutralize already formed
  FIIa/prevent new TG

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Mode of Administration

• Intravenous/Subcutaneous UF/LMWH
• Intermittent injection/or Continuous infusion.
• Treatment of VTE DVTPE

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Complications Heparin Therapy

• Hemorrhage
• HIT Moderate/Severe

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Laboratory Monitoring

• Minimize risk of hemorrhage
• Optimize ATic-effect UF/LMW
• Individual response Acquired factors

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Heparin Assays

• APTT (plasma) Automated
• Drawback overall coagulability of blood
  sample/not specific presence of heparin alone
  (Anti-FXa)
• Lupus Anticoagulant APTT (prolonged)

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Anti-FXa assays

• Clotting/ Chromogenic
• Adv Ability of Heparin-accel. AT to (-) a single
  enzyme (target)
• Use plasma/purified AT
• Clotting (-) for LMWH

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Chromogenic Method

• Residual FXa-synthetic FXa substrate
• 1 or 2 stage assays
• CM Heparin (1) S-2732
• Determine Anti FXa in UF/LMW
• Add excess FXa
• 2 competing reactions
• Dont forget CC

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Advantage of ChromogenicAnti- Factor Xa Assay

• Adv Isolate biological activity of heparin to
  one reaction
• Minimize interference from other variables
• Practical for measuring LMWH

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Coatest Heparin

• 2 Stage (chromogenic)
• Measure FXa- UF/LMW
• S-2222, FXa (bovine), AT (human), normal plasma
  (human)
• Hep-AT complex

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Coatest LMW Heparin

• 1 Stage, Non automated systems.

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Direct Thrombin Inhibitors

• Argatroban 50 (min), reversible, hepatic
• Bivalirudin 25 (min), reversible, renal
• Lepirudin 60-180 (min), irrev., renal

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Indirect Thrombin INH

• Fondaparinux (Arixtra)
• Once Daily, Highly selective
• Rapid onset
• Antidote rc FVIIa (Novoseven)
• No liver metabolism, No protein binding
• No reported cases of HIT to date
• No dose adjustment for elderly

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Coamatic Coatest AT

• FXa based
• No heparin cofactor II
• Accurate determination in patients receiving
  heparin therapy
• Ideal for patients on DTI

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Coamatic Coatest ATAssay Principle

• Determination of AA in plasma
• Patients on DTIs (hirudin, oral TIs)
• Works un/diluted plasma
• Wide range of instruments/or single test
• CM AT, CM AT (LR), CM AT 400 (leaving), CT AT R

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DiaPharma Factor XChromogenic

• Useful tool OA patients
• PT
• Determine FX activity in human citrated plasma
• In vitro
• Screen for FX deficiencies
• 2 stage principle

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DPG FX Reprint

• Arpino, Van Cott reprint
• Use of Chc FX assay, INR patients transitioning
  from Agatroban to Warfarin
• 62 patients (hospitalize)
• 45 activity, INR therapeutic
• Method- no interruption DTI therapy
• No dependence on DTI dose or thromboplastin used
  for PT