Anticoagulants and HIT

1
Anticoagulants and HIT

• Doug Tollefsen
• August 15, 2008

2
Recent Adverse Reactions to Heparin
Dramatically increased incidence of acute
hypersensitivity reactions to heparin between
November 2007 and February 2008 reported to the
FDA Symptoms included hypotension, facial
swelling, tachycardia, urticaria and nausea 81
deaths reported, generally after bolus injection
of heparin for dialysis or other
indications Problem traced to lots of
contaminated heparin produced in Changzhou,
China, for Scientific Protein Laboratories
(distributed in the US by Baxter) Events declined
after Baxter recalled all remaining lots of
heparin on February 28, 2008
3
Recent Adverse Reactions to Heparin
Dramatically increased incidence of acute
hypersensitivity reactions to heparin between
November 2007 and February 2008 reported to the
FDA Symptoms included hypotension, facial
swelling, tachycardia, urticaria and nausea 81
deaths reported, generally after bolus injection
of heparin for dialysis or other
indications Problem traced to lots of
contaminated heparin produced in Changzhou,
China, for Scientific Protein Laboratories
(distributed in the US by Baxter) Events declined
after Baxter recalled all remaining lots of
heparin on February 28, 2008
This family-owned workshop in Xinwangzhuang, a
village in Juangsu Province, China, processes pig
intestines. Mucous membranes from the intestines
are used to make heparin. New York Times, March
30, 2008
4
Recent Adverse Reactions to Heparin
Oversulfated chondroitin sulfate is a contaminant
in heparin associated with adverse clinical
events. Guerrini M et al. Nat Biotechnol 2008
Jun26(6)669-75 Contaminated heparin associated
with adverse clinical events and activation
of the contact system. Kishimoto TK et al. N
Engl J Med 2008 Jun 5358(23)2457-67
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Proposed Mechanism
Schwartz N Engl J Med 2008 Jun 5358(23) 2505-09
6
Heparin

• Administered to 12 million patients/year in the
  U.S.
• 120,000 patients/year will develop HIT (60,000
  with thrombosis)
• Repeating polymer of uronic acid and glucosamine
• Highly heterogeneous in terms of sulfation and
  polymer length
• Isolated from tissues rich in mast cells (porcine
  intestinal mucosa)
• Stabilizes enzymes in mast cell granules
• Similar molecules (heparan sulfate) on surface of
  endothelial cells
• Binds to the plasma protein antithrombin
• Antithrombin-heparin complex rapidly inhibits
  thrombin and factor Xa
• Only 1/3 of heparin polymers bind and activate
  antithrombin

7
Biosynthesis of Heparin
Adapted from Lindahl et al., Ann NY Acad Sci
1989 36 556
8
Antithrombin-binding Heparin Pentasaccharide
Petitou and van Boeckel, Angew Chem Int Ed 2004
43 3118
9
Allosteric Effect of Heparin
Jin et al., Proc Natl Acad Sci USA 1997 94 14683
Sufficient for inhibition of factor Xa
10
Template Effect of Heparin
Required for inhibition of thrombin
Thrombin
Heparin (gt18 monosaccharide units)
Antithrombin
Petitou and van Boeckel, Angew Chem Int Ed 2004
43 3118
11
Inhibition by Deformation of the Protease
Huntington et al., Nature 2000 407 923
Active protease (thrombin or Xa)
Proteolytic attack
Cleaved antithrombin
Antithrombin
Inactive protease covalently bound to antithrombin
12
Heparin Preparations Used Clinically
Thrombin inhibition (gt18 monosaccharide units)
Factor Xa inhibition (gt5 monosaccharide units)
Unfractionated Heparin
LMW Heparin
Penta
3000
6000
9000
12000
15000
18000
21000
Molecular Weight
13
Low-molecular-weight Heparins
14
Synthetic Heparin Pentasaccharides
15
Pharmacologic Properties of Heparin
16
Complications of Heparin Therapy

• Bleeding
• Major bleeding (5-10 day course) 2 with UFH
  1 with LMWH
• Increased risk with aPTT gt2.5 times normal
• Usually controlled by discontinuation of heparin
• Osteoporosis
• Decreased bone density in 30 of patients after
  1 month of full-dose UFH therapy
• Vertebral fractures in 2
• Lower incidence with LMWH
• Heparin resistance (gt40,000 U/day of UFH with
  subtherapeutic aPTT)
• Elevated factor VIII or other plasma proteins
• Antithrombin deficiency
• Increased clearance
• Monitor with anti-Xa assay (0.3-0.7 U/ml target)
• Thrombocytopenia
• Immune (onset after 5-10 days HIT antibodies
  present thrombosis likely)
• Non-immune (immediate onset HIT antibodies
  absent thrombosis unlikely)

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Pathogenesis of HIT
Formation of IgG to neoepitopes on PF4 bound to
heparin
Generation of thrombin
Warkentin, Annu Rev Med 1999 50 129
18
Iceberg Model of HIT
Incidence of HIT varies with the clinical
setting. Only a subset of PF4/heparin antibodies
activate platelets. Activation assays are more
specific than antigen assays for clinical
HIT. Thrombosis does not occur in the absence of
a significant fall in platelet count.
Warkentin, Br J Haematol 2003 121 535
19
Severity of Thrombocytopenia in HIT
Patients who tested positive for HIT antibodies
by SRA
(Thrombosis, skin lesion, or acute systemic
reaction to heparin)
(All other patients had a 50 or greater fall in
platelet count)
If platelets lt20,000, consider
post-transfusion purpura sepsis another
drug reaction
Warkentin, Br J Haematol 2003 121 535
20
Typical Time Course of HIT
Thrombosis may occur 1-2 days before
thrombocytopenia
Warkentin et al., N Engl J Med 1995 332 1330
21
Temporal Profiles of HIT
All patients received heparin during surgery (day
0) Detectable antibodies were present on or after
day 5
(up to 3 wk after heparin exposure)
2/3 of pts Recent induction of antibodies
1/3 of pts Previous induction of antibodies
(100 d)
Rare Heparin absent at onset of HIT
Warkentin, Br J Haematol 2003 121 535
22
Management of HIT

• High index of suspicion
• Unexplained thrombocytopenia (usually 50
  decrease)
• Onset 5-14 days after beginning heparin (any
  type, route or dose)
• or immediate onset if 100 days after
  prior exposure to heparin
• Thrombosis, skin lesions at heparin injection
  site, or acute systemic reaction to IV heparin
• Immediately stop all heparin (including IV
  flushes)
• Immediately begin treatment with a direct
  thrombin inhibitor (not warfarin)
• Lepirudin or argatroban (highest risk for
  thrombosis occurs after stopping heparin)
• Continue until thrombocytopenia resolved, then
  begin warfarin (30-60 days) overlap DTI
  warfarin 5 days
• LMW heparin contraindicated fondaparinux may be
  safe
• Anecdotal use of plasma exchange or IVIG in
  critically ill patients
• ACCP recommends treatment of isolated HIT
  without thrombosis
• Obtain patients blood for confirmatory tests
• ELISA for antibodies that bind to heparin/PF4
  (strength of reaction appears to be important)
• Platelet serotonin release assay (SRA)

Complete ACCP recommendations are published in
Chest 2008 Jun133(6 suppl)67S-968S
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Warfarin-induced Venous Limb Gangrenein HIT
Patients
Arterial pulses detectable Occurred in 8 of 158
patients with HIT Associated with warfarin
treatment while the patients were still
thrombocytopenic May be caused by depletion of
protein C in the setting of ongoing platelet
activation and thrombin generation
Microvascular thrombosis (venules)
Warkentin et al., Ann Intern Med 1997 127 804
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Parenteral Direct Thrombin Inhibitors
Lepirudin (Refludan) Recombinant 65 amino acid
polypeptide based on hirudin Given IV to achieve
aPTT 1.5-2.5 times the patients
baseline Half-life 80 min (increased in renal
failure) May develop antibodies that prolong the
half-life and increase the aPTT (check aPTT
daily) Minimal prolongation of the PT (target INR
2-3 during overlap with warfarin) Argatroban Synth
etic arginine analog Given IV to achieve aPTT
1.5-3.0 times the patients baseline Half-life
40-50 min (unchanged in renal failure increased
in liver failure) Prolongs PT (target INR 4
during overlap with warfarin)
Greinacher and Warkentin recommend (Thromb. Res.
2006 118 165) (1) omitting bolus, decreasing
initial infusion rate, and adjusting lepirudin
dose to aPTT 1.5-2.0 (2) administering IV
vitamin K to patients on warfarin.
25
Efficacy of Direct Thrombin Inhibitorsin HIT
with thrombosis
NS
NS
Plt0.001
Plt0.05
Reviewed in Greinacher and Warkentin, Thromb.
Res. 2006 118 165.
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Warfarin

• Identified (1924) as a toxic substance in spoiled
  sweet clover that caused bleeding in cattle
• Pharmacokinetics
• Plasma concentration peaks 2-8 h after an oral
  dose
• 99 bound to plasma proteins (albumin)
• Half-life in plasma 25-60 h
• Inhibits biosynthesis of vitamin K-dependent
  zymogens (delayed onset of action)
• Prothrombin
• Factor VII
• Factor IX
• Factor X
• Protein C
• Protein S

procoagulant
anticoagulant
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Vitamin K Cycle
Zymogen O2 CO2
g-Carboxylated Zymogen
vitamin K epoxide
reduced vitamin K
vitamin K epoxide reductase (mutations cause
warfarin resistance)
vitamin K reductase
Warfarin inhibits
Warfarin inhibits
vitamin K
28
Clearance of Vitamin K-dependent Proteins
100
90
80
70
60
Activity ()
50
Prothrombin
Factor X
40
Factor IX
Protein C
Factor VII
30
0
20
40
60
80
Time after administration of warfarin (hours)
29
Clearance of Vitamin K-dependent Proteins
100
INR
90
80
70
Antithrombotic effect
60
Activity ()
50
Prothrombin
Factor X
40
Factor IX
Protein C
Factor VII
30
0
20
40
60
80
Time after administration of warfarin (hours)
30
Clearance of Vitamin K-dependent Proteins
100
INR
90
80
70
Antithrombotic effect
60
Activity ()
50
Prothrombin
Factor X
40
Prothrombotic effect
Factor IX
Protein C
Factor VII
30
0
20
40
60
80
Time after administration of warfarin (hours)
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Conditions that Alter the Responseto Warfarin
Compliance Drugs Affect hepatic metabolism of
warfarin Affect binding to plasma
proteins Diet Availability of vitamin K Other
variables Age Race Acute venous
thromboembolism Body surface area Current
smoker Nephrotic syndrome Liver disease
Pregnancy
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Warfarin Resistance and Sensitivity

• Warfarin resistance (gt20 mg QD with
  subtherapeutic INR)
• Non-compliance
• Lab error
• Excessive vitamin K (PO or parenteral)
• Mutations in vitamin K epoxide reductase (rare)
• Rost et al., Nature 2004 427 537
• Warfarin sensitivity (lt2 mg QD with
  supratherapeutic INR)
• Vitamin K epoxide reductase polymorphisms
  (decrease the level of expression of the enzyme)
• Cytochrome P450 2C9 polymorphisms (decrease the
  rate of metabolism of warfarin)

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Cytochrome P450 2C9 Polymorphisms
Effect on daily maintenance warfarin dose
Higashi et al., JAMA 2002 287 1690
34
Complications of Warfarin Therapy

• Bleeding
• Incidence varies (4 major bleeding during
  3-month course of treatment for VTE 3-4 annual
  risk thereafter)
• Risk increases with INR gt 4
• Treated with vitamin K (delayed response) or
  fresh-frozen plasma (immediate response)
• Birth defects and abortion
• Skeletal and CNS abnormalities (hypoplastic nose,
  flat face, altered calcification)
• Contraindicated during pregnancy (heparin may be
  used)
• Skin necrosis
• Microvascular thrombosis
• May occur in patients with heterozygous protein C
  or S deficiency if a high initial dose is used or
  heparin overlap is inadequate

Embryopathy
Skin necrosis
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Risk of Recurrent Venous Thromboembolism
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Detailed Guidelines for Antithrombotic Therapy
http//hematology.im.wustl.edu