Heparin Resistance
 “Heparin resistance is a term used to describe the situation
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when patients require unusually high doses of heparin to
achieve a therapeutic APTT”
“True resistance” refers to a situation where the low APTT is
reflective of a true absence of anticoagulation
“Psuedoresistance” refers to a situation where the patient is
adequately anticoagulated despite a low APTT
Has been arbitrarily defined as the requirement for >35,000
units/24 hours
~25% of patients with VTE fulfill this requirement
Chest 2001;119:64S-94S
Heparin: Background
MOA
•Catalyzes antithrombin’s irreversible binding to clotting
factors Xa and IIa (thrombin)
• Prevents further coagulation but is not a thrombolytic
PK
Elimination
1. Rapid, saturable clearance through binding to
endothelial cells/proteins
2. Renal elimination
T1/2 – dose dependant, but typically between 1-2 hours
Heparin: Mechanism
ATIII forms irreversible
covalent bonds with
thrombin or Xa
Only heparin molecules
with at least 18 saccharides
(~6000 daltons)can bind
both antithrombin and
thrombin
Only activated coagulation
factors are targeted
Unique Pentasaccharide sequence
that interacts with antithrombin
AT III
Heparin: Monitoring
APTT
Evaluates the activity of the intrinsic
pathway (factors I,II, V, VIII, IX, XI, XII,).
APTT
Not affected by inhibition of Xa.
(target 1.5 to 2.5 times normal)
Antifactor Xa
Evaluates the amount of factor Xa that the
heparin in the blood is able to neutralize
(target 0.35 to 0.7 units/ml ref:
http://www.ncbi.nlm.nih.gov/pubmed/8267489)
http://www.fritsmafactor.com/newfritsmafactor/?p=2489
Heparin Resistance: Mechanisms
Heparin Resistance: Mechanism
Mechanisms
Effects
clearance due to
binding to acute
Phase reactants
(true resistance)
•Levels of certain acute phase reactants and other plasma proteins that
bind to and clear heparin are increased in inflammatory states.
• A study found septic patients have more heparin bound to plasma
proteins (Young Arteriosclerosis Thrombosis and vascular biology 1997;17:1568)).
•Another study found acute-MI patients(an inflammatory condition) have
more heparin bound to proteins and associated lower aPTT (Rich J Thromb
Thrombolysis 2007;23:93)
•Another study found acute-PE patients have lower free heparin levels than
acute-DVT patients (Hirsh. Circulation 1976;53:691)
ATIII Deficiency
(true resistance)
production
Cirrhosis
Loss
Nephrotic Syndrome
Enhanced consumption
Sepsis with DIC
Burn injuries
Hepatic veno-occlusive disease
CABG
Large hemotomas
Genetic: Autosomal dominant, fatal if homozygotic with prevalence rate
between 1:500-1:5000
Heparin Resistance: Mechanism
Mechanisms
Effect
 Factor VIII
(?psuedo
resistance)
•Mean factorVIII level in heparin resistant patients of 2.39 U/ml vs 1.60
U/ml in non resistant patients. APTT lower in patients with high factor
VIII. Anti-Xa assay may be more accurate reflective of degree of
anticoagulation (Levine. Ach Intern Med 1994;154:49) but some authors disagree
(British J Haematology;2010:613)
•Some observational studies have found that with progressively increasing
Factor VIII levels there is an increasing risk of venous thrombosis. (Kamphuisen.
Arterioscler Thromb Vasc Biol 2001;21:721)
•Factor VIII levels are increased in association with obesity, diabetes,
fibrinogen, triglycerides, increased age and is an acute phase reactant
(malignancy, chronic disease, infection) (Kamphuisen. Arterioscler ThrombVasc Biol
2001;21:721)
LMWH in patients with heparin
resistance?
Mechanisms Effects
Increased
clearance
due to
binding to
acute Phase
reactants
•LMWH have reduced binding to plasma proteins and
as a result have much more consistent anti-Xa and antiIIa activity. (Cosmi. Circulation 1997;95:118) (Hirsh.
Blood 1992;79:1)
ATIII
Deficiency
Factor VIII
Dependant on ATIII for their activity.
Unclear effect
Fondaparinux in patients with heparin
resistance?
Mechanisms
Effect
Increased
clearance due
to binding to
acute Phase
reactants
ATIII
Deficiency
Factor VIII
•At therapeutic concentrations fondaparinux is highly
(94%) and specifically bound to antithrombin III.
Would indicate that increased clearance via protein
binding is unlikely (Clin Pharmacokinetics 2002;41
Suppl 2:11)
Dependant on ATIII for activity
Unclear effect
Rivaroxaban in patients with heparin
resistance?
Mechanisms
Effect
Increased
clearance due
to binding to
acute Phase
reactants
ATIII
Deficiency
Factor VIII
•Mainly eliminated through metabolism (3A4, 3A5,
2J2) with remainder removed via kidneys. No
indication that pharmacokinetics are altered in sepsis
Independent of ATIII
Unclear effect
Dabigatran in patients with heparin
resistance?
Mechanisms
Effect
Increased
clearance due
to binding to
acute Phase
reactants
ATIII
Deficiency
Factor VIII
•Not highly bound to plasma proteins. Mainly
eliminated via urine/fecal routes.
Independent of ATIII
Unclear effect
Heparin Resistance Summary
 Should be evaluated for when patients are receiving >35,000
units/24 hour period
 Patients with heparin resistance may be over or under
anticoagulated depending on the etiology of their resistance
 If possible consider switching to alternative agent (LMWH,
fondaparinux or oral anticoagulant)
 If not possible consider testing anti-factor Xa levels (target
0.35 to 0.7 u/ml). If therapeutic with low aPTT then likely
psuedoresistance