3/23/2017
CHALLENGES IN ANTICOAGULATION:
HEPARIN RESISTANCE
Shelby Shemanski, PharmD.
PGY-2 Critical Care Pharmacy Resident
Saint Luke’s Hospital
March 25th, 2017
Objectives



Define heparin resistance and its proposed
etiologies
Distinguish potential treatment strategies for
management of patients with heparin resistance
Discuss the use of antithrombin for management of
heparin resistance due to antithrombin deficiency
Coagulation Overview: Clotting
Cascade
http://www.medicinecf.net/secondary-hemostasis/
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3/23/2017
Heparin:
Pharmacology/Pharmacokinetics



MOA: binds with AT +
thrombin to form a ternary
complex inactivates
thrombin
Metabolism: hepatic, may be
partially metabolized by
reticuloendothelial system
T1/2: 1-2h

Excretion: urine


With very high doses, renal
elimination may play more of a
role– dosage adjustment
remains unnecessary
May be affected by:





Obesity
Renal function
Malignancy
Presence of PE
Infection
LexiComp. Lexi-Drugs. Updated Dec 2016.
Clotting Factor Tests
Advantages
Disadvantages
ACT
• Easy to perform
• May be performed bedside
• Results available within minutes
• Subject to biological variables similar to aPTT
• Appropriate therapeutic intervals needs to be
determined for each system
• Assay may be difficult to standardize
• Susceptible to technical errors
aPTT
• Relatively inexpensive
• Widely used and accepted amongst
physicians
• Assay not standardized
• Individual labs must determine appropriate
therapeutic range for their specific system
• Many variables that can interfere with
monitoring
Anti-Xa
• Simple to perform
• Short turnaround time for results
• Minimal interference with biological
variables
• Standardization of assays possible
•More expensive than aPTT monitoring
• Biologic variables that can affect values:
↑bilirubin or ↑TGs
Olson J et al. Arch Pathol Lab Med. Sept 1998; 122:782-798.
Anti-Xa vs. aPTT: Biologic effects
Factor
aPTT
Antifactor
Xa
Antithrombin deficiency
↓
↓
Increased acute phase reactants (factor VIII or fibrinogen)
↓
↔
Increased heparin binding proteins
↓
↓
Obesity
↓
↓
Impaired renal function
↑
↑
Liver disease
↑
↔
Consumptive coagulopathy
↑
↔
Lupus anticoagulant
↑
↔
Elderly
↑
↔
Recent use of LMWH or fondaparinux
↔
↑
Hypertriglyceridemia
↔
↑
Hyperbilirubinemia
↔
↓
Vandiver J, Vondracek T. Pharmacother. 2012;32(6):546-558
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3/23/2017
Heparin Resistance
Definition

Patients requiring large
amounts of heparin to
achieve a therapeutic
aPTT


Potential Causes


Heparin clearance
Heparin-binding
proteins
 Factor VIII levels

>35,000 units daily
Cardiopulmonary
bypass surgery: inability
to maintain therapeutic
ACTs with rising doses of
heparin
Antithrombin deficiency
Increases in:


Drug-induced resistance
CHEST 2012. 141(2)(Suppl):e24s-e43S)
Arch Intern Med. 1994; 154:49-56
Guidelines for VTE: Heparin resistance

Guidance statement: “We suggest drawing a
paired aPTT and heparin anti-Xa level when
heparin resistance is suspected. If the aPTT is
subtherapeutic and the anti-Xa level is therapeutic,
the heparin dose does not require adjustment and
subsequent monitoring should occur using the antiXa level when feasible. If, despite serial dose
increases, both the aPTT and anti-Xa level remain
low, true heparin resistance may be present. “
J Thromb Thrombolysis. 2016;41:165-186
Antithrombin deficiency
Background




Estimated prevalence in patients
with VTE: 1-7%
Normal AT values:
 Neonates: 60-90%
 Adults: 80-120%
Consideration for replacement of
AT: level <60%
Treatment options:


Antithrombin
FFP
Causes







Hereditary
DIC
Acute thrombosis
Liver disease
Nephrotic syndromes
ECMO or HD
Asparaginase therapy
Consequences of deficiency

Increased thrombotic risk

Insensitivity to heparin
Bauer K. UpToDate. Updated Jul 2016.
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3/23/2017
AT deficiency treatment: Antithrombin administration
Product
Thrombate III
Atryn
Origin
Plasma derived
Recombinant
derived
T1/2 (h)
2.5*
12-18
Infuse over 1020min
Infuse LD over 15
min
Baseline
20 min post-infusion
(peak)
12h before next
infusion (trough)
Baseline
2 hours postinfusion
Once daily when
predictable levels
achieved
Administration
AT level
recommendation
Goal AT
concentration
80-120%
Adverse effects
Bleeding, infusion site reactions, dizziness
*May be decreased following surgery, hemorrhage, acute thrombosis, and/or
during heparin administration
Antithrombin Product Information. LexiComp. Updated Dec 2016.
AT deficiency treatment: Antithrombin administration


Only available product in US: Thrombate III
Dose: [desired AT-measured AT] x BW (kg) ÷ 1.4=
units of AT required
 Desired


AT recommended is 100%
Cost: $3.82 per IU
Example: 70 kg patient, measured AT=40%
 Dose:
 Cost:
100-40 x 70 ÷ 1.4 = 1500 units
$4011
Antithrombin Product Information. LexiComp. Updated Dec 2016.
Antithrombin vs. Fresh Frozen Plasma for Heparin
Resistance in Cardiopulmonary Bypass
Background


Heparin resistance
reported in 22% of
CPB patients
Most common cause:
AT deficiency
Risk Factors for Heparin Resistance
during CPB




AT ≤60%
Pre-op SQ or IV
heparin administration
Platelets ≥ 300,000
cells/mm3
Age ≥65
Spiess B. Ann Thorac Surg. 2008;85:2153-60.
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3/23/2017
AT vs. FFP in CPB
Studies with FFP
Reference
Design
Treatment
Outcome
Leong et al, 1998
Case report
500 mL
Successful ACT prolongation
Despotis et al, 1996
Case report
2 units
Heparin dose requirement reduced by 50%
Soloway et al, 1980
Case report
3 units
Goal ACT achieved (545830 sec), bleeding event occurred
Sabbagh et al, 1984
Retrospective
study (n=9)
2 units
FFP significantly prolonged ACT, mean change: 417 to 644
seconds (p<0.0001)
Design
Treatment
Outcome
Lemmer et al, 2002
Prospective
study (n=53)
500-1000 IU
Significantly increased ACT values, mean heparin-dose
response increased from 37 sec to 69 sec (p<0.0001)
Williams et al, 2000
Prospective,
crossover RCT
(n=95)
1000 IU
Significant increase in ACT, goal achieved in 95% of patients
who received AT (p=0.001)
Prospective,
RCT (n=40)
50 IU/kg
AT more effective at maintaining adequate anticoagulation
vs. heparin alone
Studies with AT
Reference
Koster et al, 2003
Spiess B. Ann Thorac Surg. 2008;85:2153-60.
AT vs. FFP in CPB
Overview of comparison supporting AT vs. FFP
Factor
AT
Published clinical reports
11
FFP
5
Risk of viral transmission
Purification process provides viral inactivation
Risk of pathogen transmission similar
to other blood products
Increased volume load
500 IU AT=10 mL
500 IU AT=500 mL (2 units)
TRALI
No reported cases
Associated with 50% of fatal cases
reported
More expensive
Requires thaw time, procedure risk
Efficiency and cost



Limitations: studies lacked more relevant clinical endpoints
Conclusions: AT appears to be safe, effective, and efficient
choice for managing HR
Further studies needed
Spiess B. Ann Thorac Surg. 2008;85:2153-60.
Summary: Heparin Resistance



Little evidence regarding HR in cases of
thromboembolic events
Several published reports in patients undergoing
cardiopulmonary bypass
Most common cause of HR is thought to be AT
deficiency
 Treatment

options: AT or FFP
Lack of high quality evidence that administering AT
improves outcomes
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Summary: Heparin Resistance

Potential options in future difficult cases:
 Check
 Check
aPTT assess correlation
AT level practical?
 Administer
AT: $$$
 FFP
 Alternative
agents to heparin
 Direct
thrombin inhibitors
 Anti-Xa inhibitors
Questions?
6