Unfractionated heparin is the cornerstone for the treatment of acute venous
thromboembolism. Although heparin is highly effective, it is always
associated with some risk of hemorrhage. Published reports also have described
failures of heparin therapy caused by subtherapeutic doses. When heparin is
given by continuous IV infusion and the dose is regulated with an appropriate
clotting time test, the incidence of serious hemorrhage is reduced and
therapeutic efficacy is assured.
Few other medications with the toxicity of heparin that have been available
for clinical use for so long have such a lack of uniformity in dosing and
monitoring recommendations. Heparin has traditionally been dosed with an IV
bolus dose of 5,000 to 10,000 units of heparin, followed by an infusion of
1,000 units per hour. Others have advocated that a more rational method of
initiating therapy is to begin with a loading dose of 50-100 units/kg of
heparin followed by a constant infusion of 15-25 units/kg/hr. Chenella, et al
have described a method for determining initial heparin infusion rates based
on the patient's individually determined volume of distribution (blood volume).
II. Monitoring parameters
- The following patient parameters should be monitored during heparin therapy:
- aPTT, obtain before initiation of heparin, every six hours thereafter until
stable, then daily.
A patient is considered stabilized when two aPTT's drawn
24 hours apart are within the therapeutic range.
- Platelet count, daily.
Heparin can cause a severe and potentially fatal form of thrombocytopenia
commonly referred to as HIT. Although HIT typically occurs 2 to 5 days after
heparin exposure, it can occur at any time.
- Prothrombin time, daily.
- Hematocrit, stool guaiac, and urinalysis (for hematuria), daily.
- Concurrent drug therapy: aspirin, dipyridamole, NSAID's.
Avoid the use of aspirin and aspirin containing drugs
during heparin therapy. Aspirin inhibits platelet function.
Current evidence indicates that aspirin can increase the risk
of bleeding in patients anticoagulated with heparin.
- Therapeutic range
The recommended therapeutic range for the treatment
of venous thrombosis is based on studies which demonstrated that
thrombus extension is prevented by a heparin dose that prolonged
the aPTT ratio to 1.5 to 2.5, corresponding to a heparin level
of 0.2 to 0.4 units/ml.
The "control" value used to determine the ratio is poorly defined,
it may be the mean value of the normal range for the aPTT, or the patient's
baseline aPTT (the aPTT measured before any heparin). Use of the patient's
baseline as the control has gained popularity based on the fact that many
patients undergoing thrombotic episodes have shortened aPTTs.
The heparin concentration required to yield a therapeutic effect varies
widely between patients. Studies by Cipolle et al, have found that the baseline
PTT value accounts for 80% of this variability, reflecting individual differences
in clotting factor concentrations and activities. Therefore, a tailored therapeutic
range, based on the patient's pretreatment PTT, is likely to be more appropriate than
one derived from the mean PTT pooled from dissimilar patients.
Unfortunately, the different commercial aPTT reagents
vary in their responsiveness to heparin. An approximation of
the therapeutic range of 0.2 to 0.4 units/ml can be made by testing
the aPTT reagent in a plasma system that has been calibrated by
addition of a range of clinically relevant concentrations of heparin.
This heparin response curve can then be entered into the Kinetics
program and used as the basis for dosage adjustments (highly recommended!).
- Initiating warfarin concurrently with heparin
The effect of warfarin on the aPTT is not well documented,
although it appears that the aPTT is increased following initiation
of warfarin and this effect may be cumulative with successive
doses. Some patients may be at risk of over-coagulation when
heparin and warfarin are combined.
Many clinicians reduce heparin dosage when warfarin
is initiated in anticipation of an increase in the aPTT.
- Draw aPTT at steady state
When the aPTT is checked at 6 hours or longer after a dosage change,
steady-state kinetics can be assumed. Non-steady-state analysis can
lead to erroneous dosing calculations.
- Adjust dosages cautiously
Dosage changes must be made slowly, and the aPTT
must be checked every six hours until stable, then daily during
the course of therapy. Close monitoring of the patient is essential.
Since the aPTT response to changes in heparin infusion rates
is not always linear the dosage adjustments should be made in
small increments of 100-200 units/hr.
Heparin dose is clearly the most important determinant of minor bleeding
episodes. When examined on a unit-per-kg per-hour basis, there is over
a 3-fold increase in the risk of bleeding in patients receiving 25
units/kg/hr as compared to patients who receive 15 units/kg/hr.
Aging is a risk factor for total and major bleeding complications. Because
of age-related changes in pharmacokinetic characteristics of heparin, aging
is associated with an increase in heparin levels after standard doses.
Heparin dose requirements are decreased in the elderly.
- The major risk factors for hemorrhage from heparin therapy are listed below:
- Age over 60
- Recent surgery
- Trauma (or risk of trauma)
- Severe hypertension
- Peptic ulcer disease (or history of ulcers)
- Drugs which offset platelet function:Aspirin, dipyridamole, NSAID's
- Presence of any potential bleeding site
- Congenital or acquired hemostatic defect
- Severe renal failure
- Severe hepatic failure
- Reversal of heparin effects
- Stop heparin
- Monitor vital signs, aPTT, Hgb, Hct, platelet count.
- Stop heparin
- Monitor vital signs, aPTT, Hgb, Hct, platelet count.
- Give blood transfusions as necessary
- Consider protamine reversal of heparin.
- Protamine rapidly neutralizes heparin's anticoagulant activity.
- In the event of a critical bleed, 1mg of protamine will
neutralize approximately 100 units of heparin.
- Protamine can cause severe, anaphylactoid reactions, use only
when severe bleeding warrants it.
- Heparin Induced Thrombocytopenia (HIT)
HIT is a widely recognized disorder that is observed in 2 to 4% of patients
who receive heparin. Heparin-induced thrombocytopenia is a transient hypercoagulable
state that occurs as a result of an immune mediated reaction to heparin and involves
activation of platelets and massive thrombin generation. HIT appears to be encountered
more frequently as use of anticoagulant therapy becomes more widespread.
The spectrum of HIT disease ranges from clinically insignificant to severe thrombosis.
Overall, thrombosis occurs in approximately 33% of patients diagnosed with HIT and is
associated with high morbidity and mortality rates. HIT thrombosis can produce
devastating complications, including necrosis of the extremities, stroke, myocardial
infarction, and pulmonary embolism.
Heparin-induced thrombocytopenia is divided into 2 types. Type I is an early-onset,
mild decline in platelet count and is reversible. This condition is thought to be
caused by the direct platelet-aggregating effect of heparin. In contrast, Type II
HIT is an immune-mediated reaction that typically occurs 2 to 5 days after the
initial heparin exposure. After re-exposure to heparin, however, patients may develop
a rapid onset Type II HIT.
The diagnosis of HIT is made on the basis of clinical features. HIT should be suspected
in any patient who is receiving heparin and has either a low platelet count or one that
has decreased 50% from the baseline level. Laboratory tests for heparin-induced thrombocytopenia
are now available to confirm the diagnosis.
Strongly consider HIT when:
- Platelet count falls within 4 to 14 days after start of heparin or sooner
if patient was previously exposed to heparin.
- > 30 to 50% from baseline and/or
- <= 150,000
- New thrombotic event occurs while receiving heparin therapy.
- Acute systemic reaction within 5 to 30 minutes of heparin bolus:
Although HIT typically occurs 4 to 14 days after heparin exposure, it can occur at
any time. Thrombosis has been reported within 30 minutes after heparin re-exposure.
Thrombosis can occur before the decline in platelet count or even when the platelet
count is recovering and rising.
HIT has several paradoxes:
- HIT is an anticoagulant-induced thrombosis
- Despite thrombocytopenia, HIT is a clotting disorder, not a bleeding disorder
- Platelet transfusions can increase risk of thrombosis.
- Warfarin is contraindicated as acute monotherapy.
- Simply stopping heparin may not prevent thrombosis.
If HIT is suspected, do not switch to a low-molecular-weight heparin, LMWH's will
cross-react with the antibody 90% of the time. Currently 2 agents are available to treat
IV. Program procedure
- Prospective dosing
The program first asks for a target therapeutic range. The target
therapeutic range is used to determine the dosage adjustment guide
which is printed on the consult form. Choose to target either 1.5
to 2.5 times the control aPTT or a heparin response curve as
determined by the your hospital laboratory.
If using the first method, the program asks for the initial aPTT, which
is either the patient's baseline aPTT (preferred) or, if unavailable,
the mean value of the normal range for the aPTT.
The program calculates Ideal initial loading dose and maintenance doses.
The user then enters a practical dose.
- Evaluation of PTT data
The program first asks for the target therapeutic range which is used
to evaluate the PTT and determine the dosage. Choose to target either
1.5 to 2.5 times the control aPTT or the heparin response curve as
determined by your hospital laboratory. If the first method is selected,
the program then asks for the initial aPTT (before Heparin), the current
aPTT, and the current dose.
The program then calculates an incremental loading dose or time to
hold the infusion, if necessary. The user then enters a practical dose.
V. Heparin Dosing Flow Chart
VI. Pharmacokinetic formulas
- Initial Dosing
- Determine dosing weight
DW = LBW + ((TBW - LBW)/3)
where TBW = total body weight
LBW = lean body weight
- Determine loading dose
If age < 70 then LD = 80 units x DW
If age >= 70 then LD = 50 units x DW
- Determine initial infusion rate
ko = 18 units/hr x DW
- Calculate heparin concentration
- Calculate Vd (blood volume)
Male: 0.3669 x (Ht)3 + 0.03219 x TBW +0.604
F: 0.3561 x (Ht)3 + 0.03308 x TBW + 0.1833
where Ht = height in meters
TBW= total body weight
- Calculate elimination rate
kel = 0.693 x F x F'
where F = 1.2 if smoker
and F' = 0.8 if age >= 70
- Calculate heparin concentration
Cp = ko / (Vd x kel)
where ko is heparin infusion rate
- Adjusting maintenance dose
|aPTT ratio ||Loading Dose ||Maintenance dose
|Less than 1.2 times control || 50 u/kg || Increase by 4 u/kg/hr
|1.2-1.3 times control || 25 u/kg || Increase by 3 u/kg/hr
|1.3-1.4 times control || None || Increase by 2 u/kg/hr
|1.5-2.5 times control || None || No change
|2.6-2.9 times control || None || Decrease by 2 u/kg/hr
|3-4 times control || Hold for 1 hour || Decrease by 3 u/kg/hr
|Greater than 4 times control || Hold for 2 hours || Decrease by 4 u/kg/hr
The control value used to determine the ratio is poorly defined,
it may be the mean value of the normal range for the aPTT, or the
patient's baseline aPTT (the aPTT measured before any heparin).
Use of the patient's baseline as the control has gained popularity
based on the fact that many patients undergoing thrombotic episodes
have shortened aPTTs.
aPTT Range (Heparin response curve)
|aPTT corresponding to ||Loading Dose ||Maintenance dose
| Less than 0.1 u/ml* || 50 u/kg || Increase by 3 u/kg/hr
| 0.1-0.15 u/ml* || 25 u/kg || Increase by 2 u/kg/hr
| 0.16-0.19 u/ml* || None || Increase by 2 u/kg/hr
| 0.2-0.4 u/ml* || None || No change
| 0.41-0.5 u/ml* || None || Decrease by 2 u/kg/hr
| 0.51-0.6 u/ml* || Hold for 1 hour || Decrease by 2 u/kg/hr
| Greater than 0.6 u/ml* || Hold for 2 hours || Decrease by 3 u/kg/hr
*As determined by local lab. An approximation of the heparin
concentration can be made by testing the aPTT reagent in a plasma
system that has been calibrated by addition of a range of clinically
relevant concentrations of heparin. This heparin response curve
can then be entered into the Kinetics program and used as the basis
for dosage adjustments (highly recommended).
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