Download Intentional low-molecular-weight heparin overdose: a case report

772 Case report
Intentional low-molecular-weight heparin overdose: a case
report and review
Michael Byrne and Marc Zumberg
The reversal of low-molecular-weight heparins, particularly
at supratherapeutic levels, remains challenging. The paucity
of literature available to guide the treatment of these
patients makes their management difficult for primary care
providers, surgeons, and subspecialists alike. We report the
case of a 34-year-old woman, who intentionally overdosed
on enoxaparin (Lovenox) in a suicide attempt. Her initial
antifactor Xa activity level was 8.3 IU/ml, the highest level
reported in the literature to date. She was initially managed
conservatively, however, within 24 h of admission she
developed evidence of acute blood loss. Protamine sulfate
and three doses of recombinant activated factor VII (rFVIIa)
were administered in an effort to control bleeding. We report
the effects of these measures and review the literature to
date. Our study is one of the first to graph in-vivo antifactor
Xa activity levels and to suggest a drug half-life of
Introduction
Low-molecular-weight heparins (LMWH) are routinely
used for the treatment and prophylaxis of venous thromboembolism (VTE). There are several advantages to
their use including weight-based dosing and few drug
and dietary interactions leading to stable dosing. One
drawback, however, is that the reversal of LMWH can be
challenging in the setting of bleeding or the need for
emergent surgery.
Case report
A 34-year-old Caucasian woman was brought to the
emergency department (ED) for a suicide attempt involving the self-injection of 1600 mg of enoxaparin (20
syringes of 80 mg). After the injection, she slit her wrists
and hanged herself. She is heterozygous for the factor V
Leiden mutation and had a pulmonary embolus 2.5 years
prior to this admission. She had been prescribed enoxaparin 1 mg/kg (80 mg) Q 12 h by her primary provider.
In the ED, central venous access was attempted in her
bilateral femoral veins. An initial antifactor Xa activity
level was 8.3 IU/ml (therapeutic range 0.5–1.1 IU/ml for
twice daily dosing, 1.0–2.0 IU/ml for once daily dosing),
which was measured via serial dilutions. Partial thromboplastin time (PTT) on admission was 98 s (23–38 s).
Initial hemoglobin and hematocrit were 12.6 g/dl
(12–16 g/dl) and 38.1% (35–45%), respectively. Apart
from mild oozing from her wrists and intraosseous
access site, she had no clinical evidence of bleeding.
She was admitted to the medical ICU for close observation. Her PTT peaked 6 h after admission at 169 s.
0957-5235 ß 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
approximately 25 h. Blood Coagul Fibrinolysis 23:772–774
ß 2012 Wolters Kluwer Health | Lippincott Williams &
Wilkins.
Blood Coagulation and Fibrinolysis 2012, 23:772–774
Keywords: enoxaparin, heparin, low-molecular-weight, overdose, protamine
sulfate
Department of Hematology and Medical Oncology, University of Florida,
Gainesville, Florida, USA
Correspondence to Michael Byrne, University of Florida, Box 100278, 1600 SW
Archer Road, Gainesville, FL 32610-0278, USA
Tel: +1 352 273 7832; e-mail: [email protected]
Received 25 March 2012 Revised 26 June 2012
Accepted 3 August 2012
Serial antifactor Xa activity levels and PTT values are
shown (Figs 1 and 2).
Our initial management was supportive as the patient was
clinically stable and without evidence of bleeding. After
approximately 15 h, serial complete blood counts had
revealed a drop in her hematocrit to 28.8% and she
was transfused two units of packed red blood cells. A
repeat hematocrit 3 h later was 22.7% necessitating the
transfusion of two additional units (Fig. 3). Computed
tomography (CT) of the abdomen and pelvis showed
bilateral retroperitoneal hematomas.
Given active bleeding, the decision was made to administer protamine sulfate 50 mg IV (25 h after admission).
Three doses of rFVIIa, 45 mg/kg, were also administered
at 24, 26, and 28 h with the effects on antifactor Xa
activity and PTT shown (Figs 1 and 2).
Despite factor V Leiden heterozygosity, no thrombotic
complications were seen after rFVIIa administration. By
hospital day number five, the patient’s antifactor Xa
activity level had fallen to subtherapeutic levels.
Discussion
Antithrombin III (AT-III) circulates naturally at high
concentrations in the blood stream albeit in a poorly
reactive conformation. Through interactions with the
pentasaccharide sequence found in unfractionated
heparin, AT-III becomes an efficient inhibitor of coagulation at the levels of factors IXa, Xa, and thrombin.
Smaller heparin fragments, such as those in LMWHs,
are also effective antithrombotic agents. LMWHs accelerate the inhibitory rate of AT-III on factors IXa and Xa
DOI:10.1097/MBC.0b013e328358e8af
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Reversal of low-molecular-weight heparins Byrne and Zumberg 773
Fig. 1
Fig. 3
Hematocrit vs time
50
60.00
180.00
40.00
160.00
20.00
140.00
0.00
120.00
0
100.00
0.00
2
20
10
0
80.00
4
60.00
6
40
30
40.00
8
20.00
Hematocrit (%)
Anti-Xa activity
Antifactor Xa activity vs time
10
Time (h)
Time (h)
Antifactor Xa activity vs. time. Protamine sulfate was administered at
25 h (solid arrow). rFVIIa was administered at 24, 26, 28 h (hash
marks). The half-life is approximately 25 h.
Hematocrit (%) vs. time. The patient was transfused a total of 4 units of
packed red blood cells. Two units at 15 h and two units at 18 h (arrow
heads).
but have a lesser effect on the inhibition of thrombin.
Protamine sulfate primarily works to reverse the effects
of anticoagulation by the inhibition of the heparin-AT-III
complex. There is little effect on antifactor Xa activity,
and thus LMWHs are only partially reversed.
thrombin and thus prolong the PTT. At supratherapeutic
doses, the effect on the PTT becomes apparent, as there
are more large chain molecules to inhibit thrombin
through interactions with AT-III.
With LMWHs, the PTT correlates poorly with antifactor
Xa activity. This is because the primary effect of
LMWHs is through the potentiation of AT-III mediated
inhibition of factor Xa. Thus, the PTT is often normal or
only minimally prolonged at therapeutic LMWH doses.
For this reason, the antifactor Xa activity level is the
preferred method to monitor LMWHs. This phenomenon is illustrated in our case in which, 24 h after
admission, our patient’s PTT had fallen to within the
normal range whereas her anti-Xa activity level remained
markedly elevated (Figs 1 and 2).
The elevation in the PTT at supratherapeutic LMWH
doses illustrates that although the LMWHs are predominantly shorter chain polysaccharides, some larger chain
molecules are also present in these preparations. These
larger molecules, similar to those found in unfractioned
heparin, potentiate the AT-III-mediated inhibition of
Fig. 2
aPTT (s)
200
150
100
50
0
20.00
40.00
The American College of Chest Physicians (ACCP)
recommendations for the treatment of LMWH overdose
are consistent with the manufacturer’s instructions. If
reversal is sought within 8 h of LMWH administration,
their guidelines recommend protamine 1 mg/100 antifactor Xa units followed by a second dose of 0.5 mg
protamine/100 antifactor Xa units if clinically indicated.
Smaller doses may be considered in patients more than
8 h out from injection [1]. The maximum recommended
single dose of protamine sulfate is 50 mg, which would be
ineffective in large overdoses such as in our patient.
Higher doses may lead to untoward effects including
anaphylactic reactions and hemorrhage [2].
In animal models, the administration of protamine sulfate
has shown reductions in blood loss. The effects of the
anticoagulant, however, were still evident suggesting
only an incomplete reversal [3].
PTT vs time
0.00
Over the last several years, there have been multiple case
reports of patients requiring reversal of LMWH for a
variety of reasons ranging from life-threatening bleeding
to the need for emergency surgery. Efforts to develop an
antidote or other means to reverse LMWH have been
limited.
60.00
Time (h)
PTT vs. time. Protamine sulfate was administered at 25 h (solid arrow).
rFVIIa was administered at 24, 26, and 28 h (hash marks).
Reports of using protamine sulfate for the reversal of
LMWH in humans have yielded similar results. Patients
with supratherapeutic antifactor Xa activity levels have
had ongoing bleeding despite protamine administration,
suggesting a limited benefit. A patient with perioperative
renal failure and hemorrhage who was treated with protamine had only minimal improvement in her antifactor
Xa activity level from 1.65 to 1.34 IU/ml and continued to
have clinical evidence of bleeding (described as continued transfusion requirements) [4]. Partial reversal was
also noted in a patient with subdural hemorrhage with an
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774 Blood Coagulation and Fibrinolysis 2012, Vol 23 No 8
antifactor Xa activity level of 1.02 IU/ml. He received a
total of three doses of protamine (60 mg) with less than a
50% reduction in antifactor Xa activity and concurrent
clinical deterioration suggestive of continued bleeding
[5].
A cohort of 18 patients from the United Kingdom requiring LMWH reversal due to bleeding or emergency
surgery reported clinical benefit in a subset of patients
with antifactor Xa activity levels less than 1 IU/ml. These
patients had clinical resolution of their bleeding following the administration of protamine sulfate. Six received
only one dose whereas two received a subsequent dose.
Of the four patients, who had antifactor Xa activity levels
greater than 1.0 IU/ml, two had persistent bleeding
despite repeated doses of protamine [6].
Protamine sulfate was administered in the setting of a
10-fold overdose in a 4 kg infant, which resulted in an
antifactor Xa activity level greater than 3 IU/ml. She was
treated with protamine 35 mg IV over the course of 7.5 h
with improvement of her antifactor Xa activity level.
There was no clinically significant bleeding described
[7]. When plotted, the antifactor Xa activity levels
followed nonlinear pharmacokinetics with a pattern
similar to that of our patient.
Due to incomplete reversal with protamine, rFVIIa has
been used in a small number of patients. Three patients,
all with known underlying hypercoagulable disorders,
developed bleeding while on LMWH. In all three cases,
the patients were treated with rFVIIa with reported
improvement of bleeding. No patient suffered a thrombotic event [8].
Others have conservatively managed patients with
supratherapeutic antifactor Xa activity levels without
the use of protamine or rFVIIa including a patient with
the previously highest antifactor Xa activity level
reported to date. This patient presented with an antifactor Xa activity level of 6.2 IU/ml and was managed
with observation alone. Pharmacokinetics, as a function
of antifactor Xa activity, followed a linear trajectory but
few data points were noted. A second patient was also
safely observed without evidence of bleeding [9].
Conclusion
Although protamine sulfate and rFVIIa have both been
cited as options in the treatment of LMWH overdose, the
data suggests only partial reversal. Our patient with a
markedly elevated antifactor Xa activity level and PTT
had only minimal improvement from these interventions.
ACCP guidelines currently recommend treatment with
protamine sulfate if clinically indicated. More studies are
needed to further evaluate treatment of overdoses of
LMWHs as well as newly developed anticoagulants.
Acknowledgements
Conflicts of interest
There are no conflicts of interest.
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