using low molecular weight heparin in special patient populations

Using low molecular weight heparin in special patient populations

Wendy Lim

Published online: 10 November 2009

� Springer Science+Business Media, LLC 2009

Abstract Clinical trials evaluating low molecular weight

heparin (LMWH) for the prevention and treatment of

venous thromboembolism and acute coronary syndromes

have led to their regulatory approval for these indications

in the general population. However, certain patient popu-

lations have been excluded from these landmark clinical

trials, including patients with renal insufficiency, obese

patients and pregnant women. In these special populations,

data on safety and efficacy is limited and typically based on

pharmacokinetic studies often performed in healthy sub-

jects, or small cohort studies which are generally not

powered to evaluate clinical outcomes such as bleeding or

recurrent thrombosis. Because LMWH is mainly cleared

renally, patients with severe renal insufficiency are at risk

of LMWH accumulation and increased bleeding risks. In

obese patients, there is concern regarding possible over-

dosing of therapeutic dose LMWH, since LMWH does not

distribute in fat tissue. There are also concerns about

possible underdosing of prophylactic dose LMWH in obese

individuals using the standard fixed doses, particularly in

the extremely obese individuals undergoing bariatric sur-

gery. Last, pregnancy poses challenges with regards to the

safety of LMWH during pregnancy and use of LMWH

around delivery. This review summarizes the existing data

in these special populations and proposes general recom-

mendations for practice.

Keywords Low molecular weight heparin �Venous thromboembolism � Special populations �Renal insufficiency � Obesity � Pregnancy

Regulatory approval for the use of antithrombotic agents in

clinical practice is typically based on the results of large

randomized clinical trials demonstrating the efficacy and

safety of these agents in large patient populations. How-

ever, patient populations that are typically excluded from

these clinical trials include patients with renal insuffi-

ciency, those at the extremes of weight and pregnant

women. In these ‘special populations’, data on efficacy and

safety is largely observational in nature or extrapolated

from pharmacokinetic studies. It is notable that many of

these pharmacokinetic studies are conducted in healthy

patients with no known disease (i.e., healthy patients with

no thrombotic disease but have renal insufficiency or are

obese). Consequently, the use of these agents in these

special populations is frequently uncertain or if used,

advised with caution.

Low molecular weight heparin (LMWH) has largely

replaced unfractionated heparin (UFH) for the prevention

and treatment of venous thromboembolism (VTE).

LMWH is superior to UFH for the prevention of VTE and

is at least equivalent to UFH for the treatment of patients

with acute deep vein thrombosis (DVT) or pulmonary

embolism (PE) [1–3]. LMWHs have gained popularity as

a result of their improved pharmacokinetics compared to

UFH, which allow for weight-based dosing that can be

administered on an outpatient basis without the need for

laboratory monitoring. However, the same properties

which have resulted in their increasing use in the general

population have also resulted in limitations in specific

patient populations.

W. Lim (&)

Department of Medicine, Division of Hematology-

Thromboembolism, McMaster University, St. Joseph’s Hospital,

50 Charlton Avenue East, Hamilton, ON L8N 4A6, Canada

e-mail: [email protected]

123

J Thromb Thrombolysis (2010) 29:233–240

DOI 10.1007/s11239-009-0418-z

The lower molecular weight and lesser negative charge

of LMWHs results in an increased dependency on renal

elimination for clearance, compared to UFH which is

cleared through a combination of hepatic and renal routes.

Consequently, when LMWH is given to patients with

impaired renal function, there is a risk of LMWH accu-

mulation and bleeding. In obese patients, there is concern

among clinicians that the weight-based treatment dosing

regimens will result in very large doses of LMWH, which

may result in overdosing and increased bleeding. However

in the same population, LMWH thromboprophylaxis is

generally given in fixed doses which may result in under-

dosing in morbidly obese patients undergoing bariatric

surgery. Last, concerns regarding LMWH use and dosing

in pregnant women are focused on changes in maternal

weight as the pregnancy progresses, the possible effects of

LMWH on the fetus and issues surrounding its safe use at

the time of delivery and in the post-partum period. This

review will discuss the use of LMWH in these three patient

populations, with a focus on the available evidence in the

literature supporting these practices.

Monitoring LMWH therapy

UFH is subject to nonspecific binding to the vascular

endothelial cells and plasma proteins in the circulation. The

degree of nonspecific binding is variable between indi-

viduals and results in an unpredictable anticoagulant effect,

necessitating laboratory monitoring with the activated

partial thromboplastin time (aPTT) to ensure that patients

are receiving an appropriate UFH dose. The phenomenon

of non-specific binding is entirely dependent on heparin

chain length. LMWH is produced by the chemical or

enzymatic depolymerization of UFH, and the resulting

shorter chains are less subject to nonspecific binding to

plasma proteins in the circulation compared to UFH. As a

result, the anticoagulant effect of LMWH is much more

predictable and LMWH dosing for the treatment of VTE is

based on weight-adjusted dosing regimens that do not

require routine laboratory monitoring. This lack of need for

monitoring and the ability to be administered subcutane-

ously has led to the routine outpatient treatment of VTE, a

practice supported by large randomized controlled trials

and systematic reviews [4, 5].

However, there are certain clinical situations where the

anticoagulant effect of LMWH is unpredictable or uncertain.

In these situations LMWH therapy can be monitored using an

anti-factor Xa level. Anti-Xa levels measure the anticoagu-

lant effect of LMWH rather than the LMWH drug concen-

tration. In clinical practice, anti-Xa levels have been used to

guide therapy, although there is limited data to support the

association between the clinical efficacy of LMWH and peak

anti-Xa levels [6]. Anti-Xa levels have also be used as a

surrogate measure for the risk of bleeding, as some studies

have shown that a high anti-Xa level is associated with an

increased bleeding risk [6, 7], although this has not been

found in other studies [8–10]. Importantly, the clinical trials

evaluating LMWHs did not use target anti-Xa levels to guide

dosing since LMWH dosing has typically been based on

patient weight. Therefore, target anti-Xa levels for the var-

ious LMWHs have been determined retrospectively, are not

well established and vary according to the type of LMWH.

When used to guide therapy, anti-Xa levels are typically

measured 4 h following LMWH administration to assess the

peak effect, and assess if dosing is adequate. A conservative

peak anti-Xa level for twice daily, therapeutic dose LMWH

is 0.6 to 1.0 IU/ml (enoxaparin and nadroparin), and for once

daily dosing is approximately 1.0 IU/ml (0.85 IU/ml for

tinzaparin,[1.0 IU/ml for enoxaparin, 1.05 IU/ml for dal-

teparin and 1.3 IU/ml for nadroparin) [11]. For prophylactic

doses, optimal peak anti-Xa levels are unknown, since

monitoring of prophylactic dose LMWH is generally not

performed. However, peak anti-Xa levels of approximately

0.2–0.5 IU/ml have been suggested. Anti-Xa levels can also

be measured as a trough level, typically to assess if there is a

residual anticoagulant effect. However, there is no consensus

on an acceptable trough anti-Xa level for treatment dose

LMWHs, although at prophylactic doses trough anti-Xa

levels should be undetectable. Despite the imperfect evi-

dence base related to anti-Xa measurement, the lack of

dosing data in special populations has resulted in consensus

guidelines recommending that anti-Xa monitoring be per-

formed when LMWHs are used in special patient popula-

tions [11].

Use of LMWH in patients with severe renal

insufficiency

At therapeutic doses, clearance of UFH from the plasma

occurs primarily through binding of the UFH chains to

liver macrophages and endothelial cells, which results in

depolymerization and removal of UFH [11]. At very high

doses, clearance of UFH by the liver is saturated and

elimination occurs through a non-saturable renal mecha-

nism. In contrast, the shorter heparin chains of LMWH are

less able to bind to liver macrophages and endothelial cells

and clearance from the body is much more dependent on

the non-saturable renal mechanism.

The risk of LMWH accumulation is dependent on several

factors, with the severity of renal impairment being one

important consideration. Measurement of renal function is

most commonly performed in the clinical setting using

calculated estimates, including the Cockcroft-Gault formula

and the Modification of Diet in Renal Disease (MDRD)

234 W. Lim

123

equation to estimate the glomerular filtration rate (GFR).

Chronic kidney disease can be classified into stages 1–5,

based on declining estimates of GFR [12].

A GFR or creatinine clearance (CrCl) of less than 30 ml/

min has been used most commonly in the literature as the

threshold for dose reduction of LMWH. Although there is

evidence that LMWH accumulation occurs with CrCl

greater than 30 ml/min, this threshold appears to be asso-

ciated with clinically significant increased risks of accu-

mulation and bleeding [13]. This corresponds to patients

who have severe renal insufficiency, defined as stage 4 and

5 chronic kidney disease with GFR 15–29 ml/min and less

than 15 ml/min, respectively.

Clinical trials evaluating treatment of VTE and acute

coronary syndromes (ACS) in patients with renal insuffi-

ciency have generally excluded patients with CrCl less than

30 ml/min. As a result, there is little data available to guide

LMWH dosing in these patients for these indications.

Furthermore, the presence of renal insufficiency itself is a

recognized risk factor for bleeding in patients receiving

antithrombotic agents [14].

Risks of accumulation and bleeding in patients

with severe renal insufficiency

Prophylactic dose LMWH

The bleeding risk associated with prophylactic dose

LMWH in patients with severe renal insufficiency (CrCl

less than 30 ml/min) appears to be low. However it is

important to note that this hypothesis has not been tested

in large randomized studies, since studies examining

LMWH for thromboprophylaxis have excluded patients

with severe renal insufficiency [15]. In a prospective

study of 138 critically ill patients with CrCl less than

30 ml/min, prophylactic dose dalteparin (5000 IU daily)

was associated with a major bleeding rate of 7.2% (95%

confidence interval [CI] 4.0–12.8%) and a minor bleeding

rate of 17.4% (95% CI 12.0–24.6%) [15]. While these

bleeding rates appear high in comparison to the bleeding

rates observed in the thromboprophylaxis studies in the

general medical population, it should be noted that there

was no control group and the median trough anti-Xa level

was only 0.1 IU/ml. No relationship was observed

between bleeding events and the measured trough anti-Xa

levels. No patients had an anti-Xa level greater than

0.4 IU/ml, and there was no evidence of dalteparin

accumulation.

Small prospective studies have evaluated prophylactic

dose LMWH in elderly patients with age-related renal

insufficiency using serial anti-Xa levels as a measure of

LMWH accumulation. In one such study of elderly patients

with CrCl 20 to 50 ml/min, there was no evidence of tin-

zaparin (4500 IU daily) accumulation over 8 days com-

pared to enoxaparin (4000 IU daily) [16]. In a prospective

study using dalteparin (5000 IU daily), 24 elderly patients

with CrCl less than 30 ml/min had no significant accu-

mulation of anti-Xa activity after 6 days of treatment, and

no correlation between bleeding and anti-Xa levels was

observed [17]. Thus, when anti-Xa levels are used to

measure LMWH accumulation, there does not appear to be

significant accumulation of dalteparin or tinzaparin when

used in prophylactic doses in patients with moderate to

severe renal insufficiency whereas there may be accumu-

lation with enoxaparin [16]. Major bleeding events were

rare in these studies, suggesting that bleeding risks are low,

but notably these studies were not adequately powered to

detect differences in bleeding.

Therapeutic dose LMWH

A systematic review and meta-analysis of 12 studies

comprising 4,971 patients found that use of LMWH in

patients with CrCl 30 ml/min or less compared with CrCl

greater than 30 ml/min was associated with increased

major bleeding (5.0 vs. 2.4%; odds ratio (OR) for major

bleeding 2.25, 95% confidence interval (CI) 1.19–4.27;

P = 0.01) [13]. When analyzed by LMWH type, increased

major bleeding was evident using therapeutic dose enox-

aparin (8.3 vs. 2.4%; OR 3.88, 95% CI 1.78–8.45). This

meta-analysis did not establish that empiric dose reduction

of enoxaparin reduces bleeding risk (0.9% with adjustment

vs. 1.9% without; OR for major bleeding 0.58, 95% CI

0.09–3.78). There was insufficient data to assess the

bleeding risk associated with other LMWHs.

Prospective registry data of patients with severe renal

insufficiency who receive LMWH also demonstrate that

bleeding is more frequent compared to patients without

renal impairment. In the RIETE registry, an prospective

registry of patients with VTE, an analysis of 1,037 patients

with CrCl less than 30 ml/min found that major bleeding

occurred in 7.3% compared to 2.1% of patients with CrCl

greater than 30 ml/min [18]. In the GRACE registry, a

prospective registry of patients with ACS, the rate of major

bleeding in patients on admission with CrCl less than

30 ml/min was 8.1%, compared to 2.3% in those with CrCl

greater than 30 ml/min (P \ 0.0001) [19]. In-hospital

major bleeding during LMWH treatment was observed in

5.9 and 1.2%, respectively, (P \ 0.0001) [20]. While it is

clear that patients with severe renal insufficiency have

higher bleeding rates, the degree that LMWH has con-

tributed to this is unknown.

Data from subgroups of patients with renal insufficiency

enrolled in large randomized trials of VTE or ACS have

Using low molecular weight heparin in special patient populations 235

123

provided some insight into the bleeding risks associated

with LMWH use in patients with severe renal insufficiency.

In a retrospective analysis of the TIMI 11b and ESSENCE

databases (non-ST elevation ACS trials), a total of 143

patients had CrCl less than 30 ml/min [21]. In the subgroup

of patients who had CrCl less than 30 ml/min and received

enoxaparin, the risk of major bleeding was 6-fold higher

compared to patients who received enoxaparin and had

CrCl greater than 30 ml/min (7.5 vs. 1.2%). Among

patients with a CrCl less than 30 ml/min, there was a trend

towards increased bleeding in the enoxaparin-treated

patients compared to the UFH-treated patients (7.5 vs.

5.8%) but the result was not statistically significant given

the small number of patients in the analysis. In the SYN-

ERGY trial evaluating enoxaparin compared to UFH in

high-risk patients with non-ST ACS undergoing early

invasive treatment, 156 patients had CrCl less than 30 ml/

min [22]. Like the prior analysis, there was no difference in

bleeding in patients with CrCl less than 30 ml/min treated

with enoxaparin or UFH, suggesting that renal insuffi-

ciency affected outcomes similarly. However, like the

analysis of the TIMI 11Ib and ESSENCE trials, the number

of patients was relatively small and the effect of unadjusted

dose enoxaparin on bleeding is unclear.

The effect of LMWH type on the risks of accumulation

and bleeding

It is notable that different types of LMWH may be asso-

ciated with differences in the extent of accumulation and

differences in bleeding risk when administered in thera-

peutic doses. Two observational studies using therapeutic

dose tinzaparin in elderly patients with age-related renal

insufficiency and VTE have shown no evidence of LMWH

accumulation by anti-Xa levels when used for 10–30 days

[23, 24]. In both studies, peak anti-Xa levels were mea-

sured 5 h after tinzaparin administration with no significant

change in the anti-Xa levels when measured every 2–

3 days over a 10 day course [23], or when measured

weekly over a 30 day course with a mean of 20 days of

treatment [24]. There was no relationship observed

between renal function and anti-Xa levels. However, it is

notable that trough anti-Xa levels were not performed in

these studies and the mean CrCl of the patients in these

studies was 41 and 51 ml/min (corresponding to patients

with moderate renal insufficiency). There are no large

prospective studies evaluating the bleeding risk with ther-

apeutic dose tinzaparin in patients with CrCl less than

30 ml/min. Currently, there are no recommendations for

dose-adjustment of tinzaparin in patients with severe renal

insufficiency, but monitoring with anti-Xa levels is rec-

ommended in this population until further data are

available.

Lowering bleeding risk when LMWH is used

in patients with severe renal insufficiency

Bleeding risk may be decreased using three strategies.

First, recognizing renal insufficiency can potentially pre-

vent excessive anticoagulation. This is commonly seen in

elderly individuals with decreased muscle mass who have a

low CrCl despite a seemingly normal serum creatinine

measurement. Second, dose adjustment of LMWH may

decrease bleeding risk. In patients with CrCl less than

30 ml/min, the enoxaparin product monograph recom-

mends a 50% dose reduction compared to the standard

dosing; thus for patients requiring treatment of acute VTE

or ACS, the recommended dose is 1 mg/kg once daily and

the prophylactic dose is 30 mg once daily [25]. There are

no specific recommendations for dalteparin or tinzaparin

dose adjustment in patients with CrCl less than 30 ml/min,

but anti-Xa monitoring is recommended.

The effect of dose-adjusted enoxaparin on accumulation

and bleeding complications in patients with CrCl less than

30 ml/min has been studied [26, 27]. A pharmacokinetic

study of 19 patients showed that the reduced dose of en-

oxaparin 1 mg/kg every 24 h is associated with peak anti-

Xa levels in the target range of 0.5–1.0 IU/ml in 74% of

patients. The mean trough level measured after 1–2 doses

was 0.12 IU/ml [27].

In the ExTRACT-TIMI 25 trial comparing enoxaparin

versus UFH as an adjunct to fibrinolysis therapy in patients

with ST-elevation myocardial infarction, patients with

CrCl less than 30 ml/min received a reduced enoxaparin

dose of 1 mg/kg every 24 h [26]. Major bleeding rates

were similar for enoxaparin and UFH in patients with CrCl

greater than 90 ml/min (1.2 vs. 0.8%). However, with each

30 ml/min decline in renal function, the risk of major or

minor bleeding associated with enoxaparin increased by

approximately 50%. In patients with CrCl less than 30 ml/

min, major bleeding was observed in 5.7% with dose-

reduced enoxaparin, compared to 2.8% with UFH. The net

clinical benefit of enoxaparin, weighing antithrombotic

efficacy (death, nonfatal recurrent myocardial infarction)

and nonfatal major bleeding was seen only in patients with

CrCl greater than 60 ml/min.

Lastly, bleeding risk may be minimized with LMWH

monitoring using anti-Xa levels in patients with severe

renal insufficiency, the recommendation endorsed by the

American College of Chest Physicians (ACCP) [11]. As

discussed above, anti-Xa monitoring has not been studied

in large trials and physicians must have access to timely

anti-Xa levels if this strategy is used to guide dose

adjustment. However, until other diagnostic tests become

available for LMWH monitoring, anti-Xa monitoring in

patients with severe renal insufficiency is the standard of

care.

236 W. Lim

123

Use of LMWH in obese patients

Subcutaneous administration of LMWH has close to 100%

bioavailability, but is predominantly concentrated in the

plasma and highly vascular tissues with little distribution in

fat tissue. By definition, obese patients have a body mass

index (BMI) greater than 30 kg/m2, and have a lower

proportion of lean body mass compared to their total body

weight. Consequently, concern regarding potential over-

dosing of LMWH in obese patients has resulted in some

clinicians capping the dose at a maximum absolute dose,

typically at the maximum prefilled syringe dose. However,

the bleeding risk when weight-based dosing (without a

dose maximum) is used appears to be low.


Studies based on target anti-Xa levels have shown that

weight-based dosing according to actual body weight in

obese individuals achieves anti-Xa levels similar to those

measured in non-obese controls [28, 29]. Notably, many of

these studies have been conducted in obese patients who

are otherwise healthy (i.e., have no need for anticoagula-

tion) [29, 30]. Cohort studies using enoxaparin [31] and

dalteparin [32] have demonstrated that LMWH dosing

regimens should be based on the patient’s actual body

weight, as opposed to the patient’s ideal body weight. The

cohort study assessing enoxaparin was a prospective study

which measured peak anti-Xa levels and demonstrated that

mean anti-Xa levels were similar between healthy weight

patients and obese patients, whether dosed once or twice

daily for treatment of atrial fibrillation, ACS or VTE [31].

The dalteparin study was a retrospective review of 193

patients and evaluated bleeding and thromboembolic out-

comes among patients with VTE exceeding 90 kg. Dal-

teparin was given as a once-daily dose of 200 IU/kg and

only two patients had a major bleeding event, which

occurred several weeks post diagnosis and unlikely to be

caused by dalteparin therapy [32].

Compared to patients weighing 50–100 kg, bleeding and

thrombotic outcomes did not differ significantly among

294 patients weighing over 100 kg in the prospective RI-

ETE registry [33]. In the retrospective analysis of the TIMI

IIb and ESSENCE studies, the rate of major hemorrhage

did not differ between obese patients compared to non-

obese patients (0.8 vs. 1.3%), and there was no difference

between UFH and enoxaparin (1.2 vs. 0.4%) [21]. Similar

results were observed in the subgroup of obese patients in

the SYNERGY trial [34]. A total of 3137 patients (32% of

the SYNERGY population) were obese. Enoxaparin was

dosed as 1 mg/kg regardless of body weight and there was

no maximum dose. Despite this, underdosing (i.e., a dose

less than what would be calculated based on the patient’s

actual body weight) was observed in 15% of patients ran-

domized to enoxaparin and obese patients were more likely

to be underdosed compared to non-obese patients. Obesity

was not an independent predictor of in-hospital bleeding,

but like the other subgroup analyses, the data are still

limited by relatively small numbers of patients. This is

reflected in the product monographs for many of the

LMWHs, which continue to have a maximum recom-

mended dose.


Whereas clinicians have concerns about potential over-

dosing with therapeutic dose LMWHs, there are concerns

about potential underdosing when prophylactic dose

LMWHs are used in obese patients. Retrospective sub-

group analyses of obese patients enrolled in the large VTE

prophylaxis trials, including MEDENOX (enoxaparin

40 mg daily vs. placebo) and PREVENT (dalteparin

5000 IU daily vs. placebo), demonstrate no significant

difference in efficacy compared to non-obese patients [35,

36]. Consequently, no specific recommendation for obese

patients exist in published consensus guidelines [37].

However, the extremely obese patients undergoing bariat-

ric surgery may represent a higher risk population due to

their extreme weight and the nature of the surgery. Bari-

atric surgery is indicated for treatment of individuals with

BMI exceeding 35–40 kg/m2. The reported cumulative

incidence of VTE in patients undergoing bariatric surgery

ranges from 0.1 to 1.0% [38, 39], and many of the VTE

events associated with bariatric surgery appear to occur

after hospital discharge. This may be related to the

increasing proportion of laparoscopic gastric bypass pro-

cedures that are performed on an outpatient basis. The

studies evaluating thromboprophylaxis for bariatric surgery

have mainly been relatively small cohort studies comparing

standard dose versus higher dose LMWH [40], and weight-

adjusted doses of LMWH [41]. The results of these limited

studies suggest that thromboprophylaxis should be used

and should be given at higher than standard doses. In-

hospital versus extended duration prophylaxis has also

been studied [42]. Although limited, thromboprophylaxis

given for at least 10 days appears to reduce the incidence

of VTE, although the optimal dose, timing and duration of

thromboprophylaxis in bariatric surgery requires evaluation

in a large scale, randomized controlled trial. The ACCP

guidelines recommend that for patients undergoing inpa-

tient bariatric surgery, thromboprophylaxis with LMWH,

low dose UFH three times daily, fondaparinux or one of

these options with optimally used intermittent pneumatic

compression be used; consideration for higher doses of

LMWH or UFH compared to nonobese patients is sug-

gested [37].


123

Use of LMWH in pregnancy

Use of anticoagulants in the pregnant population is chal-

lenging because of uncertainties associated with changes in

maternal weight as the pregnancy progresses, bleeding

risks in the mother and fetus and risks of bleeding asso-

ciated with delivery. Furthermore, most of the data

regarding pregnancy are extrapolated from the non-preg-

nant population, or case reports and case series of pregnant

woman, resulting in the quality of the data being relatively

poor and based on expert opinion.

Safety of LMWH during pregnancy

Both UFH and LMWH are relatively large, negatively

charged polysaccharide molecules that do not cross the

placenta and there are no reports of fetal teratogenicity.

UFH and LMWH are also safe during breastfeeding. UFH

is not excreted into breast milk, although there may be

detectable levels of LMWH. However, heparins have poor

bioavailability when ingested orally and any ingestion of

LMWH in breast milk has no clinical relevant anticoagu-

lant effect on the fetus [43].

Use of prophylactic dose LMWH during pregnancy does

not appear to result in increased bone loss compared to the

normal physiologic losses during pregnancy [44] and

LMWH appears to have lower risks of osteoporosis com-

pared to UFH [43].


Prophylactic dose LMWH in pregnancy is used in the same

fixed doses as the non-pregnant population. The efficacy of

LMWH also appears to be the same, although the indica-

tion for prophylaxis is usually for prevention of VTE

during pregnancy in women with risk factors (i.e., previous

history of VTE, thrombophilia) or in the setting of pre-

vention of pregnancy loss (not discussed here), as opposed

to the in-hospital use for thromboprophylaxis in general

medical and surgical patients. A systematic review of

LMWH use during pregnancy which included a total of 64

studies and 2,777 pregnancies showed significant bleeding

occurring in 1.98% (95% CI 1.50–2.57%) [45]. The rate of

antepartum hemorrhage was 0.43%, postpartum hemor-

rhage 0.94% and wound hematoma 0.61%. Therefore,

LMWH appears to have very low bleeding risks when used

in prophylactic doses in pregnant women.


The incidence of VTE during pregnancy ranges from 0.6 to

1.3 per 1000 deliveries, which represents a 5–10 fold

increase in VTE risk compared to non-pregnant women of

comparable age. Two-thirds of all DVT occur in the

antepartum period, and are equally distributed across all

trimesters of pregnancy. Treatment of VTE during preg-

nancy is entirely extrapolated from trials in the non-preg-

nant population and LMWH is used in the same manner.

However, the only issue during pregnancy is the uncer-

tainty with dosing with increasing maternal weight as the

pregnancy progresses. The need for dose adjustments

remains controversial. Small studies suggest that increasing

LMWH doses are required to maintain anti-Xa levels in the

expected therapeutic range [46, 47], whereas other experts

point to the relatively wide therapeutic window for

LMWHs, making dose adjustments unnecessary unless

excessive changes in weight occur [48].

Use of therapeutic dose LMWH also poses challenges at

delivery. To ensure that there is no anticoagulant effect at

delivery, expert recommendations suggest that LMWH be

discontinued 24–36 h before elective induction of labor or

caesarean section [43]. Anti-Xa levels may be checked and

protamine may be given if the anti-Xa level is high or if

bleeding occurs. Lastly, optimal duration of anticoagula-

tion for women diagnosed with VTE during pregnancy

remains unknown. Data are again extrapolated from non-

pregnant populations and most experts recommend a

minimum of 3–6 months with treatment continued until at

least 6 weeks postpartum in all cases.

Summary

All patients receiving therapeutic dose LMWH should have

an assessment of renal function, usually using a calculated

estimate of CrCl. Patients with CrCl less than 30 ml/min

who require therapeutic dose anticoagulation should

receive enoxaparin in reduced doses and other LMWHs

must be used with care. Anti-Xa level monitoring should be

employed until further data is available. In obese patients,

therapeutic dose LMWH should be given according to the

patient’s actual weight. LMWH thromboprophylaxis can

likely be given at fixed doses until further data are avail-

able. However, in obese patients undergoing bariatric sur-

gery, higher doses of LMWH are recommended and

consideration for extended duration thromboprophylaxis

may be given as an increasing number of procedures are

performed on an outpatient basis or have short in-hospital

stays. Lastly, LMWH is safe in pregnancy and can be used

in the same doses as the non-pregnant population for pro-

phylaxis and possibly for treatment, although adjustments

for significant increases in maternal weight may be given.

Based on consensus opinion, LMWH should be discon-

tinued 24–48 h prior to elective induction of labour to

minimize any residual anticoagulant effect at the time of

delivery. Treatment duration in pregnant women should

238 W. Lim

123

encompass the 6 week postpartum period, and should

occur for a minimum of 3–6 months.

Acknowledgments No funding was received for the preparation of

this manuscript. WL has received an unrestricted educational grant

from Leo Pharma, and is on the speaker’s bureau for Leo Pharma and

Pfizer and has received honoraria for these presentations.

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using low molecular weight heparin in special patient populations

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