DOI: 10.1111/sdi.

12932

REVIEW ARTICLE

Anticoagulation in hemodialysis: A narrative review

Sophie E. Claudel1,2  | Lauren A. Miles3 | Mariana Murea3

1
Wake Forest School of Medicine,
Winston-Salem, NC, USA Abstract
2
Department of Internal Medicine, Boston Systemic anticoagulation in maintenance hemodialysis (HD) has historically been con-
Medical Center, Boston, MA, USA
3
sidered necessary to maintain the extracorporeal circuit (ECC) and preserve dialysis
Department of Internal Medicine, Section
on Nephrology, Wake Forest School of efficiency. Unfractionated heparin (UFH) is the most commonly used anticoagulant
Medicine, Winston-Salem, NC, USA due to low cost and staff familiarity. Despite widespread use, there is little standardi-
Correspondence zation of heparin dosing protocols in the United States. Although the complication
Sophie E. Claudel or Mariana Murea, Wake rates with UFH are low for the general population, certain contraindications have led
Forest School of Medicine, Winston-
Salem, NC, USA. to exploration in alternative anticoagulants in patients with end-stage kidney disease
Email: Sophie.claudel@bmc.org (S. E. C.); (ESKD). Here we review the current evidence regarding heparin dosing protocols,
mmurea@wakehealth.edu (M. M.)
complications associated with heparin use, and discuss alternatives to UFH including
Funding informationNo funding was
obtained to support this work. anticoagulant-free routine HD.

1  |   H E M O D I A LYS I S A N D B LO O D platelet consumption and clotting compared with polyacrylonitrile,

C LOT TI N G
Since hemodialysis (HD) was first applied in the 1920s with collo-
dion membranes and hirudin as an anticoagulant, clotting has been
a major limitation to effective HD. During HD, blood is conducted
through an extracorporeal circuit (ECC), activating coagulation by
a complex interplay of patient and circuit (Figure 1). Occluding mi-
crothrombi (suspected clots in tubing or dialyzer membranes) and
macrothrombi (visually evident clots in tubing or dialyzers) hinder
dialysis efficiency, increase cost, and contribute to anemia via blood
1
loss.
1.1  |  Mechanisms of clotting
The most common element that incites circuit clotting is reduced
blood flow rate, usually the result of mechanical abnormalities in the
vascular access or in the ECC. 2,3 Bio-incompatibility between blood
and synthetic extracorporeal circuitry leads to synthesis of proco-
agulant mediators, promoting platelet clumping.4–6 Circulation of
blood through tubing and devices activates leukocytes and platelets
due to sheer stress and triggers release of tissue factor via mem-
7,8
brane microparticles. Different dialysis membranes and tubing
composition have been associated with different risks of clotting
activation. Cuprophane dialyzers have been associated with more
polysulfone, or polymethylmalonylacetate dialyzers.9–14 Even the
composition of the blood tubing may be implicated, and tubing com-
posed of silicone rubber is associated with more platelet and fibrin
accumulation compared to that observed with other plastic materi-
als.15 These prothrombogenic mechanisms are exacerbated by the
underlying coagulopathies in patients with end-stage kidney disease
(ESKD) who have an increased prevalence of atrial fibrillation, en-
dothelial damage, and other prothrombotic comorbidities. The use
of cellophane tubing and unfractionated heparin (UFH) in the 1940s
led to the first practical application of HD by allowing sustained pa-
tency of the dialysis circuit.16 While circuit clotting is a major risk
factor for decreased dialysis efficiency, the concern must also be
balanced against an increased risk of bleeding due to uremic platelet
dysfunction and treatment with systemic anticoagulant/antiplatelet
agents.17
1.2  |  Clotting assessment in the ECC
Circuit clotting can be evaluated through visual assessment of the fil-
ter or drip chamber, early session termination due to access alarms,
and (with dialyzer reuse) by residual dialyzer volume. Very dark blood
within the circuit, streaks within the dialyzer, or the presence of fibrin
on the walls of the arterial or venous chambers may indicate clotting.
The ECC pressures, measured in the arterial and venous pressure

Seminars in Dialysis. 2021;34:103–115. wileyonlinelibrary.com/journal/sdi© 2020 Wiley Periodicals LLC.     103 |

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104      CLAUDEL et al.

F I G U R E 1  Factors involved in hemodialysis circuit clotting. During intermittent hemodialysis, the patient's blood is exposed to many
substances, including the blood tubing, chambers and headers, and the dialyzer membrane. These surfaces exhibit variable degrees of
thrombogenicity and activate the intrinsic coagulation system, the tissue factor, the leukocytes and platelets. Patient-related factors are at
interplay with circuit-related factors and collectively lead to formation of micro- or macrothrombi during hemodialysis [Color figure can be
viewed at wileyonlinelibrary.com]

chambers, also indicate impending clot. After every treatment, dia-
lyzer inspection and degree of fiber clotting provide information
that can be used to adjust the anticoagulation regime for subsequent
treatments. A quantitative assessment of clotting within the dialyzer
involves in vitro measurement of the fiber bundle volume or residual
volume within the blood compartment of the dialyzer at the end of the
HD treatment.18 Dialyzer clotting can also be monitored in real time
using ultrasonic flow-dilution sensors placed pre- and post-dialyzer
19
connected to a monitoring system. The advantage of real-time as-
sessment of clotting is the ability to alter the dose of anticoagulant or
stop treatment before significant clotting and subsequent blood loss
occurs. A recently developed micro-computer tomography (CT) tech-
nique is an emerging gold standard in the research setting, offering
the potential to objectively assess coagulation effects of various dia-
lyzer designs and anticoagulation strategies.20,21 Using the micro-CT
approach, Vanommeslaeghe and colleagues counted individual pat-
ent fibers via cross-sectional imaging of dried, post-HD dialyzers and
compared the approach to standard visual clotting assessments.20
The ability to objectively assess fiber patency throughout the entire
membrane, rather than just the visually observed exterior fibers, in an
automated fashion may provide a more accurate assessment of dia-
lyzer clotting in future studies.20
2  |  C LOT TI N G PR E V E NTI O N
Currently, empiric doses of heparin preparations are used to pre-
vent clotting in the ECC. Heparin has long been considered as a
safe and effective method of anticoagulation for intermittent HD.
Historically, studies of alternative strategies have been limited to
patient populations with an increased risk of bleeding or those with
known heparin intolerance. Increased attention to the potential risks
of heparinization during HD has led to investigation in alternative
strategies to prevent intradialytic clotting. Additionally, increased
utilization of single-use dialyzers due to decreased cost has led to
further interest in anticoagulant-free treatments. Below, we summa-
rize the existing evidence regarding heparin administration during
routine intermittent HD and address non-heparin-based strategies
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CLAUDEL et al.       105

TA B L E 1  Strategies for anticoagulation during hemodialysis

Advantages Disadvantages

Systemic anticoagulation
Unfractionated heparin, standard
dose28,33
Unfractionated heparin, low dose32
83,86
Low molecular weight heparin
Heparinoids103,112,115
Direct thrombin inhibitors104
Alternative strategies
Mechanical (saline flushes)118,138
Regional anticoagulation
Heparin (with protamine reversal)139
Citrate (with Ca2+
replacement)92,94,95,140
Citrate-based dialysate98–100
Coated dialyzers
Heparin121,128,131,133
Albumin124
Vitamin E125,126,128
Circuit priming
Saline132
133
Albumin
Heparin118,123,132,135
Heparin + albumin132,134,136
Heparin + albumin + citrate132
Ease of use Bleeding risk (access site, internal organs)
Easily reversed with protamine Hypertriglyceridemia
Short half-life HIT
Lower cost Theoretical: osteoporosis, hyperkalemia
Reduced exposure to heparin Lower risk of bleeding
Lower risk of HIT Higher cost
No reversal agent
Risk of bioaccumulation
Can be used in patients with HIT High cost
Cleared with high-flux dialyzers
Can be used in patients with HIT Physician/personnel unfamiliarity with dosing regimens
Simple strategy Controversial results regarding effectiveness in clot
Low cost prevention
Lower risk of bleeding Complexity in administration
High cost
Lower risk of bleeding Calcium monitoring
May improve inflammatory profile
Lower risk of bleeding Limited data as sole anticoagulant strategy
May improve inflammatory profile
Lower risk of bleeding High cost
Increased rates of circuit clotting
Lower risk of bleeding High cost
Can be used in patients with HIT
Lower risk of bleeding High cost
Can be used in patients with HIT
Low cost Ineffective as sole anticoagulant strategy
Lower risk of bleeding High cost
Limited data
Lower risk of bleeding High cost
Limited data
Lower risk of bleeding High cost
Limited data
Lower risk of bleeding High cost
Limited data

Note: Cost comparison was limited to drug pricing and did not include specialized equipment, nursing demands, or laboratory tests required for
monitoring.
Abbreviation: HIT, heparin-induced thrombocytopenia.

to reduce clotting. A summary of findings is provided in Table 1 and
proposed dosing protocols are summarized in Table 2.
2.1  |  Unfractionated heparin
The most common anticoagulant during HD is systemic UFH. UFH is a
heterogeneous mixture of negatively charged mucopolysaccharide mol-
ecules that bind antithrombin III (at lower doses) and heparin cofactor
II (at higher doses), and increases tissue factor inhibitor in order to pro-
duce an anticoagulant effect.22,23 UFH is affordable and considered
safe for repeated use. The rapid onset of action (3–5 minutes) and short
half-life (approximately 1 hour) also favor its use.24–27 UFH is predomi-
nantly cleared by hepatic and vascular endothelial heparinases, though
non-specific binding to plasma proteins and leukocytes has been re-
ported to influence half-life.25 Due to these pharmacokinetic proper-
ties, UFH is known to have heterogeneous effects and an unpredictable
dose–response relationship that can complicate clinical application.22
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106      CLAUDEL et al.

TA B L E 2  Dosing protocols for anticoagulants used during hemodialysis

Dosing protocols reported in the literature

Modality Loading dose/bolus Maintenance dose Monitoring Reversal agent

Unfractionated heparin
Standard dose, 2000–4000 IU 500–2000 IU/h aPTT 1.5 to 2.0 X Protamine sulfate (1 mg/100 IU
USA 28,33,141 pre-HD level heparin)
25–30 IU/kg Lower the starting weight-based ACT 150-200 s (target:
dose by 500 IU every hour ~150% of pre-HD
level)
Standard dose, 50 IU/kg 800-1500 IU/h aPTT Protamine sulfate
Europe33
Low dose32,33 10–25 IU/kg 1000 IU/h aPTT Protamine sulfate
(or 10 IU/kg/h)
15–20 IU/kg 500 IU/h aPTT, ACT Protamine sulfate
Low molecular weight heparin
Enoxaparin7,142 0.50–0.67 mg/kg NA Plasma anti-Xa activity Protamine sulfate
(target: 0.5–1.0 IU (0.5 mg/1 mg enoxaparin) (<60%
anti-Xa/mL) reversibility)
Tinzaparin7,143 2500–3500 IU NA Plasma anti-Xa activity Protamine sulfate (1 mg/100
Dalteparin 144
5000 IU anti-Xa IU) (85% reversibility)

Regional citrate
Citrate94 NA 100 ml/h trisodium citrate Ionized calcium (target: Calcium chloride
(500 mmol/L) with 35 mmol/h within 10% of
calcium chloride (500 mmol/L). baseline level)
Adjust in increments of 2.5 to
5 mmol/h to keep iCa within
10% of baseline level
Direct thrombin inhibitors
Argatroban104,105,108 250 μg/kga  NA aPTT None
250 μg/kg  a
2 μg/kg/min ACT (target: >140%
baseline)
NA a  2 μg/kg/min
250 μg/kga  1.7–3.3 μg/kg/min
Hirudins
Bivalirudin145,146 NA 0.2 mg/kg/h aPTT No specific reversal agent,
NA 0.15 mg/kg/h (for ClCr>60 ml/min) though Factor VII can be
0.08–0.1 mg/kg/h (for ClCr tried
30-59 ml/min)
0.03–0.05 mg/kg/h (for ClCr
<29 ml/min)
Lepirudin105 0.05–0.1 mg/kga  NA aPTT
Hirudin levels
Heparinoids
Danaparoid106 3750 Ua  NA Anti-Xa levels None
112
Fondaparinux 0.03 mg/kga,b 

Abbreviations: ACT, activated clotting time; aPTT, activated partial thromboplastin time; ClCr, clearance of creatinine; HD, hemodialysis; NA, not applicable.
a
Critically ill patients and/or patients with diagnosed HIT.
b
Hemodiafiltration.

2.1.1  |  Dosing
In contrast to Europe,28,29 dosing protocols for UFH in HD vary widely
in the United States (US), with some centers using consistent doses and
others using weight-based protocols. A nation-wide study of heparin
dosing practices demonstrated a median dose of 4000 units (IQR:
2625-6000), with significant regional variation.30 Inclusion of patient-
and facility-level characteristics only accounted for approximately
25% of dosing variation, suggesting that physician preferences may be
driving the disparity in dosing practices.30 Early attempts to improve

CLAUDEL et al.
dosing protocols through the use of complex pharmacodynamic mod-
els failed to demonstrate improved clinical outcomes.23
Unfractionated heparin is administered either as an initial bolus
dose followed by a constant infusion (less common) or by interval
bolus dosing. Typical dosing for a constant infusion uses a lower load-
ing dose, followed by an infusion rate of 1000-1500 units/h. For ini-
tial bolus dosing, a common protocol in the US is a loading dose of
1500–2000 units (or 75–100 units/kg) with a maintenance dose of
1000–1500 units/h.1,31 Alternative protocols forgo the loading dose
and start with a higher maintenance dose, followed by a taper in the
second hour of treatment.26 Low-dose protocols, such as 15–20 units/
kg loading and 500 units/h maintenance, have been shown to be both
safe and effective, without increasing clotting risk.32,33 For example,
Murea et al demonstrated that the use of low-dose heparin was as-
sociated with a reduction in erythropoietin-stimulating agent doses
while maintaining a single-pool Kt/Vurea (spKt/Vurea) of 1.54 and
urea reduction ratio of 73.0.32 There was a non-statistically significant
decrease in dialyzer reuse with the use of low-dose heparin, though
now less clinically relevant in the era of single-use dialyzers. With all
protocols, maintenance infusions are typically stopped 30–60 minutes
prior to the end of the treatment to reduce bleeding during decannula-
tion.26,31 Although the volume of distribution of heparin changes with
body weight, most centers do not adjust heparin dosing in patients
weighing 50–90 kg. “Tight” heparin protocols are generally reserved
for patients at an increased risk of bleeding who cannot achieve effec-
tive HD without anticoagulation. A constant infusion protocol is most
common, avoiding the peaks and troughs associated with bolus dosing.
2.1.2  |  Measuring anticoagulation
The variability in UFH pharmacokinetics and narrow therapeutic
window make optimal dosing strategies difficult to define. Objective
measurement of the anticoagulant effect of heparin during HD is
the ideal way of achieving optimal anticoagulation, measured as the
time taken for clot formation. To be practical in the clinical setting,
the assessment method must be inexpensive, convenient, and result
in real time to allow for dose adjustments during HD.
The activated partial thromboplastin time (aPTT) and activated
clotting time (ACT) have been used to measure the anticoagulant
effect of UFH. However, the aPTT produces inconsistent results,
especially at the high serum levels of heparin required for adequate
34
anticoagulation in extracorporeal therapies. When using aPTT to
monitor UFH, it is recommended that a reagent-specific therapeutic
range be established using heparin concentrations in the serum. The
ACT is a point-of-care test first described in 1966 to screen for disor-
35
ders of coagulation and to monitor UFH therapy. In this assay, whole
blood is mixed with an activator of the extrinsic clotting cascade and
the time necessary for blood to congeal is measured. For HD, the goal
of anticoagulant therapy is to limit clotting in the dialyzer and circuit
without causing excessive clinical bleeding.36 To establish this goal, an
ACT of 170–220 seconds is recommended.37 An alternative goal is an
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      107
increase in ACT of 140%–180% above baseline. These levels of ACT
generally prevent visible clotting in the dialyzer and blood tubing.38
Despite these methods of monitoring UFH dosing during HD, in
clinical practice, neither aPTT nor ACT is used to dose UFH. Empiric
UFH dose adjustments are instead used, typically based on dialyzer
clotting, bubble trap clotting, and/or prolonged post-session access
bleeding. This is likely due to the combination of inconvenience and cost
of testing, low risk of bleeding complications, and Clinical Laboratory
Improvement Amendments (CLIA) certification requirements.1
2.1.3  |  Complications
Bleeding
Systemic UFH increases bleeding both at the vascular access site and
other organs, such as the gastrointestinal tract, brain, and vitreous.
Incidence of clinically significant bleeding—defined as bleeding into a
major organ, requiring hospitalization, or transfusion—is approximately
3.33% in patients dialyzed with UFH.39 Despite the high level of con-
cern regarding gastrointestinal bleeding, after excluding patients taking
warfarin, Shen and colleagues found that most patients resume dialyz-
ing with UFH during their first treatment following hospitalization for
a non-variceal bleed.40 Contrary to expectation, UFH dose reductions
following did not appear to be a standard practice.40 The safety of
using concomitant oral anticoagulant/antiplatelet agents is undefined,
though limited evidence suggests acceptable use of these agents in
the setting of systemic heparinization with UFH during HD.39,41 A re-
cent observational study of warfarin use in patients with ESKD found
a strong association with all-cause mortality and significant bleeding,
but was unable to stratify by type of anticoagulant used for HD.42
Heparin-induced thrombocytopenia
Heparin-induced thrombocytopenia is a serious, potentially life-
threatening complication of heparin characterized by severe
thrombocytopenia and hypercoagulability. The repeated UFH ex-
posure with HD raises concern for elevated risk of HIT in ESKD
patients. Prevalence of HIT in HD patients is poorly characterized
due to variable diagnostic definitions in the literature,43 though
a national study in the United Kingdom reported 0.26 per 100
patients.44 Conventionally, HIT is diagnosed by development of
thrombocytopenia following heparin exposure, thrombosis, recov-
ery of platelets following heparin withdrawal, and detectable HIT
antibodies (platelet factor 4/heparin [PF4-H]) or functional plate-
let assays).43 The authors of one study regarding HIT incidence in
HD patients argued that clotting of the ECC should be considered
an early manifestation of HIT, though this continues to be debated
in clinical practice.45,46 The impracticality of avoiding heparin ex-
posure in dialysis patients who develop HIT has led to several case
reports of successful heparin reintroduction following platelet re-
covery and antibody seroreversion.47–50 Interim non-heparin anti-
coagulation can be achieved with alternative agents as discussed
below.
 |
108      CLAUDEL et al.
Small, cross-sectional, and cohort studies have detected sub-
acute HIT (positive antibodies without thrombocytopenia) in
1.3%–35.7% of HD patients. 51–57 The wide variability is attrib-
utable to assay technique and dialysis vintage, as there appears
to be a strong temporal pattern of antibody seroconversion re-
lated to dialysis initiation, wherein titers are highest within the
58
first 6 months of treatment. Outcomes in patients with isolated
57,59
PF4-H antibodies reveal no increased risk of thrombosis,
increased risk of mortality. 55,60–63 This mortality effect has been
demonstrated with detection of IgG-specific PF4-H antibodies
alone and in combination with a platelet serotonin release assay,
as well as a dose–response effect in those with highest PF4-H
titers. 63 The increased mortality is thought to be driven by an
increase in cardiovascular disease 54 and cardiovascular-specific
55,63
mortality. Intriguingly, Asmis and colleagues also showed el-
evated PF4-H antibodies in peritoneal dialysis patients, who are
not routinely exposed to heparin. 53 In combination with cardio-
vascular outcomes, these findings suggest that PF4-H antibod-
ies may be more representative of general endothelial damage
and vascular disease in HD patients. 53,55,64 Routine monitoring of
PF4-H antibodies is not recommended as a preventive strategy in
HD patients without clinical manifestations of HIT.
Hypertriglyceridemia
Heparin (fractionated or unfractionated) is known to deplete lipo-
protein and hepatic lipase, which together reduce triglyceride clear-
ance and fraction of high-density lipoprotein in the plasma.
Patients with ESKD already have an elevated risk of dyslipidemia
due to underlying endothelial dysfunction. Studies have shown car-
diovascular and mortality benefits to initiating statin therapy prior
to initiation of dialysis,67,68 but not in existing dialysis patients,69
possibly due to unique lipid derangements associated with dialy-
sis.70 Although it has been speculated that heparin-mediated dys-
lipoproteinemia may contribute to progressive atherosclerosis in
patients with ESKD,71–73 the overall effect of heparin exposure in
dialysis patients is unknown.
Osteoporosis
74
A theoretical adverse effect of heparin is osteoporosis. Several in
vitro and animal studies on the effects of heparin on osteogenesis
showed controversial results, citing possible decreased osteoblastic
74
or increased osteoclastic activity. In a crossover study of 40 pa-
tients on intermittent HD, anticoagulation was switched from UFH
to low molecular weight heparin (LMWH), and biochemical mark-
ers for bone metabolism and bone densitometry were monitored
longitudinally.73 Four months after conversion to LMWH, tartrate-
resistant acid phosphatase, which reflects osteoclastic activity, was
reduced by 13%. When converted back to UFH, the biochemical
indices returned to pre-LMWH levels, suggesting that LMWH may
partially alleviate UFH-associated osteoporosis. However, due to
limited research on this topic, it remains unclear if these risks are
exacerbated by chronic heparin use.
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3  |  A LTE R N ATI V E S TO U FH
Low molecular weight heparin
Use of LMWH for anticoagulation in HD is increasing. These drugs
(including enoxaparin, tinzaparin, dalteparin, and nadroparin) have
shorter saccharide chains derived from UFH. 24,75 LMWH prevents
but activation of factor X through binding antithrombin III but has a
minor effect on thrombin. 23 In contrast to the bolus-infusion model
of UFH, LMWH requires only a single injection at the start of HD
60
(unless treatment is greater than 6 hours).76,77 Pharmacokinetics of
LMWH appear superior to UFH due to higher bioavailability, pre-
dictable response, longer half-life, and dose-independent clear-
ance. However, the pharmacokinetics are less predictable in ESKD
patients7 and vary slightly between specific formulations (Table 3).
Since 2002, the European Best Practice Guidelines have recom-
mended LMWH for routine HD in patients with no increased risk of
bleeding risk. 29
Feared complications of LMWH include bleeding, incomplete
reversibility with protamine,78,79 and the theoretical risk of bio-
accumulation causing supratherapeutic levels due to primary
renal excretion. Recent advances in chemosynthesis techniques
may allow for homogenous, synthetic LMWH with greater re-
versibility. 80 Although the anticoagulant effect of LMWH can be
monitored with factor Xa levels, clinical utility is limited as levels
may not correlate with biological effect (i.e., clinically significant
65,66
hemorrhage), and it is impractical to have separate assays for each
agent. 81,82 Multiple analyses have demonstrated no increased
risk of major bleeding or time to first major bleed with the use of
LMWH compared to UFH, with reduced risk in some studies 39,83,84
A meta-analysis demonstrated similar dialysis efficacy and circuit
thrombosis between LMWH and UFH, though thorough analysis
of bleeding events was limited by the small number of available
studies. 85 A follow-up meta-analysis of head-to-head trials was
conducted by Lazrak and colleagues to evaluate bleeding risk,
demonstrating a relative risk of 0.76 for combined major and minor
bleeding. 86 A small increase in minor bleeding events was ob-
served for patients taking oral anticoagulants while dialyzing with
LMWH as compared to UFH, 83 though an additional study sup-
ports the safety of using LMWH for HD in the setting of chronic
oral anticoagulation. 39
Increased cost is a common critique of routine LMWH for inter-
mittent HD. However, early international investigations show sim-
ilar or reduced costs when considering preparation (LMWH comes
in a single, pre-dosed needle), nursing time (LMWH requires only
single bolus dosing), and intrinsic drug cost. 23,85,87,88 It is reason-
able to hypothesize that reduced membrane clotting with LMWH
may reduce costs through increased dialyzer reuse and improved
clearance/efficiency. Unfortunately, more recent cost compari-
sons, since decreased price of LMWH compared to UFH and wide-
spread use of LMWH for multiple clinical indications, have not been
conducted.

CLAUDEL et al.
TA B L E 3  Half-life and route of
elimination of LMWH
Enoxaparin23,147,148
Dalteparin148,149
Nadroparin150
Tinzaparin23,148,151
Abbreviations: CrCl, creatinine clearance; LMWH, low molecular weight heparin.
3.1  |  Regional citrate anticoagulation
A well-studied approach to reduce heparin exposure is the use of
regional citrate anticoagulation (RCA). A single center in Slovenia
reported performing over 10 000 successful dialysis sessions with
RCA in 2015.89 Importantly, severe liver failure is an absolute con-
traindication to RCA due to primary hepatic metabolism of citrate
and a high risk of citrate toxicity and hypocalcemia.90 Use of RCA
is as follows: first, trisodium citrate is infused into the arterial port,
then calcium chloride is infused into the venous return just before
the needle.90,91 The calcium infusion neutralizes the citrate prior to
infusion into the patient, reducing the risk of citrate-induced hypoc-
alcemia. Dialysate bath adjustments are required, namely reduced
bicarbonate (although severe metabolic alkalosis is rare as the in-
92,93
fused citrate is eliminated by the dialyzer) and sodium (due
to the sodium content of the citrate solution).92,93 Magnesium is
chelated by citrate, and magnesium-containing dialysate is recom-
mended.90,91,94 Bleeding and clotting event rates are comparable to
conventional HD.91,95
The most feared complication of RCA is symptomatic hypocalce-
mia precipitating adverse cardiac events, yet clinically significant hy-
pocalcemia has rarely been observed in multiple studies.90–92,94–96 In
an early study by Apsner and colleagues comparing RCA and LMWH
for anticoagulation in HD, the lowest observed ionized calcium was
0.98 mmol/L and, at the end of dialysis, there was no significant dif-
ference in measured calcium between the two groups.91 More re-
cently, Gubensek and colleagues randomized patients receiving RCA
to a standard or low targeted ionized calcium.92 The low target group
experienced a statistically significant increase in intact parathyroid
92 96
hormone (PTH), similarly observed in other studies. The low tar-
get group also experienced a positive mean calcium mass balance,
though lower than the standard target group.92 The presence of a
positive calcium mass balance even in sessions tolerating mild hypo-
calcemia raises concerns for future vascular calcification in patients
receiving long-term RCA for HD if normocalcemia is targeted, and
|
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      109
Half-life Clearance in patients with
(h) Route of elimination kidney failure
4.5 Predominantly renal, Patients with CrCl <30 ml/
some hepatic min may show a 30%
reduction in clearance
3–5 Renal Patients with CrCl <30 ml/
min may have mean
terminal half-life
prolonged to 5-7 h
3.5 Predominantly renal Patients with varying renal
impairment may show a
30%–40% reduction in
clearance
1.5 Predominantly renal, Patients with CrCl <30 ml/
some endothelial min may show a 24%
reduction in clearance
therefore the authors recommend permissive mild hypocalcemia.92
Minor differences in protocols in RCA studies have resulted in varied
calcium balance.90,92,95 The long-term clinical significance of mildly
increased intact PTH is not clear.92,96 Further studies are needed
before drawing conclusions regarding specific dosing protocols and
overall calcium balance for long-term bone and vascular health.
Common concerns regarding RCA are the perceived complexity
and need for constant monitoring of ionized calcium, increasing nurs-
ing requirements and cost. Although ionized calcium levels are drawn
at frequent intervals in clinical trial protocols, this is not needed in clin-
ical practice, as the safety of the RCA has been repeatedly demon-
strated. Eliminating the need for intensive ionized calcium monitoring
reduces the overall cost of RCA,91 and the cost of citrate itself is low.89
Simplified infusion protocols have largely replaced the need for com-
plex delivery systems and monitoring,91,93,95 and future technological
developments may further automate calcium substitution.
A simpler method for taking advantage of the anticoagulant
properties of citrate includes the use of citrate-containing dial-
ysate. Kossmann et al. examined the effects of citrate-based di-
alysate on dialysis efficiency (measured as equilibrated Kt/Vurea
[eKt/Vurea] and pre-dialysis concentrations of blood urea nitro-
gen) in 142 patients with prevalent ESKD, switched from bicarbon-
ate dialysate acidified by acetate to bicarbonate dialysate acidified
with citrate, while the HD prescription and the administration of
systemic UFH during HD remained unchanged. In their study, the
authors observed that citrate-based dialysis, used in addition to
UFH, resulted in better solute clearance: eKt/Vurea rose from
mean (SD) 1.51 (0.01) to 1.57 (0.01) (p < 0.0001) and pre-dialysis
blood urea nitrogen decreased from 48.4 (14.4) to 46.5 (14.8) mg/
dl (p = 0.007).97 However, preliminary evidence from a small, sin-
gle-center study did not demonstrate a reduction in intradialytic
heparin requirements with use of citrate-containing dialysate. In
their randomized, double-blind, crossover trial involving 20 main-
tenance HD patients, Leung et al. found that the mean cumulative
dose of UFH did not change significantly between acetic ac-
id-containing dialysate and citrate-containing dialysate.98 Further
 |
110      CLAUDEL et al.
evidence is needed to determine the anticoagulant efficacy of ci-
trate dialysate in routine HD. Aside from its anticoagulant proper-
99
ties, citrate dialysate may also reduce inflammation and vascular
calcification,100 which are risk factors for poor cardiovascular out-
comes in patients on HD.
3.2  |  Non-heparin agents
Despite the large number of dialysis patients prescribed oral an-
101
ticoagulants for various clinical indications, evidence regard-
ing non-heparin systemic anticoagulants is primarily in cases of
HIT102–105 or in critically ill patients.106,107 The principal concerns
with these agents are clearance during dialysis and lack of reversal
agents. Current options include direct thrombin inhibitors (arga-
troban104,108,109 and hirudin110,111), synthetic heparinoids (fonda-
parinux),103,112 naturally occurring heparinoids (danaparoid),106
113
and vitamin K antagonists (warfarin). The most well studied,
argatroban, is minimally cleared during dialysis and has been fre-
quently selected for dialysis after HIT.114 Murray and colleagues
report on three separate argatroban dosing regimens for HD, with
a urea reduction ration range of 70–73 and a spKt/Vurea range
108
of 1.5–1.6. A small crossover study of 10 patients taking oral
vitamin K antagonists reported the feasibility of HD without ad-
ditional anticoagulation, without reduction in spKt/Vurea, or
113
increased clotting. Fondaparinux was shown to facilitate suc-
cessful HD treatment in a single patient following development of
HIT, but citrate-containing dialysate was also used, confounding
this report.103 Fondaparinux is less effective when using high-flux
dialyzers due to significant clearance,115 but has been reported
effective in hemodiafiltration.112 Reliance on case studies and ret-
rospective reviews limits the application of these studies. Further
evidence from randomized controlled trials is needed before con-
clusions can be drawn regarding the safety and efficacy of non-
heparin systemic anticoagulants for routine HD.
4  |  A NTI COAG U L A NT- FR E E
H E M O D I A LYS I S
Patients at highest risk of bleeding may need to avoid all pharma-
cologic anticoagulation, and when no anticoagulant is used clotting
1
occurs 5-10% of the time. Mechanical interventions to decrease
clotting include increasing flow rates, specialized airless tubing,116
flushing with saline boluses, or using a continuous saline infu-
sion.117–119 While saline-based interventions allow for the dialysis
session to proceed, they often reduce overall dialysis efficiency,
require multiple dialyzer changes, and increase the volume of fluid
119,120
administered to the patient. A prospective study of anticoagu-
lant-free HD reported clotting events leading to premature session
termination in greater than 50% of treatments using either saline
flushes or continuous saline.118 Furthermore, the nursing demands
of this approach are high, as frequent monitoring of circuit patency
1525139x, 2021, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/sdi.12932 by CAPES, Wiley Online Library on [31/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
and repeated flushes are required. This approach is not viewed as
cost effective.
4.1  |  Coated dialyzer membranes
Another approach to anticoagulant-free HD is the use of coated
dialyzer membranes. These membranes can be coated with hepa-
rin,118,121–123 albumin,124 and vitamin E125–128 to reduce clotting.
While this approach may reduce membrane surface clotting, it
does little to achieve an anticoagulant effect in the remainder
of the circuit. Coated dialyzers are often proprietary, thus more
expensive, and some authors posit shorter lifespan due to clot-
ting events. 33 A randomized trial comparing anticoagulant-free
HD with vitamin E- or heparin-coated dialyzer membranes con-
cluded that the failure rates were unacceptably high (22% for vi-
tamin E-coated and 19% for heparin-coated).128 This is contrary
to the HepZero study, which demonstrated non-inferiority of
a heparin-grafted membrane for use in anticoagulant-free HD,
deeming the membranes effective.121 However, the reported
failure rates were high for both the heparin-coated membranes
and saline flush/predilution protocol (31.5% and 49.6%, respec-
tively).121 Dialysis efficiency and clotting events were not re-
ported in this study, and the ECC was flushed with heparinized
saline prior to treatment.129 Overall, use of a heparin-coated
dialyzer may be superior to saline flushes alone, 21,118,121 but ap-
pears less effective than other heparin-sparing modalities.130,131
Routine use of coated dialyzers would likely require either circuit
priming with an anticoagulant or systemic anticoagulation to be
sustainable.123,128,132,133
4.2  |  Circuit priming
Circuit priming is another approach that avoids systemic delivery
of anticoagulant agents. This method involves flushing the ECC
with a solution that coats the plastic tubing, reducing interaction
with blood. The fluid is removed from the circuit prior to contact
with the patient, minimizing systemic uptake. Studied priming tech-
niques include saline, albumin, and citrate flushes, each with and
without heparin.132–136 In a recent comparison of several dialyzers
in conjunction with albumin priming for anticoagulant-free HD,
dialyzer patency was not substantially improved with the priming
protocol.133 In a comparison of three methods of priming (hep-
arinized saline, heparin + albumin, and heparin + albumin + citrate)
and a heparin-coated dialyzer, the lowest need for supplemental
LMWH boluses was found with the heparin + albumin + citrate
priming protocol.132 No treatments were prematurely terminated
in this group.132 In one case report, HIT recurred due to priming
the ECC with heparinized saline.137 Although rare, this remains a
significant safety concern. Both increased cost and decreased di-
alysis efficiency are noted as limitations to priming-based meth-
ods. Similar to the use of coated dialyzers, circuit priming may be

CLAUDEL et al.
most useful as an adjunctive therapy to reduce dosing of systemic
anticoagulation.132
5  |  CO N C LU S I O N S
While use of UFH for systemic anticoagulation in maintenance HD
remains the standard of care in much of the US, there is increasing
evidence for the safety and efficacy of alternative strategies for
maintaining circuit patency. The evidence for use of LMWH or RCA
suggests that some patients may benefit from being offered these
alternatives. Clinicians may be more comfortable with using newer
modalities for anticoagulation in HD if dosing protocols are stand-
ardized. Presently, more robust clinical data are needed before oral
anticoagulants can be safely recommended for use in routine HD.
Additional studies are also needed to assess the economic implica-
tions of transitioning appropriately selected patients to an alter-
native modality of anticoagulation for long-term maintenance HD.
C O N FL I C T O F I N T E R E S T
The authors declare no conflict of interest.
ORCID
Sophie E. Claudel  https://orcid.org/0000-0002-7695-4674
Mariana Murea  https://orcid.org/0000-0003-3217-1691
REFERENCES
1. Daugirdas JT, Blake PG, Ing TS. Chapter 14: anticoagulation. In:
Handbook of Dialysis. 5th edn. Philadelphia, Penn: Wolters Kluwer
2014:254–255.
2. Swartz R. Hemorrhage during high-risk hemodialysis using con-
trolled heparinization. Nephron. 1981;28(2):65–69.
3. Swartz RD, Port FK. Preventing hemorrhage in high-risk he-
modialysis: regional versus low-dose heparin. Kidney Int.
1979;16(4):513–518.
4. Craddock PR, Fehr J, Brigham KL, Kronenberg RS, Jacob HS.
Complement and leukocyte-mediated pulmonary dysfunction in
hemodialysis. N Engl J Med. 1977;297(14):769–774.
5. Hakim RM, Breillatt J, Lazarus J, Port FK. Complement activation
and hypersensitivity reactions to dialysis membranes. N Engl J
Med. 1984;311(14):878–882.
6. Boyer CJ, Swartz RD. Severe clotting during extracorporeal dialy-
sis procedures. Semin Dial. 1991;4(2):69–71.
7. Davenport A. Review article: low-molecular-weight heparin as an
alternative anticoagulant to unfractionated heparin for routine out-
patient haemodialysis treatments. Nephrology. 2009;14(5):455–461.
8. Davenport A. What are the anticoagulation options for intermit-
tent hemodialysis? Nat Rev Nephrol. 2011;7(9):499–508.
9. Knudson F, Nielsen A. Polycarbonate versus cuprophan dialyzers:
effect on platelet function. Blood Purif. 1984;2(3):173–180.
10. Schmitt G, Moake J, Rudy C, Vicks S, Hamburger R. Alterations in
hemostatic parameters during hemodialysis with dialyzers of dif-
ferent membrane composition and flow design. Platelet activation
and factor VIII-related Von Willebrand factor during hemodialysis.
Am J Med. 1987;83(3):411–418.
11. Docci D, Turchi F, Del Vecchio C, Bilancioni R, Cenciotti L, Pretolani
E. Hemodialysis-associated platelet loss: study of the relative con-
tribution of dialyzer membrane composition and geometry. Int J
Artif Organs. 1984;7(6):337–340.
|
1525139x, 2021, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/sdi.12932 by CAPES, Wiley Online Library on [31/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
      111
12. Sreeharan N, Crow M, Salter M, Donaldson D, Rajah S, Davison
A. Membrane effect on platelet function during hemodialysis:
a comparison of cuprophan and polycarbonate. Artif Organs.
1982;6(3):324–327.
13. Berrettini M, Buoncristiani U, Parise P, Ballatori E, Nenci G.
Polyacrilonytrile versus cuprophan membranes for hemodialysis:
evaluation of efficacy and biocompatibility by platelet aggregation
studies. Int J Artif Organs. 1981;4(5):219–222.
14. Moll S, De Moerloose P, Reber G, Schifferli J, Leski M. Comparison
of two hemodialysis membranes, polyacrylonitrile and cellu-
lose acetate, on complement and coagulation systems. Int J Artif
Organs. 1990;15(3):273–279.
15. Bjornson J. Thrombus formation in the artificial kidney. Platelet
and fibrin(ogen) content of experimental thrombi detected by ra-
dioisotope technique. Scand J Urol Nephrol. 1978;12(3):251–257.
16. Cameron JS. Practical haemodialysis began with cellophane
and heparin: The crucial role of William Thalhimer (1884–1961).
Nephrol Dial Transplant. 2000;15(7):1086–1091. https://doi.
org/10.1093/ndt/15.7.1086
17. Elliott MJ, Zimmerman D, Holden RM. Warfarin anticoagulation in
hemodialysis patients: a systematic review of bleeding rates. Am J
Kidney Dis. 2007;50(3):433–440.
18. Krivitski NM, Kislukhin VV, Snyder JW, et al. In vivo measure-
ment of hemodialyzer fiber bundle volume: theory and validation.
Kidney Int. 1998;54(5):1751–1758.
19. Ross EA, Paugh-Miller JL, Nappo RW. Interventions to improve
hemodialysis adequacy: protocols based on real-time monitoring
of dialysate solute clearance. Clin Kidney J. 2018;11(3):394–399.
20. Vanommeslaeghe F, Van Biesen W, Dierick M, Boone M, Dhondt
A, Eloot S. Micro-computed tomography for the quantification of
blocked fibers in hemodialyzers. Sci Rep. 2018;8(2677):1–9.
21. Vanommeslaeghe F, De Somer F, Josipovic I, et al. Evaluation with
micro-CT of different anticoagulation strategies during hemodial-
ysis in patients with thrombocytopenia: a randomized crossover
study. Artif Organs. 2019;43:756–763.
22. Derbalah A, Duffull S, Newall F, Moynihan K, Al SH. Revisiting
the pharmacology of unfractionated heparin. Clin Pharmacokinet.
2019;58:1015–1028.
23. Davenport A. The rationale for the use of low molecular
weight heparin for hemodialysis treatments. Hemodial Int.
2013;17(SUPPL1):28–32.
24. Chandarajoti K, Liu J, Pawlinski R. The design and synthesis of
new synthetic low molecular weight heparins. J Thromb Haemost.
2016;14(6):1135–1145.
25. Wilhelmsson S, Lins L. Heparin elimination and hemostasis in he-
modialysis. Clin Nephrol. 1984;22(6):303–306.
26. Brunet P, Simon N, Opris A, et al. Pharmacodynamics of unfrac-
tionated heparin during and after a hemodialysis session. Am J
Kidney Dis. 2008;51(5):789–795.
27. McAvoy TJ. Pharmacokinetic modeling of heparin and its clinical
implications. J Pharmacokinet Biopharm. 1979;7(4):331–354.
28. Ashby D, Borman N, Burton J, et al. Renal association clinical prac-
tice guideline on haemodialysis. BMC Nephrol. 2019;20(1). https://
doi.org/10.1186/s1288​2-019-1527-3
29. European Best Practice Guideline. V.2 Prevention of clotting in
the HD patient with normal bleeding risk. Nephrol Dial Transplant.
2002;17:64–66. https://doi.org/10.1093/ndt/17.suppl_7.64
30. Shen JI, Montez-Rath ME, Mitani AA, Erickson KF, Winkelmayer
WC. Correlates and variance decomposition analysis of hepa-
rin dosing for maintenance hemodialysis in older U.S. patients.
Pharmacoepidemiol Drug Saf. 2014;23(5):515–525.
31. Davenport A. Optimization of heparin anticoagulation for hemodi-
alysis. Hemodial Int. 2011;15(SUPPL. 1):43–48.
32. Murea M, Russell GB, Daeihagh P, et al. Efficacy and safety of low-
dose heparin in hemodialysis. Hemodial Int. 2018;22(1):74–81.
 |
112      CLAUDEL et al.
33. Shen JI, Winkelmayer WC. Use and safety of unfractionated hep-
arin for anticoagulation during maintenance hemodialysis. Am J
Kidney Dis. 2012;60(3):473–486.
34. Smythe MA, Koerber JM, Westley SJ, et al. Use of the activated
partial thromboplastin time for heparin monitoring. Am J Clin
Pathol. 2001;115(1):148–155.
35. Hattersley PG. Activated coagulation time of whole blood. J Am
Med Assoc. 1966;196(5):436–440.
36. Congdon JE, Karinal CG, Wallin JD. Monitoring heparin therapy in
hemodialysis. JAMA. 1973;226(13):1529–1533.
37. Mehta R. Anticoagulation during continuous renal replacement
therapy. ASAIO J. 1994;40(4):931–935.
38. Wilhelmsson S, Lins L. Whole-blood activated coagulation time
for evaluation of heparin activity during hemodialysis: a compari-
son of administration by single-dose and by infusion. Clin Nephrol.
1983;19(2):82–86.
39. Nadarajah L, Fan S, Forbes S, Ashman N. Major bleeding in he-
modialysis patients using unfractionated or low molecular weight
heparin: a single-center study. Clin Nephrol. 2015;84(5):274–279.
40. Shen JI, Mitani AA, Winkelmayer WC. Heparin use in hemodial-
ysis patients following gastrointestinal bleeding. Am J Nephrol.
2014;40(4):300–307.
41. Brunelli SM, Cohen DE, Marlowe G, et al. Safety and efficacy of
heparin during dialysis in the context of systemic anticoagulation
and antiplatelet medications. J Nephrol. 2019;32:453–460.
42. Lin MC, Streja E, Soohoo M, et al. Warfarin use and increased mor-
tality in end stage renal disease. Am J Nephrol. 2017;46(4):249–256.
43. Syed S, Reilly RF. Heparin-induced thrombocytopenia: a renal per-
spective. Nat Rev Nephrol. 2009;5(9):501–511.
44. Hutchison CA, Dasgupta I. National survey of heparin-induced
thrombocytopenia in the haemodialysis population of the UK pop-
ulation. Nephrol Dial Transplant. 2007;22(6):1680–1684.
45. Yamamoto S, Koide M, Matsuo M, et al. Heparin-induced
thrombocytopenia in hemodialysis patients. Am J Kidney Dis.
1996;28(1):82–85.
46. Matsuo T. Heparin-induced thrombocytopenia and hemodialysis.
J Blood Disord Transfus. 2013;s2. https://doi.org/10.4172/2155-
9864.S2-002
47. Matsuo T, Matuo M, Wanaka K, Sakai R. Heparin re-exposure after
heparin-induced thrombocytopenia in a chronic hemodialysis pa-
tient. Clin Lab Haem. 2003;25:333–334.
48. Matsuo T, Kobayashi H, Matsuo M, et al. Frequency of anti-hepa-
rin-PF4 complex antibodies (HIT antibodies) in uremic patients on
chronic intermittent hemodialysis. Pathophysiol Haemost Thromb.
2006;35(6):445–450.
49. Matsuo T, Kusano H, Wanaka K, Ishihara M, Oyama A. Heparin-
induced thrombocytopenia in a uremic patient requiring hemodial-
ysis: an alternative treatment and reexposure to heparin. Clin Appl
Thromb. 2007;13(2):182–187.
50. Wanaka K, Matsuo T, Matsuo M, et al. Re-exposure to heparin
in uremic patients requiring hemodialysis with heparin-induced
thrombocytopenia. J Thromb Haemost. 2010;8(3):616–618.
51. O'Shea SI, Sands JJ, Nudo SA, Ortel TL. Frequency of anti-hepa-
rin-platelet factor 4 antibodies in hemodialysis patients and cor-
relation with recurrent vascular access thrombosis. Am J Hematol.
2002;69(1):72–73.
52. Greinacher A, Zinn S, Wizemann BUW. Heparin-induced antibodies
as a risk factor for thromboembolism and haemorrhage in patients
undergoing chronic haemodialysis. Lancet. 1996;348(9029):764.
53. Asmis LM, Segal JB, Plantinga LC, et al. Heparin-induced antibod-
ies and cardiovascular risk in patients on dialysis. Thromb Haemost.
2008;100(3):498–504.
54. Liu CC, Chou LP, Chen TS, Chen CA, Tsai YF. Significant associa-
tion of anti-platelet factor 4/heparin antibody with cardiovascular
1525139x, 2021, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/sdi.12932 by CAPES, Wiley Online Library on [31/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
disease in hemodialysis patients: a longitudinal 7-year study. Int
Urol Nephrol. 2018;50(12):2289–2297.
55. Krane V, Berger M, Lilienthal J, Winkler K, Schambeck C, Wanner
C. Antibodies to platelet factor 4—heparin complex and outcome
in hemodialysis patients with diabetes. Clin J Am Soc Nephrol.
2010;5(5):874–881.
56. Sitter T, Spannagl M, Banas B, Schiffl H. Prevalence of heparin-in-
duced PF4-heparin antibodies in hemodialysis patients. Nephron.
1998;79(2):245–246.
57. Palomo I, Pereira J, Alarcón M, et al. Prevalence of heparin-in-
duced antibodies in patients with chronic renal failure undergoing
hemodialysis. J Clin Lab Anal. 2005;19(5):189–195.
58. Maharaj S, Chang S, Seegobin K, et al. Temporality of heparin-in-
duced antibodies: a retrospective study in outpatients undergo-
ing hemodialysis on unfractionated heparin. Exp Hematol Oncol.
2018;7(1):1–9.
59. Carrier M, Knoll GA, Kovacs MJ, Moore JC, Fergusson D, Rodger
MA. The prevalence of antibodies to the platelet factor 4-hepa-
rin complex and association with access thrombosis in patients on
chronic hemodialysis. Thromb Res. 2007;120(2):215–220.
60. Carrier M, Rodger MA, Fergusson D, et al. Increased mortality in
hemodialysis patients having specific antibodies to the platelet
factor 4-heparin complex. Kidney Int. 2008;73(2):213–219.
61. Shavit L, Bar-Lev M, Lifschitz M, Fink D, Rudensky B, Slotki I.
Prevalence and clinical significance of heparin induced antibodies
in chronic hemodialysis patients and cardiac surgery patients. Int J
Artif Organs. 2011;34(12):1172–1178.
62. Mureebe L, Coats RD, Silliman WR, Shuster TA, Nichols WK,
Silver D. Heparin-associated antiplatelet antibodies increase
morbidity and mortality in hemodialysis patients. Surgery.
2004;136(4):848–853.
63. de la Vega LP, Miller RS, Benda MM, et al. Association of hep-
arin-dependent antibodies and adverse outcomes in hemo-
dialysis patients: a population-based study. Mayo Clin Proc.
2005;80(8):995–1000.
64. Williams RT, Damaraju LV, Mascelli MA, et al. Anti-platelet fac-
tor 4/heparin antibodies: an independent predictor of 30-day
myocardial infarction after acute coronary ischemic syndromes.
Circulation. 2003;107(18):2307–2312.
65. Chan MK, Persaud J, Varghese Z, Moorhead JF. Pathogenic roles
of post-heparin lipases in lipid abnormalities in hemodialysis pa-
tients. Kidney Int. 1984;25(5):812–818.
66. Näsström B, Stegmayr B, Gupta J, Olivecrona G, Olivecrona T. A
single bolus of a low molecular weight heparin to patients on hae-
modialysis depletes lipoprotein lipase stores and retards triglycer-
ide clearing. Nephrol Dial Transplant. 2005;20:1172–1179.
67. Streja E, Gosmanova EO, Molnar MZ, et al. Association of contin-
uation of statin therapy initiated before transition to chronic di-
alysis therapy with mortality after dialysis initiation. JAMA Netw
Open. 2018;1(6):e182311.
68. Soohoo M, Moradi H, Obi Y, et al. Statin therapy before transi-
tion to end-stage renal disease with posttransition outcomes. J Am
Heart Assoc. 2019;8:e011869.
69. Fellström BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and
cardiovascular events in patients undergoing hemodialysis. N Engl
J Med. 2009;360:1395–1407.
70. Vlad C, Burlacu A, Florea L, Artene B, Badarau S, Covic A. A com-
prehensive review on apolipoproteins as nontraditional cardiovas-
cular risk factors in end-stage renal disease : current evidence and
perspectives. Int Urol Nephrol. 2019;51(7):1173–1189.
71. Liu G, Bengtsson-Olivecrona G, Ostergaard P, Olivecrona T. Low-
M(r) heparin is as potent as conventional heparin in releasing lipo-
protein lipase, but is less effective in preventing hepatic clearance
of the enzyme. Biochem J. 1991;273(3):747–752.

CLAUDEL et al.
72. Wiemer J, Winkler K, Baumstark M, Marz W, Scherberich JE.
Influence of low molecular weight heparin compared to con-
ventional heparin for anticoagulation during haemodialysis
on low density lipoprotein subclasses. Nephrol Dial Transplant.
2002;17(12):2231–2238.
73. Lai KN, Ho K, Cheung R, et al. Effect of low molecular weight hep-
arin on bone metabolism and hyperlipidemia in patients on main-
tenance hemodialysis. Int J Artif Organs. 2001;24(7):447–455.
74. Signorelli SS, Scuto S, Marino E, Giusti M, Xourafa A, Gaudio
A. Anticoagulants and osteoporosis. Int J Mol Sci. 2019;20(21).
https://doi.org/10.3390/ijms2​0215275
75. Merli GJ, Groce JB. Pharmacological and clinical differences be-
tween low-molecular-weight heparins implications for prescribing
practice and therapeutic interchange. P T. 2010;35(2):95–105.
76. Klingel R, Schwarting A, Lotz J, Eckert M, Hohmann V, Hafner G.
Safety and efficacy of single bolus anticoagulation with enoxapa-
rin for chronic hemodialysis: results of an open-label post-certifi-
cation study. Kidney Blood Press Res. 2004;27(4):211–217.
77. Dhondt A, Pauwels R, Devreese K, Eloot S, Glorieux G, Vanholder
R. Where and when to inject low molecular weight heparin in
hemodiafiltration? A cross over randomised trial. PLoS One.
2015;10(6):1–13.
78. Crowther MA, Berry LR, Monagle PT, Chan AKC. Mechanisms re-
sponsible for the failure of protamine to inactivate low-molecu-
lar-weight heparin. Br J Haematol. 2002;116(1):178–186.
79. Schroeder M, Hogwood J, Gray E, Mulloy B, Hackett AM,
Johansen KB. Protamine neutralisation of low molecular weight
heparins and their oligosaccharide components. Anal Bioanal
Chem. 2011;399(2):763–771.
80. Xu Y, Cai C, Chandarajoti K, et al. Homogeneous low-molecu-
lar-weight heparins with reversible anticoagulant activity. Nat
Chem Biol. 2014;10(4):248–250.
81. Lai S, Coppola B. Use of enoxaparin in end-stage renal disease.
Kidney Int. 2013;84(3):433–436.
82. Brophy DF, Martin EJ, Gehr TWB, Carr ME. Enhanced anticoagu-
lant activity of enoxaparin in patients with ESRD as measured by
thrombin generation time. Am J Kidney Dis. 2004;44(2):270–277.
83. Lazrak HH, René E, Elftouh N, Lafrance JP. Association between
low-molecular-weight heparin and risk of bleeding among hemodi-
alysis patients: a retrospective cohort study. Can J Kidney Heal Dis.
2018;5. https://doi.org/10.1177/20543​58118​792010
84. Lord H, Jean N, Dumont M, Kassis J, Leblanc M. Comparison be-
tween tinzaparin and standard heparin for chronic hemodialysis in
a Canadian center. Am J Nephrol. 2002;22(1):58–66.
85. Lim W, Cook DJ, Crowther MA. Safety and efficacy of low mo-
lecular weight heparins for hemodialysis in patients with end-
stage renal failure: a meta-analysis of randomized trials. J Am Soc
Nephrol. 2004;15(12):3192–3206.
86. Lazrak HH, René É, Elftouh N, Leblanc M, Lafrance JP. Safety of
low-molecular-weight heparin compared to unfractionated hepa-
rin in hemodialysis: a systematic review and meta-analysis. BMC
Nephrol. 2017;18(1):1–12.
87. Kronenberg F, König P, Neyer U, et al. Influence of various hepa-
rin preparations on lipoproteins in hemodialysis patients: a multi-
centre study. Thromb Haemost. 1995;74(04):1025–1028.
88. Kronenberg F, Konig P, Lhotta K, Steinmetz A, Dieplinger H.
Low molecular weight heparin does not necessarily reduce
lipids and lipoproteins in hemodialysis patients. Clin Nephrol.
1995;43(6):399–404.
89. Buturovic-Ponikvar J. Is regional citrate anticoagulation the future
of hemodialysis? Ther Apher Dial. 2016;20(3):234–239.
90. Wright S, Steinwandel ULI, Ferrari P. Citrate anticoagulation using
ACD solution A during long-term haemodialysis. Nephrology.
2011;16(4):396–402.
|
1525139x, 2021, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/sdi.12932 by CAPES, Wiley Online Library on [31/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
      113
91. Apsner R, Buchmayer H, Lang T, et al. Simplified citrate an-
ticoagulation for high-flux hemodialysis. Am J Kidney Dis.
2001;38(5):979–987.
92. Gubensek J, Orsag A, Ponikvar R, Buturovic-ponikvar J. Calcium
mass balance during citrate hemodialysis: a randomized con-
trolled trial comparing normal and low ionized calcium target
ranges. PLoS One. 2016;1–14. https://doi.org/10.1371/journ​
al.pone.0168593
93. Lin T, Song LI, Huang R, et al. Modified regional citrate antico-
agulation is optimal for hemodialysis in patients at high risk of
bleeding: a prospective randomized study of three anticoagulation
strategies. BMC Nephrol. 2019;20(1):472. https://doi.org/10.1186/
s1288​2-019-1661-y
94. Apsner R, Buchmayer H, Gruber D, Sunder-Plassmann G. Citrate
for long-term hemodialysis: prospective study of 1,009 con-
secutive high-flux treatments in 59 patients. Am J Kidney Dis.
2005;45(3):557–564.
95. Singer RF, Williams O, Mercado C, et al. Regional citrate antico-
agulation in hemodialysis: an observational study of safety, ef-
ficacy, and effect on calcium balance during routine care. Can
J Kidney Heal Dis. 2016;1–10. https://doi.org/10.1186/s4069​
7-016-0113-x
96. Gubenšek J, Kovač J, Benedik M, et al. Long-term citrate anti-
coagulation in chronic hemodialysis patients. Ther Apher Dial.
2011;15(3):278–282.
97. Kossmann RJ, Gonzales A, Callan R, Ahmad S. Increased efficiency
of hemodialysis with citrate dialysate: a prospective controlled
study. Clin J Am Soc Nephrol. 2009;4(9):1459–1464.
98. Leung KCW, Tai DJ, Ravani P, Quinn RR, Scott-Douglas N,
MacRae JM. Citrate vs. acetate dialysate on intradialytic heparin
dose: a double blind randomized crossover study. Hemodial Int.
2016;20(4):537–547.
99. Dellepiane S, Medica D, Guarena C, et al. Citrate anion im-
proves chronic dialysis efficacy, reduces systemic inflammation
and prevents Chemerin-mediated microvascular injury. Sci Rep.
2019;9(1):1–10.
100. Villa-Bellosta R, Hernández-Martínez E, Mérida-Herrero E,
González-Parra E. Impact of acetate- or citrate-acidified bi-
carbonate dialysate on ex vivo aorta wall calcification. Sci Rep.
2019;9(1):1–7.
101. Jain N, Reilly RF. Clinical pharmacology of oral anticoagulants in pa-
tients with kidney disease. Clin J Am Soc Nephrol. 2019;14:278–287.
102. Linkins L-A, Dans AL, Moores LK, et al. Treatment and pre-
vention of heparin-induced thrombocytopenia. Chest.
2012;141(2):e495S–e530S.
103. Wellborn-Kim JJ, Mitchell GA, Terneus WF, et al. Fondaparinux
therapy in a hemodialysis patient with heparin-induced thrombo-
cytopenia type II. Am J Heal Pharm. 2010;67:1075–1079.
104. Murray PT, Hursting MJ. Heparin-induced thrombocytopenia in
patients administered heparin solely for hemodialysis. Ren Fail.
2006;28:537–539.
105. Fischer KG. Essentials of anticoagulation in hemodialysis. Hemodial
Int. 2007;11(2):178–189.
106. Magnani HN. A review of 122 published outcomes of danap-
aroid anticoagulation for intermittent haemodialysis. Thromb Res.
2010;125(4):e171–e176.
107. Link A, Girndt M, Selejan S, Mathes A, Bohm M, Rensing H.
Argatroban for anticoagulation in continuous renal replacement
therapy. Crit Care Med. 2009;37(1):105–110.
108. Murray PT, Reddy BV, Grossman EJ, et al. A prospective compar-
ison of three argatroban treatment regimens during hemodialysis
in end-stage renal disease. Kidney Int. 2004;66:2446–2453.
109. Reddy BV, Grossman EJ, Trevino SA, Hursting MJ, Murray PT.
Argatroban anticoagulation in patients with heparin-induced
 |
114      CLAUDEL et al.
thrombocytopenia requiring renal replacement therapy. Ann
Pharmacother. 2005;39:1601–1605.
110. Pöschel KA, Bucha E, Esslinger H-U, et al. Anticoagulant efficacy
of PEG-Hirudin in patients on maintenance hemodialysis. Kidney
Int. 2004;65:666–674.
111. Van Wyk V, Badenhorst PN, Luus HG, Kotze HF. A comparison
between the use of recombinant hirudin and heparin during hemo-
dialysis. Kidney Int. 1995;48:1338–1343.
112. Mahieu E, Claes K, Jacquemin M, et al. Anticoagulation with
fondaparinux for hemodiafiltration in patients with heparin-in-
duced thrombocytopenia: dose-finding study and safety evalua-
tion. Artif Organs. 2013;37(5):482–494.
113. Krummel T, Scheidt E, Borni-Duval C, et al. Haemodialysis in
patients treated with oral anticoagulant: should we heparinize?
Nephrol Dial Transplant. 2014;29(4):906–913.
114. Hursting MJ, Murray T. Argatroban anticoagulation in
renal dysfunction: a literature analysis. Nephron Clin Pract.
2008;109:c80–c94.
115. Sombolos KI, Fragia TK, Gionanlis LC, et al. Use of fondaparinux as
an anticoagulant during hemodialysis: a preliminary study. Int J Clin
Pharmacol Ther. 2008;46:198–203.
116. Safadi Jr S, Albright Jr RC, Dillon JJ, et al. Prospective study of
routine heparin acute care inpatient practice. Kidney Int Reports.
2017;2(4):695–704.
117. Ivanovich P, Xu C, Kwaan H, Hathiwala S. Studies of coagulation
and platelet functions in heparin-free hemodialysis. Nephron.
1983;33:116–120.
118. Guery B, Alberti C, Servais A, et al. Hemodialysis without
systemic anticoagulation: a prospective randomized trial to
evaluate 3 strategies in patients at risk of bleeding. PLoS One.
2014;9(5):e97187.
119. Stamatiadis D, Helioti H, Mansour M, Pappas M, Bokos J, Stathakis
C. Hemodialysis for patients bleeding or at risk for bleeding, can be
simple, safe, and efficient. Clin Nephrol. 2004;1:29–34.
120. Casati S, Moia M, Granziani G, et al. Hemodialysis without an-
ticoagulants: efficiency and hemostatic aspects. Clin Nephrol.
1984;21(2):102–105.
121. Laville M, Dorval M, Fort Ros J, et al. Results of the HepZero study
comparing heparin-grafted membrane and standard care show
that heparin-grafted dialyzer is safe and easy to use for hepa-
rin-free dialysis. Kidney Int. 2014;86:1260–1267.
122. Morena M, Jaussent I, Chalabi L, et al. Biocompatibility of hep-
arin-grafted hemodialysis membranes: impact on monocyte
chemoattractant protein-1 circulating level and oxidative status.
Hemodial Int. 2010;14:403–410.
123. Chanard J, Lavaud S, Kazes I, Vitry F, Rieu P. The clinical evalu-
ation of low-dose heparin in haemodialysis: a prospective study
using the heparin-coated AN69 ST membrane. Nephrology.
2008;23:2003–2009.
124. Wu X, Chen H. Clinical study of heparin-free hemodialysis with
the inside of hollow fibers in dialyzer coated by human albumins.
Nephron. 2002;92:925–928.
125. Huraib S, Tanimu D, Shaheen F, Hejaili F, Giles C, Pagayon V. Effect
of vitamin-E-modified dialysers on dialyser clotting, erythropoi-
etin and heparin dosage: a comparative crossover study. Am J
Nephrol. 2000;20:364–368.
126. Kiaii M, Aritomi M, Nagase M, Farah M, Jung B. Clinical evaluation
of performance, biocompatibility, and safety of vitamin E-bonded
polysulfone membrane hemodialyzer compared to non-vitamin
E-bonded hemodialyzer. J Artif Organs. 2019;22(4):307–315.
127. Lines SW, Carter AM, Dunn EJ, Lindley EJ, Tattersall JE, Wright MJ.
A randomized controlled trial evaluating the erythropoiesis stim-
ulating agent sparing potential of a vitamin E-bonded polysulfone
dialysis membrane. Nephrol Dial Transplant. 2014;29:649–656.
1525139x, 2021, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/sdi.12932 by CAPES, Wiley Online Library on [31/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
128. Islam MS, Hassan ZA, Chalmin F, et al. Vitamin E-coated and
heparin-coated dialyzer membranes for heparin-free hemodial-
ysis: a multicenter, randomized crossover trial. Am J Kidney Dis.
2016;68(5):752–762.
129. Rydzewska-Rosolowska A, Gozdzikiewicz-Lapinska J, Borawski
J, Koc-Zorawska E, Mysliwiec M, Naumnik B. Unexpected and
striking effect of heparin-free dialysis on cytokine release. Int Urol
Nephrol. 2017;49(8):1447–1452.
130. Meijers KI, Poesen R, Evenepoel P. Heparin-coated dia-
lyzer membranes: is non-inferiority good enough ? Kidney Int.
2014;86:1084–1086.
131. Evenepoel P, Dejagere T, Verhamme P, et al. Heparin-coated poly-
acrylonitrile membrane versus regional citrate anticoagulation: a
prospective randomized study of 2 anticoagulation strategies in
patients at risk of bleeding. Am J Kidney Dis. 2007;49(5):642–649.
132. Skagerlind MS, Stegmayr BG. An evaluation of four modes of low-
dose anticoagulation during intermittent haemodialysis. Eur J Clin
Pharmacol. 2018;74:267–274.
133. Vanommeslaeghe F, De Somer F, Josipovic I, Boone M, Van Biesen
W, Eloot S. Evaluation of different dialyzers and the impact of pre-
dialysis albumin. Kidney Int Reports. 2019;4:1538–1545.
134. Skagerlind M, Stegmayr B. Heparin albumin priming in a clinical
setting for hemodialysis patients at risk for bleeding. Hemodial Int.
2017;21:180–189.
135. Frank RD, Mu U, Lanzmich R, Groeger C, Floege J. Anticoagulant-
free Genius haemodialysis using low molecular weight hepa-
rin-coated circuits. Nephrol Dial Transplant. 2006;21:1013–1018.
136. Fransson F, Kyrk T, Skagerlind M, Stegmayr B. Rinsing the extra
corporeal circuit with a heparin and albumin solution reduces the
need for systemic anticoagulant in hemodialysis. Int J Artif Organs.
2013;36(10):725–729.
137. Lim JH, Kang KP, Lee S, Park SK, Kim W. Recurrent heparin-in-
duced thrombocytopenia due to heparin rinsing before priming
the machine in a hemodialysis patient: a case report. Hemodial Int.
2017;21:E30–E33.
138. Caruana RJ, Raja RM, Bush JV, Kramer MS, Goldstein SJ. Heparin
free dialysis: comparative data and results in high risk patients.
Kidney Int. 1987;31(6):1351–1355.
139. Gordon L, Perkins H, Richards V. Studies in regional hepariniza-
tion. I. The use of simultaneous neutralization with protamine;
preliminary studies. N Engl J Med. 1956;255(22):1025–1029.
140. Strobl K, Harm S, Weber V, Hartmann J. The role of ionized calcium
and magnesium in regional citrate anticoagulation and its impact
on inflammatory parameters. Int J Artif Organs. 2017;40(1):15–21.
141. Cronin RE, Reilly RF. Unfractionated heparin for hemodialysis: still
the best option. Semin Dial. 2010;23(5):510–515.
142. Naumnik B, Pawlak K, Myśliwiec M. Different effects of enox-
aparin and unfractionated heparin on some thrombogenesis
markers during hemodialysis: a cross-over study. Thromb Res.
2009;123(4):631–636.
143. Pettigrew M, Soltys GIM, Bell RZ, et al. Tinzaparin reduces health
care resource use for anticoagulation in hemodialysis. Hemodial
Int. 2011;15(2):273–279.
144. Leung KCW, MacRae JM. Anticoagulation in CKD and ESRD. J
Nephrol. 2019;32(5):719–731.
145. Al-Ali FS, Elsayed M, Khalifa S, et al. Successful use of a bivalirudin
treatment protocol to prevent extracorporeal thrombosis in am-
bulatory hemodialysis patients with heparin-induced thrombocy-
topenia. Hemodial Int. 2016;20(2):204–207.
146. Young G, Yonekawa KE, Nakagawa P, Blain R, Lovejoy AE, Nugent
DJ. Recombinant factor VIIa reverses the anticoagulant effects
of argatroban, bivalirudin, fondaparinux, enoxaparin, and hep-
arin as assessed ex vivo by thromboelastography. Blood Coagul
Fibrinolysis. 2007;18(6):547–553.
 |

1525139x, 2021, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/sdi.12932 by CAPES, Wiley Online Library on [31/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
CLAUDEL et al.       115

147. Sanofi-Aventis. Lovenox (Enoxaparin Sodium Injection) [package 151. Celgene. Innohep (Tinzaparin Sodium Injection) [package insert].
insert]. U.S. Food and Drug Administration. https://www.acces​ U.S. Food and Drug Administration. https://www.acces​sdata.fda.
sdata.fda.gov/drugs ​atfda_docs/label/​2 017/02016 ​4s110 ​l bl.pdf. gov/drugs​atfda_docs/label/​2008/02048​4s011​lbl.pdf. Accessed
Accessed September 26, 2020 September 26, 2020
148. Johansen KB, Balchen T. Tinzaparin and other low-molecu-

lar-weight heparins: what is the evidence for differential depen-
dence on renal clearance? Exp Hematol Oncol. 2013;2:21.
How to cite this article: Claudel SE, Miles LA, Murea M.
149. Pfizer. Fragmin (Dalteparin Sodium Injection) [package insert]. U.S.
Anticoagulation in hemodialysis: A narrative review. Semin
Food and Drug Administration. https://www.acces​ sdata.fda.
gov/drugs​atfda_docs/label/​2019/02028​7s072​lbl.pdf. Accessed Dial. 2021;34:103–115. https://doi.org/10.1111/sdi.12932
September 26, 2020
150. Barradell L, Buckley M. Nadroparin calcium: a review of its phar-
macology and clinial applications in the prevention and treatment
of thromboembolic disorders. Drugs. 1992;44:858–888.