Scholarly article on topic 'Anticoagulation in Chronic Hemodialysis: Progress Toward an Optimal Approach'

Anticoagulation in Chronic Hemodialysis: Progress Toward an Optimal Approach Academic research paper on "Clinical medicine"

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Academic research paper on topic "Anticoagulation in Chronic Hemodialysis: Progress Toward an Optimal Approach"

Reviews

Anticoagulation in Chronic Hemodialysis: Progress Toward

an Optimal Approach

Michèle Kessler,* Frédérique Moureau,! and Philippe Nguyen{

"Department of Nephrology, University Hospital, Vandœuvre-les-Nancy, France, fBaxter-Gambro, Meyzieu, France, and {Department of Hematology, University Hospital, Reims, France

ABSTRACT _

Appropriate anticoagulation for hemodialysis (HD) requires a subtle balance between under- and over-heparini-zation to prevent extracorporeal circuit (ECC) clotting and bleeding, respectively. We discuss five key issues relating to anticoagulation therapy for chronic HD in adults following a review of relevant literature published since 2002: (i) options for standardization of anticoagulation in HD settings. The major nephrology societies have issued low evidence level recommendations on this subject. Interven-tional studies have generally investigated novel low-molecular weight heparins and provided data on safety of dosing regimens that cannot readily be extrapolated to clinical practice; (ii) identification of clinical and biological parameters to aid individualization of anticoagulation

treatment. We find that use of clinical and biological monitoring of anticoagulation during HD sessions is currently not clearly defined in routine clinical practice; (iii) role of ECC elements (dialysis membrane and blood lines), dialysis modalities, and blood flow in clotting development; (iv) options to reduce or suppress systemic heparinization during HD sessions. Alternative strategies have been investigated, especially when the routine mode of anticoagulation was not suitable in patients at high risk of bleeding or was contraindicated; (v) optimization of anticoagulation therapy for the individual patient. We conclude by proposing a standardized approach to deliver anticoagulation treatment for HD based on an individualized prescription prepared according to the patient's profile and needs.

Maintaining full patency in the extracorporeal circuit (ECC) during hemodialysis (HD) sessions is a prerequisite for optimal HD quality (1-4). A complex disturbance of the coagulation system is commonly encountered in patients at the terminal stage of chronic kidney disease (CKD), leading to considerable morbidity and mortality (5). Although HD reduces the bleeding risk by the removal of ure-mic toxins, interaction between blood and artificial surfaces contributes to activate coagulation pathways. This nonphysiological environment leads to clotting on these foreign surfaces which reduces HD efficiency, shortens circuit lifetime, and increases patient blood loss, nursing workload, disposable consumption, and thus the cost of treatment (3,4).

Address correspondence to: Professor Michele Kessler, Department of Nephrology, University Hospital, 54511 Van-cteuvre-les-Nancy, France, Tel.: +33 3 83 15 31 69, Fax: +33 3 83 15 31 63, or e-mail: m.kessler@chu-nancy.fr. Seminars in Dialysis—Vol 28, No 5 (September-October) 2015 pp. 474-489 DOI: 10.1111/sCi.12380

© 2015 The Authors. Seminars in Dialysis published by Wiley Periodicals, Inc.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Appropriate anticoagulation requires a subtle balance between under- and over-heparinization to prevent ECC clotting and bleeding, respectively. HD patients are prone to prolonged bleeding episodes from dialysis fistula, as well as gastrointestinal and intracranial hemorrhage (5). Conversely, they may develop a prothrombotic status or comorbid conditions requiring oral anticoagulants or antiplat-elet agents (1,5). Of interest, the dialysis population represents the only group of patients to receive hep-arin three times per week, with a potential long-term cumulative effect associated with an increased risk of osteoporosis, aldosterone suppression and hyperkalemia, and a deterioration of lipid profile and endothelial function (2,4,6).

The objective of this article was to address the key issues on anticoagulation therapy for chronic HD in adults by presenting an overview of literature published since 2002 with regard to guidelines, clinical practices, assessment procedures, and alternative options. Key topics to be covered include the following: options for the standardization of anticoagulation in HD settings; identification of clinical and biological parameters to aid individualization of anticoagulation treatment; role of ECC elements (dialysis membrane, blood lines), dialysis modalities and blood flow in clotting development; options to reduce or suppress systemic heparinization during HD sessions; and the optimization of anticoagulation therapy for the individual patient.

Concise Search Strategy

The scope of the literature search was to cover clinical data dealing with anticoagulation for chronic HD. The search was limited to references published in English from January 2002 to August 2014.

For the search, we used the following bibliographic databases: Ovid MEDLINE, Ovid EMBASE, Ovid Evidence-Based Medicine Reviews - Cochrane Database, ACP Journal Club, Database of Abstracts of Reviews of Effects, PubMed, and Clinical and Current Controlled trials databases. We also searched the Baxter-Gambro Renal Replacement Therapies internal and private database.

The main search concepts included were as follows: HD, chronic renal dialysis; anticoagulation; unfrac-tionated or low-molecular-weight heparins (UFH or LMWH); renal therapies guidelines; adverse events; bleeding; dialyzer, dialysis membrane, blood lines, circuit clotting, dialyzer biocompatibility, home HD, nocturnal home HD, priming, vascular access patency, and single needle. Acute renal failure, continuous renal replacement therapies, pediatrics and locking solutions used in vascular access, as well as congress abstracts and posters were excluded.

The selection process relied on regular exchanges and meetings among the authors. The articles

included in this review were selected based on the analysis of the full text. Any disagreements were discussed until a consensus was reached.

The flowchart outlining the process for selecting references is presented in Fig. 1. The complete search strategy is detailed in Data S1.

Results

Options for the Standardization of Anticoagulation in HD Settings

Anticoagulation with heparin or its derivatives during HD sessions is not evidence-based and is unlikely to ever be tested in randomized clinical trials (7). The major nephrology societies have issued recommendations or position statements surrounding the prevention of ECC clotting during HD (3,4,8-15). However, observational and interven-tional studies have since been published; do they provide new approaches or raise new questions?

Recommendations by Nephrology Societies

Clinical practice guidelines on anticoagulation for chronic HD have been developed by nephrology societies in Europe, United Kingdom, United States, Canada, Australasia, and Japan (3,4,9-15).

Records screened (n = 534)

Full-text articles assessed (n = 423)

Records excluded with reasons (n = 111)

References selected for the manuscript (n = 143)

Additional searches: guidelines, clinical trials, bleeding, clotting, priming, vascular access patency, home hemodialysis, single needle, FHN references (n = 951)

Fig. 1. Flowchart outlining the process for selecting bibliographical references. FNN, Frequent Hemodialysis Network.

The Canadian Society Hemodialysis Clinical Practice Guidelines have simply stated that adequate anticoagulation may be used to increase urea clearance and possibly dialysis adequacy (14). Recommendations from the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) (4), the British Renal Association (9), the National Kidney Foundation (10-12), the Japanese Society for Dialysis Therapy (13), and the Caring for Australasians with Renal impairment (CARI) recently expanded to patients with cardiovascular diseases (KHA-CARI) (3,15) are summarized in Table 1.

The CARI guidelines have underlined the lack of clear difference between UFH and LMWH regarding HD adequacy and risk of thrombosis and hemorrhage (3). The National Kidney Foundation has highlighted limited data for LMWH in a core curriculum providing clinically relevant practical information in dialysis patients (11). The last update of the European Best Practice Guidelines (EBPG) on anticoagulation for HD advocate the use of LMWH (4), but in contrast, the British Renal Association recommend UFH as the standard anticoagulant and LMWH as an alternative agent (9).

Regarding the dosage of heparin in dialysis patients with a normal bleeding risk, the European and UK recommendations are based on a loading dose of UFH followed by a continuous infusion; no detailed dosage information for LMWH is available (many different molecules) (4,9).

Some anticoagulation strategies have been recommended for specific populations with increased bleeding risk as detailed in Table 1 (4,9-11,13,15). In Europe, regular saline flushing seems to be the preferred solution with no use of anticoagulant or a minimal dose of UFH (4,9). Regional citrate infusion is considered a complex technique which is unsuitable for routine use or should be limited to intensive care (4,9,12).

These recommendations outline the substantial heterogeneity of results available from clinical studies, and thus the low level of underlying evidence for creating clinical practice guidelines.

Data From Observational Studies (2002-2014)

Anticoagulation practices and extracorporeal thrombosis or bleeding events occurring within HD sessions were analyzed in four observational studies conducted in Germany, Spain, the United States, and China (16-19), as well as two event reports in the United States (20,21).

In a large cohort of 781 stable chronic HD patients monitored for 32 weeks in Germany, no clinically relevant clotting was observed macroscopi-cally in 97.1% of 24,117 regular HD treatments performed mainly with a loading dose of enoxaparin (70 IU/kg) (16). In a cross-sectional national survey proposed by the Task Force for Anticoagulation of the Spanish Society of Nephrology, the majority of HD units prescribed both types of heparin: UFH

(intermittent administration) and LMWH (single initial bolus), with a choice based on medical condition and ease of administration (17). Factors to consider for dose adjustment included body weight, coagulation of the dialyzer/lines and bleeding after disconnection. In the week prior to the survey, 4.4% of patients experienced bleeding episodes and 1.9% had thrombotic complications.

In a recent US cohort of 17,722 HD patients aged 67 years or older, a variety of heparin dosing schedules reflected a patient-centered decisionmaking process (18). Although most patterns in heparin dosing were linked to clinical characteristics, such as patient weight and duration of HD sessions, some remained unexplained suggesting that heparin dosing could be improved in some individuals (18). Recently, two consecutive surveys in Northern China (2007-2012) showed a favorable evolution in anticoagulation practices toward individualized management following the implementation of national blood purification standard operating procedures (19). In summary, these studies performed on a national scale highlight a large degree of heterogeneity in the criteria used when prescribing anticoagulants for HD.

Analysis of US event reports has revealed that clotting in ECC is the second most commonly reported adverse event, and identified that many adverse events and errors observed in HD units are related to omission of heparin administration (20,21). These data suggest that heparin administration should be confirmed before anticoagulant treatment is modified in cases where clotting occurs unexpectedly in a clinically stable patient.

Results From Interventional Clinical Studies (2002-2014)

A meta-analysis of 11 randomized controlled trials (RCTs) demonstrated equal efficacy and safety of anticoagulation with LMWH and UFH. However, these results should be interpreted with caution as the studies varied in terms of LMWH doses administered and dose adjustment strategies employed (22).

Seven clinical trials have evaluated the efficacy and safety of different LMWH with monitoring of ECC clotting by visual inspection, recording of bleeding episodes, and measurement of access compression times (Table 2) (23-29). Three studies including stable HD patients investigated the efficacy and safety of each LMWH with weight-based dosing regimens (tinzaparin, enoxaparin) (23-25). Two additional studies compared tinzaparin with UFH and suggested comparable safety and comparable (26) or superior efficacy of tinzaparin (27). Two other studies which compared tinzaparin with dalteparin (28), and nadroparin with enoxaparin (29), showed no significant difference.

In conclusion, most reported interventional studies were phase III or IV clinical trials investigating novel LMWH. Although these studies provided data on the safety of several LMWH dosing

TABLE 1. Recommendations on anticoagulation in hemodialysis published by five major national and international nephrology societies

Guidelines on AC in HD

European Renal Association-European Dialysis and Transplant Association (ERA-EDTA (4)

British Renal Association (9)

The National Kidney Foundation (10-12)

Caring for Australasians with Renal Impairment (CARI)

and for cardiovascular disease in dialysis patients (KHA-CARI) (3.15)

Japanese Society for Dialysis Therapy (13)

UFH or LMWH? Which dosage?

In patients with low bleeding risk

See below

See below

Guideline V.2.1: Low-dose of UFH or LMWH (Evidence level A) LTFH: in routine, loading dose is50 IU/ kg followed by a continuous infusion 800-1500 IU/hour) LMWH: see suggestions by the manufacturer; reduced dose on an individual basis for patients requiring antiplatelets or antivitamin K Guideline V.2.2: LMWHs over UFH due to Proven safety (Evidence level A) Equal efficacy (Evidence level A) Easy handling (Evidence level C.) Other benefits of LMWHs: Improved lipid profile (Evidence level B) Less hyperkalemia (Evidence level B) Less blood loss (Evidence level C.)

Guideline 7.1: UFH or LMWH

(Evidence level 1A) UFH = standard AC loading dose (unspecified) followed by a continuous infusion of 500-1500 units/ hour discontinued -30 minutes before the end of the session LMWH = alternative AC associated with lower risk of bleeding, less frequent episodes of hyperkalemia and an improved lipid profile compared with standard heparin

Most common AC is systemic heparin (11,12)

(bolus and/or incremental administration during HD); occasionally regional administration or saline flushes. In routine clinical practice, intensity of AC is not measured Alternatives: LMWH. direct thrombin inhibitors, regional citrate AC (intensive care), prostacyclin, anticoagulant-free HD with frequent saline flushes. Citrate-containing dialysate solutions (substituting citrate for acetate in the bicarbonate concentrate may reduce heparin requirements).

No recommendation (3)

a. No clear differences in HD adequacy results using UFH or LMWH (Evidence level II)

b. No differences in dialysis adequacy results using different LMWH (Evidence level II)

c. No clear difference in the risk of thrombosis or hemorrhage with LMWHs compared with standard heparins, although results of individuals studies have been quite variable (Evidence level I)

Table 1. (Continued)

Caring for Australasians with

Renal Impairment (CARI)

European Renal Association-European and for cardiovascular Japanese Society for

Guidelines on Dialysis and Transplant Association British Renal The National Kidney disease in dialysis patients Dialysis Therapy

AC in HD (ERA-EDTA (4) Association (9) Foundation (10-12) (KHA-CARI) (3.15) (13)

In patients with high bleeding risk

Guideline V.3.1: Systemic AC should be avoided (Evidence level A) Strategies (for phase immediately before and after surgery, in case of gastrointestinal blood loss): No use of AC with regular saline flushing (0.9%: 100-300 ml every 30 minutes; removal of all air from the dialyzer during priming, absolute prevention of air introduction in the ECC during HD and high blood flow rate from the beginning of HD) Regional citrate AC (a complex

technique, unsuitable for routine HD) Prostacyclin infusion (0.4-0.5 ng/kg/ minute; discontinuation of treatment if flushing, or intradialytic hypotension; disadvantage is cost) Guideline V.3.2: Regional heparinization (i.e.. heparin administration into the arterial line and protamine into the venous line) should not be performed (Evidence level A)

Guideline 7.2: Systemic AC should be avoided or kept to a minimum using a high blood flow rate, a regular flushing of the ECC with saline every 15-30 minutes or regional citrate infusion. Low-dose UFH may be used with caution in patients with intermediate risk of bleeding (Evidence level Id. Alternatively heparin may be replaced by:

a prostacyclin infusion (risk of hypotension, and expensive) or regional citrate AC (too complex for routine use. reduces the incidence of bleeding complications compared to the use of standard heparin)

Guideline 9.2.a: Cerebrovascular disease -Special considerations in dialysis patients include anticoagulation in nonvalvular atrial fibrillation: dialysis patients are at increased risk for bleeding and careful monitoring should accompany intervention (Evidence level C.) (10) AC must be based on comorbid conditions (regional methods, saline flushes, citrate infusion or citrate based dialysate) (11)

All CKD patients (eGFR < 60 ml/minute) undergoing antiplatelet or anticoagulant therapy (15)

Dose adjustment of antiplatelet and anticoagulant drugs. (Evidence level 1A)

Patients with acute coronary syndrome (15): treated as per the general population with regard to other treatments (Evidence level Id

Patients with chronic stable coronary artery disease (15): treated as per the general population with regards to other treatments (Evidence level ID)

Safety of therapy (15):

In CKD patients with eGFR <30 ml/minute: caution when using enoxaparin for ACS with a preference for dose adjustment (Evidence level IB), and glycoprotein Ilb/IIIa inhibitors (Evidence level 1A) In CKD patients at risk for. or with stable cardiovascular disease: single antiplatelet agent without an increased risk in major bleeding events (Evidence level IB) Combination of antiplatelet therapy with high-dose aspirin (325 mg) and clopidogrel or warfarin: not to be used (Evidence level IB)

Postoperative management for heart surgery in dialysis patients: If necessary, daily dialysis should be considered early after surgery. AC with a short half-life (nafamostat mesilate) Cerebral infarction: measures should be taken during administration of antithrombotic agents to prevent hemorrhagic complications such as using low-dose heparin during dialysis (Evidence level 2C. )

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regimens in selected HD patients, the results cannot be extrapolated into a real-life HD setting. Clinical practice is therefore disparate, with a wide variety of local, empirically-based therapeutic decisions being made regarding anticoagulant use in HD patients.

Identification of Clinical and Biological Parameters to Aid Individualization of Anticoagulation Treatment

Clinical Monitoring

Anticoagulation efficacy during HD sessions can be monitored by visual ECC inspection (25,27,28). Excessive transmembrane pressure as well as evidence of thrombus in the venous drip chamber (indicated by dark blood, swelling of the trap, or rising venous pressure) are common signals that indicate insufficient anticoagulation (2). In contrast, over-heparinization is suggested by a prolonged compression time at the end of the HD session (2). In a recent survey conducted in Spanish dialysis centers, the most frequently used criteria to adjust anticoagulant dose were ECC clotting (88.2% of units), bleeding of the vascular access after disconnection (75.3%), and body weight (57.6%) (17).

Biological Monitoring

The use of biological monitoring is not clearly defined in routine clinical practice. The ideal test would be a rapid bedside whole-blood test that is accurate enough for quantifying the level of anticoagulation, and identifying under- or over-heparini-zation during HD.

Different coagulation tests can be used, but their availability and the delay with obtaining results may differ from one dialysis center to another. The choice of test is dependent on the type of anticoagulant used for HD.

The activated partial thromboplastin time (aPTT) and anti-Xa measurements are currently used to monitor UFH and LMWH during HD (4). The aPTT is used with good accuracy for UFH, but is not adapted for monitoring anticoagulant effect during HD sessions as it requires a delay; its appropriateness for monitoring anticoagulant effect of LMWH during HD is also questionable (25). The determination of anti-Xa activity was used mainly to document attempts to reduce LMWH doses in clinical studies using individualized protocols (22,30). In the meta-analysis by Lim et al., therapeutic anti-Xa level for LMWH was defined over the threshold level of 0.25 IU/ml (22). Sensitivity analyses concluded that higher anti-Xa levels were associated with an increased bleeding risk.

In the recently published RHODES study using a new heparin-grafted HD membrane, heparin dose was decreased for 67% of patients during HD sessions, resulting in a lowering of anti-Xa activity by 50% (30). Successful decrease in heparin seemed to

TABLE 2. Summary of interventional clinical trials investigating extracorporeal thrombosis, bleeding events, or vascular access compression time (published between 2002 and 2014)

References

Design

Patients (HD modalities)

Anticoagulation treatment

Objective outcome measurements: clotting in ECC

Objective outcome measurements: bleeding time/bleeding episodes

Hainer et al. (23)

Bernieh et al. (24)

Vareesangthip et al. (25)

LMWH vs. LIEH

Bramham et al. (26)

Sabry et al. (27)

LMWH vs. LMWH

Beijering et al. (28)

Prospective, open-label, two-center. crossover study

Prospective, three-phase study Phase 1 (3-month): titration Phase 2 (6-month. 3479 HD sessions): safety-efficacy

Prospective, one-ami. open-label multicenter study -evaluation of one session (HENOX study)

An 8-week prospective, single-center. crossover study

A 12-month study

A 40-month prospective, multicenter. randomized, assessor-blinded study Titration'. 9 HD sessions Maintenance: 40 consecutive HD sessions

12 HD patients

Phase 1: 40 HD patients Phase 2: 54 HD patients

99 HD patients

( HD: 2-31 week, 4-5 hours)

108 patients (91 HD. 17 HDF) (HD: 3 times/week. 3-4 h)

23 HD patients

3312 HD sessions ( HD: 3 times ¡week,3-4 h )

159 chronic HD patients DALTEPARIN (n = 80) TINZAPARIN (n = 79) Followed during 5494 consecutive HD sessions (HD: 2-3 times/week, 3— 4 hours)

TINZAPARIN

2 single doses of 75 IU/kg. 2 weeks apart by 2 routes (SC on off-dialysis day. IV just before dialysis) ENOXAPARIN Phase T. Starting dose (bolus 1 mg/kg adjusted by ±10 mg) 0.43 ± 0.16 mg/ kg/HD

Phase 2\ 0.39 ± 0.15 mg/kg/HD ENOXAPARIN A single bolus of 0.7 mg/kg

UFH (8 weeks, 1489 HD sessions) 1000 IU as a bolus followed by an infusion of 500-2000 IU/hour TINZAPARIN (8 weeks, 1823 HD sessions)

bolus of 2500 IU (n = 95), increased to 5000 IU in cases of access or circuit thrombosis (n = 10). 7500 IU (n = 3) UFH (6 months. 1656 HD sessions) 5000 IU/ml as a bolus of 50 IU/kg followed by an infusion of 1000 IU/ hour

TINZAPARIN (6 months, 1656 HD sessions) starting dose calculated as 40-50% of the total UFH. adjusted by ±500 anti-Xa IU in case of clotting or bleeding

Starting dose (adjusted to obtain comparable anti-Xa activity) Optimal dose (which gave no clotting within the ECC and no bleeding complications): Adjustments of 500 or 1000 IU only if moderate or severe clotting within ECC or if relevant bleeding (1-30 dose adjustments) Mean maintenance dose (anti-Xa IU/HD

session) : DALTEPARIN: 5024 ± 2321 TINZAPARIN: 5546 ± 2395

A small amount of clotting in the dialyzer drip chamber in 1 patient (8.5% clotting) Phase 2: 0.8% clotting

Visual inspectiona clotting

LMWH: 13/1823 clotting

(0.7% clotting) UFH: 34/1489 clotting (2.2% clotting)

Visual inspectionh Less frequent clotting with LMWH vs. UFH: No air trap clotting (p = 0.04): 14 vs. 10 patients No dialvzer clotting (p = 0.001): 21 vs. 15 patients

Percentage of satisfactory, uneventful HD (score 1-2 = no clotting in dialyzer or air trap, no bleeding events) no difference between DALTEPARIN vs. TINZAPARIN: 91.8% (95%CI: 89.1-94.4%) vs. 91% (95% CI: 88.2-93.7

Bleeding episodes in 2 patients

Phase 2: 0.4% bleeding episodes

No bleeding episodes

Bleeding episodes UFH: 4 minor bleeding episodes in 3 patients LMWH: none

Bleeding episodes 3 minor bleeding with

LMWH 0 minor bleeding with UFH

Bleeding events: no difference between DALTEPARIN and TINZAPARIN Minor. 1.5% of 2629 HD in 18 TINZAPARIN patients vs. 1.4% of 2863 HD in 19 DALTEPARIN patients Major'. 1 in each group

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occur ov r th thr shold anti-Xa activity of «0.25 IU/ml. The authors proposed to me asure anti-Xa activity at th nd of som HD s ssions to identify patients who may benefit from a reduced systemic heparin dose. However, most centers do not routinely monitor anti-Xa activity as it is time-consuming and quite expensive; nevertheless, the measurement of anti-Xa levels may be useful in HD patients who are at risk of bleeding.

The anticoagulant effect of UFH has been assessed by two bedside tests (whole-blood partial thromboplastin time [WBPTT] and activated clotting time [ACT]) for anticoagulation monitoring during HD, but they are expensive and may lack accuracy as heparin doses are low (1,2). Regarding LMWH, several studies investigated the reliability of point-of-care methods for measuring their anticoagulant effect (29,31,32). A low-range activated clotting time (ACT-LR) was used in a Taiwanese study which did not conclude on the success of such monitoring (29). Addition of heparinase was used to determine anticoagulation levels with either the WBPTT or Hemochron aPTT assay; it may be used in a bedside setting as it can be completed within 10 minutes and is inexpensive (31). More recently, the Hemonox test was found as a valuable bedside test for monitoring anti-Xa activity in HD patients who received tinzaparin (32).

To identify better tools to monitor coagulation parameters in HD patients, several biomarkers have been evaluated in clinical studies including (28,3341): tissue factor pathway inhibitor (TFPI), (soluble) thrombomodulin (TM) and von Willebrand factor (vWF), three biomarkers released from the vascular endothelium; prothrombin fragment 1.2 (F 1.2), and thrombin-antithrombin complex (TAT), two markers of intravascular thrombin generation; plasminogen activator inhibitor-1 (PAI-1), the principal inhibitor of fibrinolysis; D-dimers, fibrin degradation products; and transforming growth factor-^1 (TGF-^1), a multi-functional cytokine that may act as a mediator of the pleiotropic action of heparin.

The predialysis levels of coagulation factors TFPI, TM, and vWF were significantly higher in HD patients than in healthy controls, indicating endothelial dysfunction and a prothrombotic risk (33,35,36). Both UFH and LMWH are potent stimuli of TFPI mobilization. As a direct (but absolutely untoward) consequence, TFPI stores are depleted following repeated blood anticoagulation in maintenance HD therapy (33,35-37).

UFH and LMWH may have differential effects on endothelium, as UFH but not enoxaparin caused a delayed PAI-1 and TM depletion (38). TGF-^1 appeared to be lower in patients treated with eno-xaparin compared with UFH prior to dialysis, whereas levels significantly increased during dialysis with enoxaparin but remained stable with UFH (39).

TAT was increased with LMWH in a dose-dependent manner, suggesting potential utility as a mar-

ker of thrombin neutralization by LMWH rather than excessive thrombin generation (40). However, no cut-off value could predict likelihood or severity of clotting (40).

Although these tests can aid understanding of he-mostatic disturbances in HD patients, their usefulness in routine clinical practice has not been demonstrated. Moreover, many of the tests are used in specialized laboratories and are expensive.

Role of ECC Elements (Dialysis Membrane and Blood Lines), Dialysis Modalities, and Blood Flow in Clotting Development

The passage of blood through the ECC during HD causes turbulent blood flow, high shear stress, and interaction of blood components with artificial surfaces (needles or catheters, blood lines, and dialysis membrane) as well as blood-air contact in air-detection and drip chambers (1,2). Further risk factors for premature clotting in the ECC are inadequate vascular access and specific circuit related factors such as low blood flow, high hematocrit, blood transfusions, and inflammatory state (1).

Ideal System to Optimize Anticoagulation Therapy

ECC life is influenced by many factors. The surface area of the dialysis membrane in contact with blood, about 20 times larger than the inner surface area of blood lines, is the main trigger of the coagulation cascade during extracorporeal circulation. Dialysis membrane characteristics have been improved over time to increase overall hemocompatibility and reduce thrombogenicity. Numerous attempts have been made to immobilize heparin on various membrane polymers or tubing systems in order to mimic the thromboresistant properties of vascular endothe-lium. To preserve the activity of heparin, its high affinity for antithrombin binding sites must be unaffected by the grafting process (42).

Heparin was first coated on a hemophan membrane after a cellulose membrane was modified by the addition of a positively charged N, N-diethyl-amino-ethyl (DEAE) group to bind the negatively charged heparin contained in the ECC priming solution (43). In contrast, cellulose acetate and polysulfone membranes are unable to bind heparin (44). The progressive replacement of cellulosic dialysis membranes with synthetic membranes and the lack of sufficient clinical evidence have halted further developments in this field. Physico-chemical methods to functionalize the surface of polysulfone membranes with covalent binding of heparin have recently been proposed (45). Extensive research was conducted on the hydrophilic AN69 membrane (copolymer of acrylonitrile and sodium methallyl sulfonate). The original AN69 polymer is functionalized at the blood contacting surface by polyethyleneimine polycation which prevents the activation of coagulation contact-phase, reduces

adsorption of fibrinogen and allows the coating of heparin during the priming with heparin solution (AN69ST membrane) or its grafting during the dia-lyzer manufacturing through multipoint ionic binding with high chemical and biological stability (HeprAN membrane) (46).

Little is known about the contribution of blood lines to the thrombotic process. Circuits reducing blood-air interface and turbulence areas may prevent clotting; an ideal dialysis circuit would have a single blood path through tubing of the same internal diameter with no joints and no areas of narrowed lumen diameter (47). As shown in the RHODES study, signs of clotting were primarily observed in blood lines (57% of cases) or both in dialyzer and blood lines (34%) when the systemic anticoagulation was reduced (30).

In clinical practice, the blood flow should be as high as possible (>300 ml/minute), especially with dialyzers having large surface areas as recommended by manufacturers. Premature clotting may be associated with the hemoconcentration from excessive recirculation, the reductions in blood flow required with small gauge access needles or significant venous or arterial stenosis, and by repeated alarms and interruption of blood flow. The quality of circuit degassing should be optimal with special attention paid to remove air from the dialyzer and to properly prime the heparin infusion line (47). Single-needle dialysis with alternating "to and from" blood flow or using a needle with two inner cannu-las can be used for specific situations (e.g., temporary problems with vascular access or native fistula maturation) but requires full anticoagulation as the process may activate coagulation (48).

Ideal Dialysis Modalities to Prevent Clotting During HD

High-flux membranes may require higher doses of LMWH than low-flux membranes to ensure adequate anticoagulation during HD (49). A large ultrafiltration volume in predilution hemofiltration and predilution hemodiafiltration using a polysul-fone membrane increases ECC procoagulatory activity compared with high-flux HD with similar treatment times (50). Post and mid-dilution fluid replacement is also known to generate hemoconcen-tration in the filter, with increased risk of clotting (47). A decreased anti-Xa activity reflecting a decrease in anticoagulant activity of enoxaparin was demonstrated in on-line postdilution hemodiafiltra-tion compared with HD (51).

Patients on long dialysis are mostly treated with a reduced blood flow which may lead to ECC clotting and subsequent escalation of heparin dose. Those undergoing short and frequent dialysis requires daily administration of heparin which may lead to accumulation when LMWH are used, due to their pharmacokinetic characteristics (52). However, anticoagulation in these particular HD settings has not been thoroughly studied.

Options to Reduce or Suppress Systemic Heparinization During HD Sessions

A number of alternative strategies to systemic heparinization have been investigated to improve HD performance and prolong filter life, especially when systemic anticoagulation is not desirable in patients at high risk of bleeding or contraindicated in heparin-induced thrombocytopenia (HIT) settings. Regional heparinization, use of low-dose he-parin regimens, rinsing of the circuit with saline solution as well as use of dialyzers with membrane synthetically modified to enhance heparin binding have been proposed for reducing or suppressing heparinization during HD sessions (2,53,54).

Regional Anticoagulation

The earliest approach to anticoagulation for patients at high risk of bleeding was regional heparinization of the dialysis circuit (4,55). Based on the ability of protamine to neutralize the anticoagulant effect of heparin, this technically complex method has been largely abandoned in favor of other methods such as use of low-dose heparin or heparin-free dialysis.

The use of prostacyclin, an endogenous prosta-glandin which has an antiaggregatory effect on platelets, is another option for regional anticoagulation as it is safe in patients with increased bleeding risks (4,55,56). However, use of prostacyclin has been limited due to vasodilatory effects (hypotension, flushing and headache), gastrointestinal complaints, and high drug costs.

In regional citrate anticoagulation (RCA) (57-68), citrate chelates calcium and blocks the coagulation cascade by lowering the ionized calcium level in ECC, which can be further reduced by using a calcium-free dialysate (54,55,57). RCA is cumbersome and time consuming, given that monitoring of ionized calcium is mandatory to avoid hypo- and hypercalcemia. Overall costs coupled with complexity are barriers to widespread use (54), although some simplified procedures have since been developed (5860). In addition, citrate can cause metabolic derangements such as metabolic alkalosis when it is metabolized to bicarbonate and metabolic acidosis when it is not metabolized (55,61).

An alternative based on the use of a citrate-enriched dialysate containing a much lower concentration of citric acid than required for RCA was recently investigated, but required individualized optimization with additional anticoagulation in a significant proportion of patients (65-68).

Anticoagulant-Free Dialysis

In daily practice, intermittent saline flushes (bolus of 100-200 ml injected every 15-60 minutes) or continuous saline infusion are used in place of anticoagulants to counteract increased risk of clotting in anticoagulant-free HD sessions. In a recent retrospective cohort including 12,468 HD patients aged

67 and over without a recent history of warfarin, use of heparin-free dialysis was infrequent in the United States (6.7% of patients) (69). Saline procedures require one-to-one nursing which increases the cost of the dialysis, making it a poor choice for long-term outpatient use (4,54). Furthermore, intermittent saline flushes did not alleviate clotting and led to premature termination of HD sessions (70). In a recent single-center, controlled, randomized nonblind study including 50 heparin-free HD treatments, patients with continuous saline infusion (200 ml/hour throughout the duration of HD session) were less likely to have clotted ECC than those with intermittent saline flushing (100 ml every 30 minutes while occluding the blood inlet line) (24% vs. 48% of clotted ECC, p = 0.04) (70), whereas a posthoc analysis of the HepZero study showed that saline flushes achieved higher success than the predilution continuous saline method (71). In a 7-month prospective study including 266 patients at risk of bleeding and analyzing data from 1224 anticoagulant-free HD sessions using a modified way of ECC preparation (minimizing the blood-air interface, heparin priming and negligible saline flushing of 50 ml/hour), the incidence of failure was 3.68%, and the probability of failure decreased as the blood flow increased and vice versa (72).

Role for Heparin-Coated Dialysis Membranes in Low-Dose Heparin or Anticoagulation-Free Dialysis

Strategies aimed at reducing exposure to numerous side effects of heparin have been developed in aging end-stage renal disease patients with multiple comorbidities. In order to reduce the need for systemic anticoagulation, procedures for extemporaneously rinsing ECC with a heparin solution prior to a HD session were applied with dialysis membranes that allow adsorption of heparin to their blood contacting surface (Hemophan and AN69ST).

In a prospective crossover study, HD was performed in patients at risk of bleeding using heparin-bound hemophan obtained by the recirculation of a heparin solution for 1 hour (43). Heparin concentration increased and aPTT extended 15 minutes after initiation of dialysis, and 7% of sessions resulted in severe clotting (43). Regarding the high-flux heparin-binding polyacrylonitrile membrane (AN69ST), several studies investigated biocompati-bility and showed that adequate heparinized priming at bedside (rinsed with 2 l heparinized saline 5000 IU/l, then flushed out by 1 l 0.9% saline, before connecting the venous line) allowed HD sessions without additional systemic anticoagulation (73-76). Some clinical studies comparing the AN69ST with other high-flux membranes such as polysulfone in heparin-free dialysis (77,78) or with low-dose heparin (79) failed to find any significant difference. Anticoagulation-free dialysis using the AN69ST membrane was investigated through a

crossover n-of-1 trial and compared with intermittent saline flushes and continuous saline infusion in 46 patients undergoing 224 HD sessions (80). Hepa-rin adsorption on the dialysis membrane was associated with a significant reduction in the need to interrupt the dialysis session due to clotting events (odds ratio 0.3). It was also associated with higher odds for performing 3-hour dialysis sessions and for having complete blood restitution.

The HeprAN membrane, the latest evolution of the polyacrylonitrile membrane with heparin grafted in production, was evaluated in the proof-of-con-cept prospective RHODES study concerning systemic heparinization reduction (30). A stepwise reduction in the regular heparin dose (UFH or LMWH) was performed in 45 HD patients until early signs of clotting. Heparin dose was significantly decreased for 67% of patients resulting in a 50% lowering of anti-Xa activity.

More recently, in the multinational randomized controlled HepZero study including 251 heparin-free HD patients, the success rate of heparin-free HD sessions was significantly higher with the hepa-rin-grafted membrane than with the current stan-dard-of-care using either saline flushes or predilution (68.5% vs. 50.4%, p = 0.003) (71).

Alternative Anticoagulants to Heparin

In the last decade, several new anticoagulants have been developed for HD patients (55,81-86). They can either directly inhibit thrombin or slow down thrombin generation by blocking factor Xa. Both types of molecules require careful monitoring and frequent individualized dose adjustments (86).

Danaparoid sodium, a mixture of glycosaminogly-cans with a predominant anti-Xa activity (anti-Xa/ anti-IIa ratio: 20-25), has been extensively used in patients with HIT (54,83). As danaparoid is eliminated primarily through the kidney, it is mandatory to adapt the dose (61). European guidelines advocate that patients with confirmed HIT can be routinely he-modialyzed with danaparoid (4). Danaparoid was withdrawn from US and UK markets around 2006, but is still available in Canada, Japan, and Europe (86).

The synthetic pentasaccharide, fondaparinux, is a highly selective, indirect inhibitor of factor Xa. Although contraindicated in severe renal insufficiency, it has been used as anticoagulant with varying degrees of success in HD patients with HIT (83,87-91). To date, fondaparinux is not licensed for the treatment of HIT (61).

Hirudin and its recombinant forms are strong and direct inhibitors of thrombin. Lepirudin was the first one to be licensed for treating patients with HIT, but its production ceased in 2012 (55,85,86). Bivalirudin use in HD patients needs to be confirmed (55,85,86). The usefulness and tolerability of polyethylene glycol (PEG)-hirudin, a tight-binding specific bifunctional thrombin inhibitor, was evaluated at the dose ranging from 600 to 1000 ng/ml in some HD patients (92,93).

Dermatan sulfate, a natural glycosaminoglycan that selectively but indirectly inhibits thrombin, offered a predictable anticoagulant effect during 7254 HD sessions compared with UFH during 5707 HD sessions in 102 regular HD patients (94).

Argatroban (a synthetic, arginine-derived, site-directed thrombin inhibitor, predominantly metabolized in liver) has been proposed as a safe and adequate anticoagulant to enable HD sessions in patients with HIT (95-101). However, the precise dose and administration method of argatroban for dialysis patients is unknown. In patients at high risk of bleeding, HD sessions using a very low dose of argatroban into saline flushes (0.08 mg per HD session) showed a good efficiency in preventing clotting in the ECC compared with heparin-free HD sessions (100).

Anticoagulation for HD remains challenging in HIT patients and requires a multidisciplinary approach as well as well-standardized procedures.

Optimization of Anticoagulation Therapy for the Individual Patient

An efficient and safe HD session requires that optimal anticoagulation dosing is received and is appropriate for the individual patient. Such a patient-specific therapeutic approach highlights the need for defining individual patient profiles as a first step before individual tailoring of anticoagulant therapy.

Patients at High Risk of Bleeding

Patients with intercurrent events, such as an acute bleeding, a recent cranial trauma, pericarditis, planned surgery or postoperative settings, recent biopsies, percutaneous coronary intervention, gastric ulcer, and esophageal varicose, are prone to a high risk of bleeding complications (102,103). Moreover, the risk of gastrointestinal bleeding should also be taken into account when making decisions about prescribing other medications such as anti-inflammatory drugs and glucocorticoids (104).

The incidence rate of upper gastrointestinal bleeding in a HD cohort (42.01 per 1000 person-years) was significantly higher than a control cohort (27.39 per 1000 person-years) in a multivariate data analysis from the Taiwan National Health Insurance Research Database (105). Additionally, a history of recent gastrointestinal bleeding in the past 12 months strongly predicted a future major bleeding event in the observational Dialysis Outcomes and Practice Patterns Study (DOPPS) (106).

HD treatment should be based on anticoagulant-free dialysis in patients at high risk of bleeding.

Patients Requiring Antithrombotic Therapies

Antithrombotic agents such as oral anticoagulants and antiplatelet agents are widely used in HD patients for the prevention of thromboembolic events, such as stroke in atrial fibrillation and

venous thromboembolism (106-121), as well as the secondary prevention of myocardial infarction and cardiovascular death, respectively (116,117,120).

Oral Anticoagulants. Atrial fibrillation is an increasingly common condition in HD patients, particularly in the elderly, with a prevalence ranging from 7 to 27% which is 10- to 20-fold higher than in the general population aged 60 and over (106112). Furthermore, atrial fibrillation is associated with an elevated risk of adverse clinical outcomes in HD patients (113-115).

There is no consensus on the use of oral anticoagulants in HD patients with atrial fibrillation so prescription rates for oral anticoagulants are highly variable (0.3-25%) (107,108,110,116-118). The risk of bleeding episodes in HD patients who received warfarin was approximately twice as high as in those not receiving oral anticoagulants, and increased from 3- to 10-fold compared with patients receiving warfarin in the general population (119). The incidence of major bleeding episodes in HD patients was 2.5% per person-year and increased to 3.1% per person-year of warfarin exposure (120).

Conversely, two studies suggested that warfarin use may not significantly increase the risk of bleeding (121,122). Nephrologists are therefore faced with concerns about the risk—benefit assessment before prescribing oral anticoagulants and/or additional anticoagulation to prevent clotting during the HD session without additional bleeding complications in such patients (123). The presence of a high risk of bleeding could lead nephrologists to refuse oral anticoagulant treatment in HD patients (112). Moreover, there is contradictory literature on the need for additional systemic heparin during HD sessions in patients receiving oral anticoagulation (118,124).

Thet et al. recently proposed that bleeding assessment tools, such as HEMOR2RHAGES and HAS-BLED, developed to determine bleeding risk in the general population with atrial fibrillation could be useful in daily clinical practice to aid decisions regarding warfarin in HD patients with atrial fibrillation. However, these tools need to be validated in this patient population (110). The CHADS2 score, in contrast, is not useful for HD patients (112).

Antiplatelet Agents. Although guidelines for anti-thrombotic agent use are well established in the general population, the benefits and risks of antiplat-elet agents remain unclear in HD patients (125,126). The use of antiplatelet therapy in HD patients varied widely from 3 to 25% among countries in the DOPPS (116). Additionally, nephrologists use antiplatelet therapy to prevent vascular access failure; randomized studies suggest some value for its use with Fistulas but much less evidence for any benefit in prolonging graft function (127).

Bleeding events under antiplatelet therapy were more frequent in HD patients than in non-HD patients, especially in those with diabetes mellitus (128). In a systemic review of bleeding rates asso-

ciated with long-term antiplatelet use in HD patients, the bleeding risk seemed to be increased in patients treated with dual-antiplatelet therapy or with aspirin alone, but not in those receiving another single antiplatelet agent (129).

In conclusion, these findings raise concerns about the benefits and risks of oral anticoagulant and an-tiplatelet use, singly or in combination, in HD patients, and clinicians should exercise caution before prescribing such medications (115).

Patients With Heparin-Induced Thrombocytopenia Type 2

The incidence of HIT is reported to be approximately 3-5% due to UFH compared with <1% for LMWH (130). In dialysis patients, prevalence of HIT has been reported to vary from 0 to 12% (2,131,132). A 5-10% thrombosis rate per day over the first few days of HIT, and a 50% cumulative risk over 30 days have been reported (84-86).

Management of HIT in HD patients involves a three-pronged approach, including the immediate discontinuation of all heparin exposure as soon as HIT is strongly suspected, initiation of alternative systemic anticoagulant if required, and eventual transition to an oral anticoagulant (2,81-86). Future heparin administration must still be avoided while patients test positive for HIT antibodies which may persist for several years (2,76). The reintroduction of heparin in these patients is still under debate (131).

Individual Tailoring of Anticoagulant Therapy

In light of these individual patient profiles, optimization of anticoagulation therapy for the individual HD patient necessitates a standardized approach to delivering anticoagulation treatment with an individualized prescription depending on the patient's profile and needs that we have summarized in a clinical decision tree (Fig. 2).

After ruling out HIT settings, estimating the individual risk of bleeding is the first step. For the majority of stable HD patients with a low risk of bleeding, systemic heparinization using UFH or LMWH remains the mainstay of anticoagulation therapy during the course of HD sessions, according to clinical practice guidelines issued from the major nephrology societies.

As several recent studies have shown that lowering heparin doses may allow successful HD sessions with no clotting, heparin dosing should be, however, determined using stepwise anticoagulant titration or antiXa measurement in order to find the minimally effective heparin dose for each patient and reduce risk of accumulation.

Physicians should be aware that any stable HD patient can switch from a low-risk to a high-risk bleeding situation or a prothrombotic status at any time. In such situations, anticoagulation therapy should be therefore adjusted with careful consideration of the individual risk-benefit ratio or switched

Fig. 2. Optimal approach to deliver systemic anticoagulation therapy in stable hemodialysis patients. APA, antiplatelet agents; AC, anticoagulant; AE, adverse events; HD, hemodialysis; HIT, heparin-induced thrombocytopenia; LMWH, low-molecular-weight heparin; PCI, percutaneous coronary intervention; UFH, unfractionated heparin.

in favor of anticoagulant-free alternatives, particularly in patients at high-risk of bleeding as shown in Fig. 2. Additionally, an intercurrent clotting episode should alert physicians and may necessitate a careful increase in heparin dose after excluding any error of heparin administration or any other clot-promoting factor related to the patient (high inflammatory status, high hematocrit or blood transfusion) and/or the delivery of dialysis (a too low blood flow, a convec-tive modality or a vascular access malfunction).

Conclusion

Anticoagulant management in HD patients is not evidence-based, as there is substantial heterogeneity between results from clinical studies and current guidelines, and can therefore be challenged. Individual tailoring of anticoagulant treatment at any time remains difficult in daily practice. Given that a routine bedside biological monitoring protocol is not currently available, dialysis units have developed their own standard strategies to avoid both bleeding and clotting by pragmatically and empirically adjusting doses according to ECC visual inspection and monitoring compression time at needle puncture site at the end of HD sessions.

Based on a review of literature published since the last update of EBPG guidelines on anticoagulation

for HD, we have devised a standardized approach to deliver anticoagulation therapy based on an individualized prescription that depends on the patient's profile and needs. We have also developed a clinical decision tree which may guide therapeutic decision-making by nephrologists.

Future research should be directed toward point-of-care biological monitoring for easily assessing an individual's bleeding risk, to deliver a patient-optimized anticoagulation prescription according to he-mostasis phenotype or an acute situation that increases the risk of bleeding or clotting. Further studies are needed to determine safe and efficacious dosing regimens for newer oral anticoagulant agents and appropriate monitoring strategies in HD patients, as well as to develop new synthetic anticoagulants or antithrombogenic materials to mimic the activity of heparin. Additionally, we see an urgent need for physiopathological prospective studies that focus on clinically useful markers, and more integra-tive tools that mimic what happens in the blood.

Acknowledgments

This work was sponsored by Baxter-Gambro. The authors thank Dominique Filliere (Baxter-Gam-bro) for literature search and Brigitte Bourdillat for the manuscript editing.

Disclosure

Responsibility for the selection procedure of articles included in this review and commentaries lies with the authors MK, FM and PN. All authors gave their final approval regarding submission for publication. All authors read and approved the final manuscript.

References

1. Fischer KG: Essentials of anticoagulation in hemodialysis. Hemodial Int 11:178-189, 2007

2. Suranyi M, Chow JSF: Review: anticoagulation for haemodialysis. Nephrology 15:386-392, 2010

3. Kerr P, Perkovic V, Petrie J, Agar J, Disney A: Caring for Australians with Renal Impairment (CARI): dialysis adequacy (HD) guidelines. Nephrology 10:S61-S80, 2005

4. European Best Practice Guidelines Expert Group on Hemodialysis: European Renal association: Section V: chronic intermittent hae-modialysis and prevention of clotting in the extracorporeal system. Nephrol Dial Transplant 17:63-71, 2002

5. Jalal DI, Chonchol M, Targher G: Disorders of hemostasis associated with chronic kidney disease. Semin Thromb Hemost 36:34-40, 2010

6. Lavainne F, Meffray E, Pepper R, Neel M, Delcroix C, Salama A, Fakhouri F: Heparin use during dialysis sessions induces an increase in the antiangiogenic factor soluble Flt1. Nephrol Dial Transplant 29:1225-1231, 2014

7. Zoccali C, Abramowicz D, Cannata-Andia JB, Cochat P, Covic A, Eckardt KU, Fouque D, Heimburger O, McLeod A, Lindley E, Locatelli F, Spasovski G, Tattersall J, Van Biesen W, Wanner C, Vanholder R: European best practice quo vadis? From European Best Practice Guidelines (EBPG) to European Renal Best Practice (ERBP). Nephrol Dial Transplant 23:2162-2166, 2008

8. Vanbelleghem H, Vanholder R, Levin NW, Becker G, Craig JC, Ito S, Lau J, Locatelli F, Zoccali C, Solez K, Hales M, Lameire N, Ek-noyan G: The kidney disease: improving global outcomes website: comparison of guidelines as a tool for harmonization. Kidney Int 71:1054—1061, 2007

9. Mactier R, Hoenich N, Breen C: Renal Association Clinical Practice Guideline on Haemodialysis. Nephron Clin Pract 118:c241-c286, 2011

10. K/DOQI Workgroup: K/DOQI Clinical practice guidelines for cardiovascular disease in dialysis patients. Am J Kidney Dis 45:S1-S153, 2005

11. Ikizler TA, Schulman G: Hemodialysis: techniques and prescription.

Am J Kidney Dis 46:976-981, 2005

12. Golper T, Fissell R, Fissell W, Hartle M, Sanders L, Schulman G: Hemodialysis: core curriculum 2014. Am J Kidney Dis 63:153-163, 2014

13. Hirakata H, Nitta K, Inaba M, Shoji T, Fujii H, Kobayashi S, Tabei K, Joki N, Hase H, Nishimura M, Ozaki S, Ikari Y, Kumada Y, Tsuruya K, Fujimoto S, Inoue T, Yokoi H, Hirata S, Shimam-oto K, Kugiyama K, Akiba T, Iseki K, Tsubakihara Y, Tomo T, Akizawa T: Japanese Society for Dialysis Therapy Guidelines for management of cardiovascular diseases in patients on chronic he-modialysis. Ther Apher Dial 16:387-435, 2012

14. Jindal K, Chan CT, Deziel C, Hirsch D, Soroka S, Tonelli M, Culleton B: Chapter 1: Hemodialysis adequacy in adults. J Am Soc Nephrol 17:S1-S7, 2006

15. Pilmore H, Dogra G, Roberts M, Lambers Heerspink H, Ninomiya T, Huxley R, Perkovic V: KHA-CARI guideline: cardiovascular disease in patients with chronic kidney disease. Nephrology 19:3-10, 2014

16. 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-certification study. Kidney Blood Press Res 27:211-217, 2004

17. Herrero-Calvo JA, Gonzales-Parra E, Perez-Garcia R, Tornero-Molina F: Spanish study of anticoagulation in haemodialysis. Nefrolo-gia 32:143-152, 2012

18. Shen JI, Montez-Rath ME, Mitani AA, Erickson KF, Winkelmayer WC: Correlates and variance decomposition analysis of heparin dosing for maintenance hemodialysis in older US patients. Pharma-coepidemiol Drug Saf 23:515-525, 2014

19. Huang Q, Sun X, Lin H, Zhang Z, Hao L, Yao L, Li J, Zhao D, Wang Y, Zhu H, Chen X: Current status of anticoagulant treatments and improvements for hemodialysis patients in northern Chinese cities: a five-year comparative study. Chin Med J 127:28812887, 2014

20. Holley JL: A descriptive report of errors and adverse events in chronic hemodialysis units. Nephrol News Issues 20:57-58, 60-61, 63 passim, 2006

21. Pennsylvania Patient Safety Authority: Hemodialysis administration: strategies to ensure safe patient care. Pennsylvania Patient Safety Advisory 7:87-96, 2010

22. Lim W, Cook DJ, Crowther MA: Safety and efficacy of low molecular weight heparins for hemodialysis in patients with end-stage renal failure: a meta-analysis of randomized trials. J Am Soc Neph-rol 15:3192-3206, 2004

23. Hainer JW, Sherrard DJ, Swan SK, Barrett JS, Assaid CA, Fossler MJ, Cox DS, Williams RM, Pittenger AL, Stephenson CA, Hua TA: Intravenous and subcutaneous weight-based dosing of the low molecular weight heparin tinzaparin (Innohep) in end-stage renal disease patients undergoing chronic hemodialysis. Am J Kidney Dis 40:531-538, 2002

24. Bernieh B, Boobes Y, Hakim MR, Abouchacra S, Dastoor H: Long-term use of low-molecular-weight heparin in hemodialysis patients: a 7-year experience. Blood Purif 27:242-245, 2009

25. Vareesangthip K, Thitiarchakul S, Kanjanakul I, Krairittichai U, Bannachak D: Efficacy and safety of enoxaparin during hemodialy-sis: results from the HENOX study. J Med Assoc Thai 94:21-26, 2011

26. Bramham K, Varrier M, Asgari E, Makanjuola D: Comparison of tinzaparin and unfractionated heparin as anticoagulation on hae-modialysis: equal safety, efficacy and economical parity. Nephron Clin Pract 110:c107-c113, 2008

27. Sabry A, Taha M, Nada M, Al Fawzan F, Alsaran K: Anticoagulation therapy during haemodialysis: a comparative study between two heparin regimens. Blood Coagul Fibrinolysis 20:57-62, 2009

28. Beijering RJR, ten Cate H, Stevens P, Vanholder R, Van Dorp W, van Olden R, Wickström B, Sprogel P, ten Cate J: Randomised long-term comparison of tinzaparin and dalteparin in haemodialy-sis. Clin Drug Invest 23:85-97, 2003

29. Chuang FR, Chen TC, Lee CH, Ng HY, Wang IK, Chang HW, Chuang PH, Wu CH, Yang CC, Su YJ: Clinical safety and anticoagulation efficacy of low-molecular-weight heparins in chronic hemodialysis patients: a single medical center experience. Ren Fail 33:990-997, 2011

30. Kessler M, Gangemi C, Gutierrez Martones A, Lacombe JL, Krier-Coudert MJ, Galland R, Kielstein J, Moureau F, Loughraieb N: Heparin-grafted dialysis membrane allows minimal systemic anticoagulation in regular hemodialysis patients: a prospective proof-of-concept study. Hemodial Int 17:282-293, 2013

31. Inchiosa MA, Pothula S, Kubal K, Sanchala VT, Navarro I: Toward development of a point-of-care assay of enoxaparin anticoagulant activity in whole blood. J Thromb Thrombolysis 32:47-53, 2011

32. Pauwels R, Devreese K, Van Biesen W, Eloot S, Glorieux G, Vanholder R, Dhondt A: Nephrol Dial Transplant 29:1092-1096, 2014

33. Sioulis A, Malindretos P, Makedou A, Makris P, Grekas D: Coagulation factors as biological risk markers of endothelial dysfunction. Association with the thrombotic episodes of chronic hemodialysis patients. Hippokratia 13:237-241, 2009

34. Yu A, Egberg N, Jacobson SH: Haemostatic complications in hae-modialysis patients: effect of type of vascular access and dialysis filter. Scand J Clin Lab Invest 63:127-134, 2003

35. Naumnik B, Borawski J, Mysliwiec M: Different effects of enoxapa-rin and unfractionated heparin on extrinsic blood coagulation during haemodialysis: a prospective study. Nephrol Dial Transplant 18:1376-1382, 2003

36. Stoöbe J, Siegemund A, Achenbach H, Preiss C, Preiss R: Evaluation of the pharmacokinetics of dalteparin in patients with renal insufficiency. Int J Clin Pharmacol Ther 44:455-465, 2006

37. Naumnik B, Rydzewska-Rosolowska A, Mysliwiec M: Different effects of enoxaparin, nadroparin, and dalteparin on plasma TFPI during hemodialysis: a prospective crossover randomized study. Clin Appl Thromb Hemost 17:480-486, 2011

38. Naumnik B, Pawlak K, Mysliwiec M: Unfractionated heparin but not enoxaparin causes delayed plasma PAI-1 depletion in hemo-dialysis patients: a prospective study. Clin Appl Thromb Hemost 15:84-91, 2009

39. Naumnik B, Borawski J, Pawlak K, Mysliwiec M: Enoxaparin but not unfractionated heparin causes a dose-dependent increase in plasma TGF-^1 during haemodialysis: a cross-over study. Nephrol Dial Transplant 22:1690-1696, 2007

40. Schoött U, Nilsson LG, Broman M, Engstroöm M: Monitoring of low molecular weight heparin anticoagulation during haemodialysis with a Sonoclot Analyzer. Perfusion 25:191-196, 2010

41. Brophy DF, Martin EJ, Best AM, Gehr WB, Carr ME: Antifactor Xa activity correlates to thrombin generation time, platelet contractile force and clot elastic modulus following ex vivo enoxaparin exposure in patients with and without renal dysfunction. J Thromb Haemost 2:1299-1304, 2004

42. Frank RD, Müller U, Lanzmich R, Groeger C, Floege J: Anticoagulant-free Genius haemodialysis using low molecular weight heparin-coated circuits. Nephrol Dial Transplant 21:1013-1018, 2006

43. Lee KB, Kim B, Lee YH, Yoon SJ, Kang WH, Huh W, Kim DJ, Oh HY, Kim YG: Hemodialysis using heparin-bound hemophan in patients at risk of bleeding. Nephron Clin Pract 97:c5-c10, 2004

44. Chanard J, Lavaud S, Paris B, Toure F, Rieu P, Renaux JL, Thomas M: Assessment of heparin binding to the AN69 ST hemodialysis membrane: I. Preclinical studies. ASAIO J 51:42-347, 2005

45. Ren X, Xu L, Xu J, Zhu P, Zuo L, Wei S: Immobilized heparin and its anti-coagulation effect on polysulfone membrane surface. J Biomater Sci Polym 24:1707-1720, 2013

46. Thomas M, Moriyama K, Ledebo I: AN69: evolution of the world's first high permeability membrane. Contrib Nephrol 173:119-129, 2011

47. Davenport A: Optimization of heparin anticoagulation for hemodialysis. Hemodial Int 15:S43-S48, 2011

48. Buturovic-Ponikvar J, Gubensek J, Ponikvar R: Citrate anticoagulation for single-needle hemodialysis: safety and efficacy. Ther Apher Dial 9:237-240, 2005

49. McMahon LP, Chester K, Walker RG: Effects of different dialysis membranes on serum concentrations of epoetin alfa, darbepoetin alfa, enoxaparin, and iron sucrose during dialysis. Am J Kidney Dis 44:509-516, 2004

50. Klingel R, Schaefer M, Schwarting A, Himmelsbach F, Altes U, Uhlenbusch-Körwer I, Hafner G: Comparative analysis of procoag-ulatory activity of haemodialysis, haemofiltration and haemodiafil-tration with a polysulfone membrane (APS) and with different modes of enoxaparin anticoagulation. Nephrol Dial Transplant 19:164-170, 2004

51. Sombolos KI, Fragia TK, Gionanlis LC, Veneti PE, Bamichas GI, Fragidis SK, Georgoulis IE, Natse TA: The anticoagulant activity of enoxaparin sodium during on-line hemodiafiltration and conventional hemodialysis. Hemodial Int 13:43-47, 2009

52. Polkinghorne KR, McMahon LP, Becker GJ: Pharmacokinetic studies of dalteparin (Fragmin), enoxaparin (Clexane), and danapa-roid sodium (Orgaran) in stable chronic hemodialysis patients. Am J Kidney Dis 40:990-995, 2002

53. Cronin RE, Reilly RF: Unfractionated heparin for hemodialysis: still the best option. Semin Dial 23:510-515, 2010

54. Shen JI, Winkelmayer WC: Use and safety of unfractionated hepa-rin for anticoagulation during maintenance hemodialysis. Am J Kidney Dis 60:473-486, 2012

55. Davenport A: What are the anticoagulation options for intermittent hemodialysis? Nat Rev Nephrol 7:499-508, 2011

56. Davenport A: What are the options for anticoagulation needs in dialysis for patients with heparin-induced thrombocytopenia? Semin Dial 24:382-385, 2011

57. Buturovic-Ponikvar J, Gubensek J, Ponikvar R: Regional citrate anticoagulation for hemodialysis: calcium-free vs. calcium containing dialysate- a randomized trial. Int J Artif Organs 31:418-424, 2008

58. Szamosfalvi B, Frinak S, Yee J: Automated regional citrate anticoagulation: technological barriers and possible solutions. Blood Purif 29:204-209, 2010

59. Strobl K, Hartmann J, Wallner M, Brandl M, Falkenhagen D: A target-oriented algorithm for citrate-calcium anticoagulation in clinical practice. Blood Purif 36:136-145, 2013

60. Buturovic J, Gubensek J, Cerne D, Ponikvar R: Standard citrate versus sequential citrate/anticoagulation-free anticoagulation during hemodialysis: a randomized trial. Artif Organs 32:77-81, 2008

61. Lutz J, Menke J, Sollinger D, Schinzel H, Thuörmel K: Haemostasis in chronic kidney disease. Nephrol Dial Tranplant 29:29-40, 2014

62. Evenepoel P, Dejagere T, Verhamme P, Claes K, Kuypers D, Bammens B, Vanrenterghem Y: Heparin-coated polyacrylonitrile membrane versus regional citrate anticoagulation: a prospective randomized study of 2 anticoagulation strategies in patients at risk of bleeding. Am J Kidney Dis 49:642-649, 2007

63. Gubensek J, Buturovic-Ponikvar J, Ponikvar R: Regional citrate anticoagulation for single-needle hemodialysis: a prospective clinical study. Blood Purif25:454-456, 2007

64. Ridel C, Mercadal L, Bene B, Hamani A, Deray G, Petitclerc T: Regional citrate anticoagulation during hemodialysis. Blood Purif 23:473-480, 2005

65. Cheng Y, Yu A, Tsang K, Shah DH, Kjellstrand CM, Wong SM, Lau WY, Hau LM, Ing TS: Anticoagulation during haemodialysis using a citrate-enriched dialysate: a feasibility study. Nephrol Dial Transplant 26:641-646, 2011

66. Stegmayr B, Jonsson P, Mahmood D: A significant proportion of patients treated with citrate containing dialysate need additional anticoagulation. Int J Artif Organs 36:1-6, 2013

67. Sands J, Kotanko P, Segal J, Ho CH, Usvat L, Young A, Carter M, Sergeyeva O, Korth L, Maunsell E, Zhu Y, Krishnan M, Diaz-Buxo JA: Effects of citrate acid concentrate (Citrasate®) of heparin

N requirements and hemodialysis adequacy: a multicenter, prospective noninferiority trial. Blood Purif 33:199-204, 2012

68. Rocha A, Padua V, Oliveira E, Guimaraes M, Lugon J, Strogoff de Matos J: Effects of citrate-enriched bicarbonate based dialysate on anticoagulation and dialyzer reuse in maintenance hemodialysis patients. Hemodial Int 18:467-472, 2014

69. Shen JI, Mitani AA, Chang TI, Winkelmayer WC: Use and safety of heparin-free maintenance hemodialysis in the USA. Nephrol Dial Transplant 28:1589-1602, 2013

70. Zimbudzi E: Intermittent saline flushes or continuous saline infusion: what works better when heparin-free dialysis is recommended? Int J Nephrol Renovasc Dis 6:65-69, 2013

71. Laville M, Dorval M, Fort J, Ros J, Fay R, Cridlig J, Nortier JL, Juil-lard L, Debska-Slizien A, Fernandez Lorente L, Thibaudin D, Frans-sen C, Schulz M, Moureau F, Loughraieb N, Rossignol P: A randomized controlled multicenter trial of a heparin-grafted poly-acrilonitrile membrane for no-heparin hemodialysis versus standard-of-care: results of the HepZero study. Kidney Int 86:1260-1267, 2014

72. Stamatiadis DN, Helioti H, Mansour M, Pappas M, Bokos JG, Stathakis CP: Hemodialysis for patients bleeding or at risk for bleeding, can be simple, safe and efficient. Clin Nephrol 62:29-34, 2004

73. Chanard J, Lavaud S, Maheut H, Kazes I, Vitry F, Rieu P: The clinical evaluation of low-dose heparin in haemodialysis: a prospective study using the heparin-coated AN69 ST membrane. Nephrol Dial Transplant 23:2003-2009, 2008

74. Lavaud S, Paris B, Maheut H, Randoux C, Renaux JL, Rieu P, Chanard J: Assessment of the heparin-binding AN69ST hemodialy-sis membrane: II. Clinical studies without heparin administration. ASAIO J 51:348-351, 2005

75. Richtrova P, Opatrny K, Vit L, Sefrna F, Perlik R: The AN69ST haemodialysis membrane under conditions of two different extracor-poreal circuit rinse protocols—a comparison of thrombogenicity parameters. Nephrol Dial Transplant 22:2978-2984, 2007

76. Sanchez-Canel JJ, Pons-Prades R, Salvetti M, Seores A, Vasquez M, Perez-Alba A, Tamarit E, Calvo-Gordo C, Villatoro J: Evaluation of coagulation and anti-Xa factor using a heparin-coated AN69ST dialyser. Nefrologia 32:605-612, 2012

77. Kodras K, Benesch T, Neumann I, Haas M: Comparison of two dialysers (AN69ST vs. X100) for heparin-free dialysis in patients with oral anti-coagulation. Blood Purif 26:226-230, 2008

78. Brunet P, Frances J, Vacher-Coponat H, Jaubert D, Lebrun G, Gondouin B, Duval A, Berland Y: Hemodialysis without heparin: a randomized, controlled, crossover study of two dialysis membranes (AN69ST and polysulfone F60). Int J Artif Organs 34:1165-1171, 2011

79. Sagedal S, Witczak BJ, Osnes K, Hartmann A, Os I, Eikvar L, Klingenberg O, Brosstad F: A heparin-coated dialysis filter (AN69 ST) does not reduce clotting during hemodialysis when compared to a conventional polysulfone filter (FX8). Blood Purif 32:151-155, 2011

80. GuSery B, Alberti C, Servais A, Harrami E, Bererhi L, Zins B, Tou-am M, Joly D: Hemodialysis without systemic anticoagulation: a prospective randomized trial to evaluate 3 strategies in patients at risk of bleeding. PLoS ONE 9:e97187, 2014

81. O'Shea SI, Ortel TL, Kovalik EC: Alternative methods of anticoagulation for dialysis-dependent patients with heparin-induced thrombocytopenia. Semin Dial 16:61-67, 2003

82. Szromba C: Heparin-induced thrombocytopenia (HIT) in patients on hemodialysis: an update. Nephrol Nurs J 37:185-187, 2010

83. Dutt T, Schulz M: Heparin-induced thrombocytopenia (HIT). An overview: what does the nephrologist need to know and do? Clin Kidney J 6:563-567, 2013

84. Keeling D, Davidson S, Watson H, on behalf of the haemostasis and thrombosis task force of the British Committee for standards in haematology: the management of heparin-induced thrombocytope-nia. Br J Haematol 133:259-269, 2006

85. Davenport A: Antibodies to heparin-platelet factor 4 complex: pathogenesis, epidemiology, and management of heparin-induced thrombocytopenia in hemodialysis. Am J Kidney Dis 54:361-374, 2009

86. Chang J, Parikh C: When heparin causes thrombosis: significance, recognition, and management of heparin-induced thrombocytopenia in dialysis patients. Semin Dial 19:297-304, 2006

87. Kalicki R, Aregger F, Alberio L, Lammle B, Frey F, Uehlinger D: Use of the pentasaccharide fondaparinux as an anticoagulant during haemodialysis. Thromb Haemost 98:1200-1207, 2007

88. Wellborn-Kim J, Mitchell G, Terneus W, Stowe C, Malias M, Sparkman G, Hanson G: Fondaparinux therapy in a hemodialysis patient with heparin-induced thrombocytopenia type II. Am J Health Syst Pharm 67:1075-1079, 2010

89. Brown P, Jay R, Fox A, Oliver M: Chronic fondaparinux use in a hemodialysis patient with heparin-induced thrombocytopenia type II and extracorporeal circuit thrombosis—a case report and review of the literature. Hemodial Int 17:444-449, 2013

90. Solak Y, Demircioglu S, Polat I, Biyik Z, Gaipov A, Acar K, Turk S: Heparin-induced thrombocytopenia in a hemodialysis patient treated with fondaparinux: nephrologists between two fires. Hemodial Int 17:320-323, 2013

91. Ho G, Leblanc K, Selby R, Richardson R, Hladunewich M, Batti-stella M: Use of fondaparinux for circuit patency in hemodialysis patients. Am J Kidney Dis 61:525-526, 2013

92. Ulbricht K, Bucha E, Poschel K, Stein G, Wolf G, Nowak G: The use of PEG-hirudin in chronic hemodialysis monitored by the Eca-rin Clotting Time: influence on clotting of the extracorporeal system and hemostatic parameters. Clin Nephrol 65:180-190, 2006

93. Poschel K, Bucha E, Esslinger H, Ulbricht K, Nortersheuser P, Stein G, Nowak G: Anticoagulant efficacy of PEG-hirudin in patients on maintenance hemodialysis. Kidney Int 65:666-674, 2004

94. Vitale C, Berutti S, Bagnis C, Soragna G, Gabella P, Fruttero C, Marangella M: Dermatan sulfate: an alternative to unfractionated heparin for anticoagulation in hemodialysis patients. J Nephrol 26:158-163, 2013

95. Yeh R, Jang I: Argatroban: update. Am Heart J 151:1131-1138, 2006

96. LaMonte M, Brown P, Hursting M: Alternative parenteral anticoagulation with argatroban, a direct thrombin inhibitor. Expert Rev Cardiovasc Ther 3:31-41, 2005

97. Hursting M, Murray P: Argatroban anticoagulation in renal dysfunction: a literature analysis. Nephron Clin Pract 109:c80-c94, 2008

98. Ota K, Akizawa T, Hirasawa Y, Agishi T, Matsui N: Effects of argatroban as an anticoagulant for haemodialysis in patients with antithrombin III deficiency. Nephrol Dial Transplant 18:1623-1630, 2003

99. Murray P, Reddy B, Grossman E, Hammes M, Trevino S, Ferrell J, Tang I, Hursting M, Shamp T, Swan S: A prospective comparison of three argatroban treatment regimens during hemodialysis in end-stage renal disease. Kidney Int 66:2446-2453, 2004

100. Yixiong Z, Jianping N, Yanchao L, Siyuan D: Low dose of argatro-ban saline flushes anticoagulation in hemodialysis patients with high risk of bleeding. Clin Appl Thromb Hemost 16:440-445, 2010

101. Reddy B, Grossman E, Trevino S, Hursting M, Murray P: Argatro-ban anticoagulation in patients with heparin-induced thrombocyto-penia requiring renal replacement therapy. Ann Pharmacother 39:1601-1605, 2005

102. Tsai T, Maddox T, Roe M, Dai D, Alexander K, Ho P, Messenger J, Nallamothu B, Peterson E, Rumsfeld J, for the national cardiovascular data registry: Contraindicated medication use in dialysis patients undergoing percutaneous coronary intervention. JAMA 302:2458-2464, 2009

103. Rodger M, Ramsay T, MacKinnon M, Westphal M, Wells P, Mc-Cornick B, Knoll G: Tinzaparin versus dalteparin for periprocedure prophylaxis of thromboembolic events in hemodialysis patients: a randomized trial. Am J Kidney Dis 60:427-434, 2012

104. Furkert JD, Zeier M, Schwenger V: Gastrointestinal hemorrhage in hemodialysis patients. Z Gastroenterol 46:1266-1269, 2008

105. Kuo CC, Kuo HW, Lee I, Lee CT, Yang CY: The risk of upper gastrointestinal bleeding in patients treated with hemodialysis: a population-based cohort study. BMC Nephrol 14:15, 2013

106. Marinigh R, Lane D, Lip G: Severe renal impairment and stroke prevention in atrial fibrillation. J Am Coll Cardiol 57:1339-1348, 2011

107. Cy To A, Yehia M, Collins J: Atrial fibrillation in hemodialysis patients: do the guidelines for anticoagulation apply? Nephrology 12:441-447, 2007

108. Abbott K, Neff R, Bohen E, Narayan R: Anticoagulation for chronic atrial fibrillation in hemodialysis patients: which fruit from the decision tree? Am J Kidney Dis 50:345-348, 2007

109. Quinn R, Naimark D, Oliver M, Bayoumi A: Should hemodialysis patients with atrial fibrillation undergo systemic anticoagulation? A cost-utility analysis. Am J Kidney Dis 50:421-432, 2007

110. Thet Z, Vilayur E: Atrial fibrillation and warfarin use in hemodialy-sis patients: an individualized holistic approach is important in stroke prevention. Nephrology 18:331-339, 2013

111. Juma S, Thomson B, Lok C, Clase C, Blake P, Moist L: Warfarin use in hemodialysis patients in atrial fibrillation: decisions based on uncertainty. BMC Nephrol 14:174, 2013

112. Genovesi S, Rossi E, Pogliani D, Gallieni M, Stella A, Badiali F, Conte F, Pasquali S, Bertoli S, Ondei P, Bonforte G, Pozzi C, Val-secchi MG, Santoro A: The nephrologist's anticoagulation treatment patterns/regimens in chronic hemodialysis patients with atrial fibrillation. J Nephrol 27:187-192, 2014

113. Wizemann V, Tong L, Satayathum S, Disney A, Akiba T, Fissell R, Kerr P, Young E, Robinson B: Atrial fibrillation in hemodialysis patients: clinical features and associations with anticoagulant therapy. Kidney Int 77:1098-1106, 2010

114. Chan KE, Lazarus JM, Thadhani R, Hakim RM: Warfarin use associates with increased risk for stroke in hemodialysis patients with atrial fibrillation. J Am Soc Nephrol 20:2223-2233, 2009

115. Shen J, Turakhia M, Winkelmayer C: Anticoagulation for atrial fibrillation in patients on dialysis: are the benefits worth the risks? Curr Opin Nephrol Hypertens 21:600-606, 2012

116. Sood M, Larkina M, Thumma J, Tentori F, Gillespie BW, Fukuha-ra S, Mendelssohn DC, Chan K, de Sequera P, Komenda P, Rigatto C, Robinson B: Major bleeding events and risk stratification of antithrombotic agents in hemodialysis: results from the DOPPS. Kidney Int 84:600-608, 2013

117. Chan KE, Lazarus JM, Thadhani R, Hakim RM: Anticoagulation and antiplatelet usage associates with mortality among hemodialysis patients. J Am Soc Nephrol 20:872-881, 2009

118. Ziai F, Benesch T, Kodras K, Neumann I, Dimopoulos-Xicki L, Haas M: The effect of oral anticoagulation on clotting during he-modialysis. Kidney Int 68:862-866, 2005

119. Elliott M, Zimmerman D, Holden R: Warfarin anticoagulation in hemodialysis patients: a systematic review of bleeding rates. Am J Kidney Dis 50:433-440, 2007

120. Holden RM, Harman GJ, Wang M, Holland D, Day AG: Major bleeding in hemodialysis patients. Clin J Am Soc Nephrol 3:105-110, 2008

121. Phelan PJ, O'Kelly P, Holian J, Walshe JJ, Delany C, Slaby J, Winders S, O'Toole D, Magee C, Conlon PJ: Warfarin use in he-modialysis patients: what is the risk? Clin Nephrol 3:204-211, 2011

122. Praehauser C, Grandjean R, Steiger J, Mayr M: Cohort study on the quality oforal anticoagulation therapy in chronic haemodialysis patients treated with phenprocoumon. Swiss Med Wkly 143:w13730,2013

123. Finazzi G, Minguardi G: Oral anticoagulant therapy in hemo-dialysis patients: do the benefits outweigh the risks? Intern Emerg Med 4:375-380, 2009

124. Krummel T, Scheidt E, Borni-Duval C, Bazin D, Lefebvre F, Nguyen P, Hannedouche T: Haemodialysis in patients treated with oral anticoagulant: should we heparinize? Nephrol Dial Transplant 29:906-913, 2014

125. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schunemann HJ, for the American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel: Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141:7S-47S, 2012

126. Makris M, Van Veen JJ, Tait CR, Mumford AD, Laffan M on behalf of the Bristish Committee for Standards in Haematology: Guideline on the management of bleeding in patients on antithrom-botic agents. Br J Haematol 160:35-46, 2012

127. Palmer SC, Di Micco L, Razavian M, Craig JC, Ravani P, Perkovic V, Tognoni G, Graziano G, Jardine M, Pellegrini F, Nicolucci A, Webster A, Strippoli GF: Antiplatelet therapy to prevent hemo-dialysis vascular access failure: systematic review and meta-analysis. Am J Kidney Dis 61:112-122, 2013

128. Daimon S, Terai H: Influence of antiplatelet medications on bleeding events in hemodialysis patients. Ther Apher Dial 15:454459, 2011

129. Hiremath S, Holden RM, Fergusson D, Zimmerman DL: Antiplatelet medications in hemodialysis patients: a systematic review of bleeding rates. Clin J Am Soc Nephrol 4:1347-1355, 2009

130. Girtovitis FI, Boutou AK, Ioannidis G, Makris PE: Heparin-induced thrombocytopenia type II. A treatment review. Haema 8:582-589, 2005

131. Davenport A: HIT on dialysis. When is it safe to re-challenge? Nephron Clin Pract 104:c149-c150, 2006

132. Cuker A: Heparin-induced thrombocytopenia: present and future. J

Thromb Thrombolysis 31:353-366, 2011

Supporting Information

Additional supporting information may be found in the online version of this article. Data S1 Complete Search Strategy.