This is the current release of the guideline.

Heparin-induced thrombocytopenia (HIT)

Evaluation
Management
Prevention
Treatment

Cardiology
Critical Care
Family Practice
Internal Medicine

Physicians

To provide evidence-based guidelines on the recognition, treatment, and prevention of heparin-induced thrombocytopenia (HIT)

• Patients receiving therapeutic-dose unfractionated heparin (UFH)
  • Patients receiving porcine UFH for the treatment of venous or arterial thrombosis
• Postoperative patients receiving UFH antithrombotic prophylaxis
  • Postoperative orthopedic, cardiac, and vascular surgery patients receiving UFH for 1 to 2 weeks
• Patients in whom heparin-induced thrombocytopenia (HIT) is infrequent (0.1 to 1%)
  • Medical/obstetric patients receiving prophylactic-dose UFH for the prevention of thrombosis
  • Postoperative patients receiving low molecular weight heparin (LMWH)
  • Postoperative/critical care patients receiving UFH flushes
  • Medical patients receiving LMWH after having received one or more preceding doses of UFH
• Patients in whom HIT is rare (<0.1%)
  • Medical/obstetric patients receiving LMWH
• Patients undergoing cardiopulmonary bypass (CPB) surgery
• Patients undergoing percutaneous coronary interventions (PCIs)

Evaluation

1. Platelet count
2. Activated clotting time (ACT)
3. Activated partial thromboplastin time (APTT)
4. Ecarin clotting time (ECT)
5. International normalized ratio (INR)
6. Protein C level
7. Thrombin-antithrombin complex
8. Platelet activation (or "functional") assay using washed platelets (e.g., ¹⁴C-SRA, heparin-induced platelet activation assay)
9. Platelet factor 4 (PF4)-dependent enzyme immunoassay
10. Ultrasonography of the lower-limb veins

Treatment

1. Heparins
   • Unfractionated heparin (UFH)
     • Bovine lung UFH
     • Porcine gut UFH
   • Low-molecular-weight heparin (LMWH)
2. Vitamin K antagonists
   • Warfarin
   • Phenprocoumon
3. Direct thrombin inhibitors (DTI)
   • Lepirudin
   • Argatroban
   • Bivalirudin
4. Factor Xa inhibitors
   • Danaparoid (Note: Withdrawn from US market; still available in Canada, continental Europe, and New Zealand)
   • Fondaparinux
5. Ancrod (defibrinogenating snake venom)
6. Dextran
7. Vitamin K
8. Platelet transfusions
9. Epoprostenol
10. Tirofiban
11. Vasopressors

• Frequency of heparin-induced thrombocytopenia (HIT)
• Frequency of HIT antibody formation
• Incidence of new thrombosis
• Mortality
• Limb amputation
• Drug anaphylaxis
• Platelet count recovery
• Repeat formation of HIT antibodies
• Procedural success
• Vitamin K antagonist (VKA) therapy-associated thrombosis, including venous limb gangrene and skin necrosis
• Sensitivity and specificity of diagnostic tests
• Predictive value of diagnostic tests

Hand-searches of Published Literature (Primary Sources)
Searches of Electronic Databases

Not stated

Weighting According to a Rating Scheme (Scheme Given)

The rating scheme framework captures the trade-off between benefits and risks (1 or 2) (and the methodological quality of the underlying evidence (A, B, C+, or C). See "Rating Scheme for the Strength of the Recommendations."

Review of Published Meta-Analyses
Systematic Review with Evidence Tables

Summarizing Evidence

The electronic searches also included searching for systematic reviews. If authors were satisfied with a recent high-quality systematic review, evidence from that review provided a foundation for the relevant recommendation.

Pooled analyses from high-quality systematic reviews formed, wherever possible, the evidence base of the recommendations. Pooling offers the advantage of obtaining more precise estimates of treatment effects and allows for a greater generalizability of results. However, pooling also bears the risk of spurious generalization. In general, the summary estimates of interest were the different types of outcomes conveying benefit and downsides (i.e., risk, burden, and cost).

Expert Consensus (Consensus Development Conference)

The strength of any recommendation depends on the following two factors: the trade-off between the benefits and the risks, burdens, and costs; and the strength of the methodology that leads to the treatment effect. The guideline developers grade the trade-off between benefits and risks in the two categories: 1, in which the trade-off is clear enough that most patients, despite differences in values, would make the same choice; and 2, in which the trade-off is less clear, and individual patients' values will likely lead to different choices.

When randomized trials provide precise estimates suggesting large treatment effects, and the risks and costs of therapy are small, treatment for average patients with compatible values and preferences can be confidently recommended.

If the balance between benefits and risks is in doubt, methodologically rigorous studies providing Grade A evidence and recommendations may still be weak (Grade 2). Uncertainty may come from less precise estimates of benefit, harm, or costs, or from small effect sizes.

There is an independent impact of validity and consistency, and the balance of positive and negative impacts of treatment on the strength of recommendations. In situations in which there is doubt about the value of the trade-off, any recommendation will be weaker, moving from Grade 1 to Grade 2.

Grade 1 recommendations can only be made when there is a relatively clear picture of both the benefits and the risks, burdens, and costs, and when the balance between the two clearly favors recommending or not recommending the intervention for the typical patient with compatible values and preferences. A number of factors can reduce the strength of a recommendation, moving it from Grade 1 to Grade 2. Uncertainty about a recommendation to treat may be introduced if the following conditions apply: (1) the target event that is trying to be prevented is less important (confident recommendations are more likely to be made to prevent death or stroke than asymptomatic deep vein thrombosis); (2) the magnitude of risk reduction in the overall group is small; (3) the probability of the target event is low in a particular subgroup of patients; (4) the estimate of the treatment effect is imprecise, as reflected in a wide confidence interval (CI) around the effect; (5) there is substantial potential harm associated with therapy; or (6) there is an expectation for a wide divergence in values even among average or typical patients. Higher costs would also lead to weaker recommendations to treat.

The more balanced the trade-off between benefits and risks, the greater the influence of individual patient values in decision making. Virtually all patients, if they understand the benefits and risks, will take aspirin after experiencing a myocardial infarction (MI) or will comply with prophylaxis to reduce the risk of thromboembolism after undergoing hip replacement. Thus, one way of thinking about a Grade 1 recommendation is that variability in patient values is unlikely to influence treatment choice in average or typical patients.

When the trade-off between benefits and risks is less clear, individual patient values may influence treatment decisions even among patients with average or typical preferences.

Grade 2 recommendations are those in which variation in patient values or individual physician values will often mandate different treatment choices, even among average or typical patients. An alternative, but similar, interpretation is that a Grade 2 recommendation suggests that clinicians conduct detailed conversations with patients to ensure that their ultimate recommendation is consistent with the patient's values.

*These situations include RCTs with both lack of blinding and subjective outcomes, where the risk of bias in measurement of outcomes is high, or RCTs with large loss to follow-up.

While conference participants agreed that recommendations should reflect economic considerations, incorporating costs is fraught with difficult challenges. For most recommendations, formal economic analyses are unavailable. Even when analyses are available, they may be methodologically weak or biased. Furthermore, costs differ radically across jurisdictions, and even sometimes across hospitals within jurisdictions.

Because of these challenges, the guideline developers consider economic factors only when the costs of one therapeutic option over another are substantially different within major jurisdictions in which clinicians make use of their recommendations. As a result, in jurisdictions in which resource constraints are severe, alternative allocations may serve the health of the public far better than some of the interventions that are designated as Grade 1A. This will likely be true for all less industrialized countries and, with the increasing promotion of expensive drugs with marginal benefits, may be increasingly true for wealthier nations. Furthermore, recommendations change (either in direction or with respect to grade) only when the guideline developers believe that costs are high in relation to benefits. Instances in which costs have influenced recommendations are labeled in the "values and preferences" statements associated with the recommendation.

External Peer Review
Internal Peer Review

The guideline authors formulated draft recommendations prior to the conference that served as the foundation for authors to work together and critique the recommendations. Drafts of all articles including draft recommendations were available for review during the conference. A representative of each article presented potentially controversial issues in their recommendations at plenary meetings. Article authors met to integrate feedback, to consider related recommendations in other articles, and to revise their own guidelines accordingly. Authors continued this process after the conference until they reached agreement within their groups and with other author groups who had provided critical feedback. Finally, the editors of this supplement harmonized the articles and resolved remaining disagreements through facilitated discussion.

The rating scheme is defined at the end of the "Major Recommendations" field.

Recognition of Heparin-Induced Thrombocytopenia (HIT)

Platelet Count Monitoring for HIT

1. For patients receiving heparin in whom the risk of HIT is considered to be >0.1%, the guideline developers recommend platelet count monitoring over no platelet count monitoring (Grade 1C).

   Underlying values and preferences: This recommendation places a high value on diagnosis and early treatment of HIT to prevent sequelae and a lower value on the burden and cost of monitoring platelet counts.

Platelet Count Monitoring of Patients Recently Treated with Heparin

1. For patients who are starting unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) treatment and who have received UFH within the past 100 days, or those patients in whom exposure history is uncertain, the guideline developers suggest obtaining a baseline platelet count and then a repeat platelet count within 24 hours of starting heparin (Grade 2C).

Acute Systemic Reactions after Intravenous (IV) UFH Bolus

1. For patients who acquire acute inflammatory, cardiorespiratory, neurologic, or other unusual symptoms and signs within 30 min following an IV UFH bolus, the guideline developers recommend performing an immediate platelet count measurement, and comparing this value to recent prior platelet counts, in comparison with not performing a platelet count measure(Grade 1C).

Platelet Count Monitoring in Patients Receiving Therapeutic-Dose UFH

1. For patients who are receiving therapeutic-dose UFH, the guideline developers suggest at least every-other-day platelet count monitoring until day 14, or until UFH is stopped, whichever occurs first (Grade 2C).

   Underlying values and preferences: This recommendation places a high value on diagnosis and early treatment of HIT to prevent sequelae, and a lower value on the burden and cost of monitoring platelet counts.

Platelet Count Monitoring in Postoperative Patients Receiving UFH Antithrombotic Prophylaxis

1. For patients who are receiving postoperative antithrombotic prophylaxis with UFH (HIT risk >1%), the guideline developers suggest at least every-other-day platelet count monitoring between postoperative days 4 to 14, or until UFH is stopped, whichever occurs first (Grade 2C).

   Underlying values and preferences: This recommendation places a high value on diagnosis and early treatment of HIT to prevent sequelae, and a lower value on the burden and cost of monitoring platelet counts.

Platelet Count Monitoring in Patients in Whom HIT is Infrequent (0.1 to 1%)

1. For medical/obstetrical patients who are receiving prophylactic-dose UFH, postoperative patients receiving prophylactic-dose LMWH, postoperative patients receiving intravascular catheter UFH "flushes," or medical/obstetrical patients receiving LMWH after first receiving UFH (HIT risk 0.1 to 1%), the guideline developers suggest platelet count monitoring every 2 to 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs first), when practical (Grade 2C).

   Underlying values and preferences: This recommendation places a high value on diagnosis and early treatment of HIT to prevent sequelae, and a lower value on the burden and cost of monitoring platelet counts.

Platelet Count Monitoring When HIT is Rare (<0.1%)

1. For medical/obstetrical patients who are only receiving LMWH, or medical patients who are receiving only intravascular catheter UFH flushes (HIT risk <0.1%), the guideline developers suggest clinicians do not use routine platelet count monitoring (Grade 2C).

   Underlying values and preferences: This recommendation places a lower value on the rare diagnosis and early treatment of HIT to prevent sequelae, and a higher value on the burden and cost of monitoring platelet counts.

Screening for Subclinical HIT Antibody Seroconversion

1. In patients who receive heparin, the guideline developers recommend against routine HIT antibody testing in the absence of thrombocytopenia, thrombosis, heparin-induced skin lesions, or other sequelae of HIT (Grade 1C).

When Should HIT Be Suspected?

1. For patients receiving heparin, or who have received heparin within the previous 2 weeks, the guideline developers recommend excluding a diagnosis of HIT if the platelet count falls by >50%, and/or a thrombotic event occurs, between days 4 to 14 following initiation of heparin, even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred (Grade 1C).

Special Situation: Anticoagulant Prophylaxis and Platelet Count Monitoring after Cardiac Surgery

1. For postoperative cardiac surgery patients, the guideline developers recommend excluding a diagnosis of HIT if the platelet count falls by >50% (and/or a thrombotic event occurs) between postoperative days 4 to day 14 (day of cardiac surgery = day zero) [Grade 1C].

Treatment of HIT

Nonheparin Anticoagulants for HIT

1. For patients with strongly suspected (or confirmed) HIT, whether or not complicated by thrombosis, the guideline developers recommend use of an alternative, nonheparin anticoagulant, such as lepirudin (Grade 1C+), argatroban (Grade 1C), bivalirudin (Grade 2C), or danaparoid (Grade 1B), over further UFH or LMWH therapy, and over no further anticoagulation (with or without vena caval filter).
2. For patients with strongly suspected (or confirmed) HIT, whether or not there is clinical evidence of lower-limb deep vein thrombosis (DVT), the guideline developers recommend routine ultrasonography of the lower-limb veins for investigation of DVT, over not performing routine ultrasonography (Grade 1C).

Vitamin K Antagonists (VKAs)

Management of Direct Thrombin Inhibitor (DTI)-VKA Overlap

1. For patients with strongly suspected or confirmed HIT, the guideline developers recommend against the use of vitamin K antagonist (coumarin) therapy until after the platelet count has substantially recovered (e.g., to at least 100 x 10⁹/L, and preferably, 150 x 10⁹/L); that the VKA be administered only during overlapping alternative anticoagulation (minimum 5-day overlap), and begun with low, maintenance doses (maximum, 5 mg of warfarin, and 6 mg of phenprocoumon); that the alternative anticoagulant not be stopped until the platelet count has reached a stable plateau, and with at least the last 2 days the international normalized ration (INR) within the target therapeutic range (Grade 1C).

Reversal of VKA Anticoagulation

1. For patients receiving VKAs at the time of diagnosis of HIT, the guideline developers recommend use of vitamin K (Grade 2C).

LMWH for HIT

1. For patients with strongly suspected HIT, whether or not complicated by thrombosis, the guideline developers recommend against use of LMWH (Grade 1C+).

Prophylactic Platelet Transfusions for HIT

1. For patients with strongly-suspected or confirmed HIT who do not have active bleeding, the guideline developers suggest that prophylactic platelet transfusions not be administered (Grade 2C).

Special Patient Populations

Patients with Previous HIT Undergoing Cardiac or Vascular Surgery

1. For patients with a history of HIT who are HIT antibody negative and require cardiac surgery, the guideline developers recommend the use of UFH over a nonheparin anticoagulant (Grade 1C).

   Remark: Preoperative and postoperative anticoagulation, if indicated, should be administered with a nonheparin anticoagulant.

Patients with Acute or Subacute HIT Undergoing Cardiac Surgery

1. For patients with acute HIT (thrombocytopenic, HIT antibody positive) who require cardiac surgery, the guideline developers recommend one of the following alternative anticoagulant approaches (in descending order of preference):
   • Delaying surgery (if possible) until HIT antibodies are negative (see recommendation above concerning patients with previous HIT undergoing cardiac or vascular surgery) (Grade 1C);
   • Using bivalirudin for intraoperative anticoagulation during cardiopulmonary bypass (CPB) (if ecarin clotting time [ECT] available) (Grade 1C) or during off-pump cardiac surgery (Grade 1C+);
   • Using lepirudin for intraoperative anticoagulation (if ECT available and patient has normal renal function) (Grade 1C);
   • Using UFH plus the antiplatelet agent, epoprostenol (if ECT monitoring not available or renal insufficiency precludes lepirudin use) (Grade 2C);
   • Using UFH plus the antiplatelet agent, tirofiban (Grade 2C);
   • Using danaparoid for intraoperative anticoagulation (if anti-factor Xa levels are available) (Grade 2C)
2. For patients with subacute HIT (platelet count recovery, but continuing HIT antibody-positive), the guideline developers recommend delaying surgery (if possible) until HIT antibodies are negative, then using heparin (see recommendation above concerning patients with previous HIT undergoing cardiac or vascular surgery) (Grade 1C). Alternatively, the guideline developers suggest the use of a nonheparin anticoagulant (see recommendation directly above concerning patients with acute HIT [thrombocytopenic, HIT antibody positive] who require cardiac surgery) (Grade 2C).

Percutaneous Coronary Interventions (PCIs)

1. For patients with acute or previous HIT who require cardiac catheterization or PCI, the guideline developers recommend use of an alternative anticoagulant, such as argatroban (Grade 1C), bivalirudin (Grade 1C), lepirudin (Grade 1C), or danaparoid (Grade 2C), over the use of heparin.

Prevention of HIT

Reducing HIT Antibody Formation and Clinical HIT

UFH vs. LMWH

1. For postoperative orthopedic surgery patients, the guideline developers recommend the use of LMWH over UFH (Grade 1A).

Bovine vs. Porcine UFH

1. For the treatment of patients with thrombosis, the guideline developers recommend against the use of bovine UFH, in comparison with porcine UFH or LMWH (Grade 1A).
2. For patients undergoing cardiac surgery, the guideline developers recommend the use of porcine UFH for intraoperative anticoagulation, in comparison with bovine UFH (Grade 1B).

Definitions

*These situations include RCTs with both lack of blinding and subjective outcomes, where the risk of bias in measurement of outcomes is high, or RCTs with large loss to follow-up.

None provided

The type of supporting evidence is identified and graded for each recommendation (see "Major Recommendations").

Appropriate recognition, treatment, and prevention of heparin-induced thrombocytopenia (HIT)

Subgroups Most Likely to Benefit:

Patient groups most likely to benefit from platelet count monitoring are those at the highest risk of HIT (1 to 5%) and include postoperative orthopedic, cardiac, and vascular surgery patients who are receiving unfractionated heparin for 1 to 2 weeks.

There are risks involved in the use of any antithrombotic agent for treatment of heparin-induced thrombocytopenia, including risks of fatal bleeding. None of these agents has an antidote, and thus careful drug selection for the appropriate patient is a relevant issue.

• Given the availability of nonheparin anticoagulants to treat heparin-induced thrombocytopenia (HIT), low molecular weight heparin (LMWH) should be considered contraindicated for treatment of acute HIT.
• Platelet transfusions are generally considered as being relatively contraindicated for the prevention of bleeding in patients with acute HIT. This is because petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT, despite even severe thrombocytopenia, and platelet transfusions have been linked with thrombotic events, albeit only in anecdotal reports.

• In making recommendations for the management of HIT, the guideline developers have chosen to combine the approach to patients with "isolated HIT" and HIT-associated thrombosis.
• The American College of Chest Physicians (ACCP) conference members examined the question of whether they should make a general recommendation favoring LMWH over UFH for the prevention of HIT. The participants—in the view of lack of sufficient evidence for all patient groups—disagreed about making this recommendation. Some participants believed that prevention of HIT was an important primary goal, sufficiently dominant to determine the decision regarding choice of LMWH and UFH. Other participants believed that the question of whether LMWH is safer in terms of HIT prevention in non-orthopedic surgery settings is unproven, and that HIT risk should only be one among a number of considerations in the choice. Moreover, this latter group of participants noted that such a general recommendation would have considerable economic consequences, particularly in North America where costs of LMWH exceed those in Europe. Thus, the guideline developers have not provided a recommendation on this question, except in post-orthopedic surgery patients in whom randomized controlled trial evidence is available indicating a difference in both risk of HIT and HIT-associated thrombosis between LMWH and UFH.

Interpreting the Recommendations

• Clinicians, third-party payers, institutional review committees, or the courts should not construe these guidelines in any way as absolute dictates. In general, anything other than a Grade 1A recommendation indicates that the article authors acknowledge that other interpretations of the evidence, and other clinical policies, may be reasonable and appropriate. Even Grade 1A recommendations will not apply to all circumstances and all patients. For instance, the guideline developers have been conservative in their considerations of cost and have seldom downgraded recommendations from Grade 1 to Grade 2 on the basis of expense. As a result, in jurisdictions in which resource constraints are severe, alternative allocations may serve the health of the public far better than some of the interventions that are designated as Grade 1A. This will likely be true for all less industrialized countries and, with the increasing promotion of expensive drugs with marginal benefits, may be increasingly true for wealthier nations.
• Similarly, following Grade 1A recommendations will at times not serve the best interests of patients with atypical values or preferences or of those whose risks differ markedly from those of the usual patient. For instance, consider patients who find anticoagulant therapy extremely aversive, either because it interferes with their lifestyle (e.g., prevents participation in contact sports) or because of the need for monitoring. Clinicians may reasonably conclude that following some Grade 1A recommendations for anticoagulation therapy for either group of patients will be a mistake. The same may be true for patients with particular comorbidities (e.g., a recent gastrointestinal bleed or a balance disorder with repeated falls) or other special circumstances (e.g., very advanced age) that put them at unusual risk.
• The guideline developers trust that these observations convey their acknowledgment that no recommendations or clinical practice guidelines can take into account the often compelling and unique features of individual clinical circumstances. No clinician, and no body charged with evaluating a clinician’s actions, should attempt to apply these recommendations in a rote or blanket fashion.

Limitations of Guideline Development Methods

• The limitations of these guidelines include the possibility that some authors followed this methodology more closely than others, although the development process was centralized and supervised by the editors. Second, it is possible that the guideline developers missed relevant studies despite the comprehensive searching process. Third, the guideline developers did not centralize the methodological evaluation of all studies to facilitate uniformity in the validity assessments of the research incorporated into these guidelines. Fourth, if high-quality meta-analyses were unavailable, the guideline developers did not statistically pool primary study results using meta-analysis. Finally, sparse data on patient preferences and values, resources, and other costs represent additional limitations that are inherent to most guideline development methods.

Guideline Implementation Strategies

A full review of implementation strategies for practice guidelines is provided in the companion document titled "Antithrombotic and Antithrombolytic Therapy: From Evidence to Application." The review suggests that there are few implementation strategies that are of unequivocal, consistent benefit, and that are clearly and consistently worth resource investment. The following is a summary of the recommendations (see "Major Recommendations" for a definition of the recommendation grades).

To encourage uptake of guidelines, the guideline developers recommend that appreciable resources be devoted to distribution of educational material (Grade 2B).

They also suggest that:

• Few resources be devoted to educational meetings (Grade 2B)
• Few resources be devoted to educational outreach visits (Grade 2A)
• Appreciable resources be devoted to computer reminders (Grade 2A)
• Appreciable resources be devoted to patient-mediated interventions to encourage uptake of the guidelines (Grade 2B)
• Few resources be devoted to audit and feedback (Grade 2B)

Getting Better
Staying Healthy

Effectiveness
Safety

Not applicable: The guideline was not adapted from another source.

2004 Sep

American College of Chest Physicians - Medical Specialty Society

Funding was provided through an unrestricted educational grant by AstraZeneca LP, Aventis Pharmaceuticals, GlaxoSmithKline, Bristol-Myer Squibb/Sanofi-Synthelabo Partnership, and Organon Sanofi-Synthelabo LLC.

American College of Chest Physicians Consensus Panel on Antithrombotic and Thrombolytic Therapy

Primary Authors: Theodore E. Warkentin, MD (Chair); Andreas Greinacher, MD

Dr. Warkentin has received research funding from Organon and Sanofi-Synthelabo, and has received honoraria for his participation on advisory boards and/or as a speaker at educational events from Aventis, Berlex Laboratories, Genentech, Glaxo Smith Kline, Medicines Company, Novartis, NovoNordisk, Organon, Pharmion, RenalTech International, and Sanofi-Synthelabo.

Dr. Greinacher has received research funding from Celltech, Berlex, Pharmion, Novartis, and has received honoraria for his participation on advisory boards and/or as a speaker at educational events from Berlex, Pharmion, Celltech, Mitsubishi, Aventis Pharma, SheringAG.

This is the current release of the guideline.

This NGC summary was completed by ECRI on November 19, 2004. The information was verified by the guideline developer on January 12, 2005. This summary was updated by ECRI on March 6, 2007 following the U.S. Food and Drug Administration (FDA) advisory on Coumadin (warfarin sodium). This summary was updated by ECRI Institute on June 22, 2007 following the U.S. Food and Drug Administration (FDA) advisory on heparin sodium injection. This summary was updated by ECRI Institute on September 7, 2007 following the revised U.S. Food and Drug Administration (FDA) advisory on Coumadin (warfarin). This summary was updated by ECRI Institute on March 14, 2008 following the updated FDA advisory on heparin sodium injection.

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.