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Low-molecular-weight heparins for managing vaso-occlusive crises in people with sickle cell disease

  1. Esther J van Zuuren1,*,
  2. Zbys Fedorowicz2

Editorial Group: Cochrane Cystic Fibrosis and Genetic Disorders Group

Published Online: 12 JUN 2013

Assessed as up-to-date: 5 JUN 2013

DOI: 10.1002/14651858.CD010155.pub2


How to Cite

van Zuuren EJ, Fedorowicz Z. Low-molecular-weight heparins for managing vaso-occlusive crises in people with sickle cell disease. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD010155. DOI: 10.1002/14651858.CD010155.pub2.

Author Information

  1. 1

    Leiden University Medical Center, Department of Dermatology, Leiden, Netherlands

  2. 2

    The Cochrane Collaboration, UKCC (Bahrain Branch), Awali, Bahrain

*Esther J van Zuuren, Department of Dermatology, Leiden University Medical Center, PO Box 9600, B1-Q, Leiden, 2300 RC, Netherlands. E.J.van_Zuuren@lumc.nl.

Publication History

  1. Publication Status: New
  2. Published Online: 12 JUN 2013

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Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

 
Summary of findings for the main comparison. Tinzaparin compared to placebo for people with sickle cell disease

Tinzaparin compared to placebo for people with sickle cell disease

Patient or population: people with sickle cell disease
Settings: hospitals
Intervention: tinzaparin
Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

PlaceboTinzaparin

pain intensity
Numerical pain scale
Follow-up: mean 7 days
See comment1See comment1253
(1 study)
⊕⊕⊝⊝
low2

pain duration
Scale from 1 to 7
Follow-up: mean 7 days
The mean pain duration in the control groups was
4.35 days
The mean pain duration in the intervention groups was
1.78 lower
(1.94 to 1.62 lower)
253
(1 study)
⊕⊕⊕⊝
moderate2

the requirement for opiate treatment
Follow-up: mean 7 days
See comment3See comment3253
(1 study)
⊕⊕⊝⊝
low2

number of serious complications of SCD4 - not reportedSee comment4See comment4Not estimable4-See comment4

number of other sickle-related events4 - not reportedSee comment4See comment4Not estimable4-See comment4

quality of life (e.g. absence from school, lost time at work, mobility) as assessed by any validated questionnaire, either generic or SCD specific4 - not reportedSee comment4See comment4Not estimable4-See comment4

hospitalisation (number and duration)
Scale from 0 to 12.
Follow-up: mean 7 days
The mean hospitalisation (number and duration) in the control groups was
12.06 days
The mean hospitalisation (number and duration) in the intervention groups was
4.98 lower
(5.48 to 4.48 lower)
253
(1 study)
⊕⊕⊝⊝
low2

participant satisfaction with the medication assessed by any appropriate and validated questionnaire (either generic or SCD specific)4 - not reportedSee comment4See comment4Not estimable4-See comment4

adverse events associated with the use of anticoagulants (e.g. bleeding)
Follow-up: mean 7 days
RR 4.96
(0.24 to 102.31)
253
(1 study)
⊕⊕⊕⊕
high

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval (CI)) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence:
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 No precise data were reported. The authors indicated that at day 2 and at day 3, the pain severity score was lower in the tinzaparin group than in the placebo group (P < 0.01 (ANOVA)), in addition to day 4 (P < 0.05 (ANOVA)).
2 Sequence generation is unclear, as are allocation concealment and measurements to blind investigators and participants. A potential conflict of interest cannot be excluded, as one of the investigators is an employee of the manufacturer of tinzaparin. The NMS scale is not a validated tool for pain assessment.
3 All participants received standard analgesia therapy consisting of morphine 1 mg/h intravenous infusion and rehydration with normal saline.
4 This outcome measure was not assessed.

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

Please refer to an additional table for definitions of clinical terms ( Table 1).

 

Description of the condition

 

Definition and clinical features

Sickle cell disease (SCD) is one of the most common and severe genetic disorders in the world. The term SCD covers several common genotypes (Rees 2010; Steinberg 2011).

  • Sickle cell anaemia: homozygosity for the sickle haemoglobin gene (HbS). This is the most prevalent form of SCD and is caused by inheritance from both parents of an HbS gene.
  • Sickle cell-haemoglobin C (HbSC) disease: compound heterozygosity for HbS and haemoglobin C (HbC) genes. This second most common type of SCD is caused by inheritance of one sickle cell gene from one parent and another abnormal haemoglobin gene (HbC) from the other.
  • HbS–β-thalassaemia: compound heterozygosity for HbS and a β0- or β+-thalassaemia gene (Sβ0, Sβ+). The third major type of SCD, caused by inheritance of one sickle cell gene from one parent and one β0- or β+-thalassaemia gene from the other.
  • Other double heterozygous conditions such as haemoglobin SD disease (HbSD), haemoglobin SE disease (HbSE), etc.

Homozygous sickle cell (SS) disease and sickle cell/β0-thalassaemia are generally considered the more severe forms of the disease, whilst HbSC disease and sickle cell β+-thalassaemia tend to be milder (Al Hajeri 2008). Sickle cell trait (heterozygotes who carry one HbS allele and one normal adult haemoglobin (HbA) allele) is clinically benign and should not be considered a disease (Steinberg 2011). However, recent literature reports point to associations with serious conditions such as exercise-related sudden death, exertional rhabdomyolysis, venous thromboembolism and renal complications, suggesting that sickle cell trait is not as benign as it was previously considered to be (Austin 2007; Austin 2009; Goldsmith 2012; Key 2010).

Individual heterogeneity between people with SCD makes clinical manifestations of the diseases highly variable in frequency and severity, ranging from completely asymptomatic cases to very severe forms. However, most patients (about 70%) have a moderate phenotype (Inati 2009).

Sickle cell diseae can be broadly divided into distinct clinical phenotypes characterised by either haemolysis or vaso-occlusion (Ballas 2010; Ballas 2012; Inati 2009). During haemolysis the red blood cells lyse prematurely and the content of the cells, that is, the haemoglobin, is released into the surrounding fluid; during vaso-occlusion the sickled red blood cells clump together, obstructing blood flow and damaging corresponding tissues and organs. Vaso-occlusion leads to both acute and chronic complications (Mousa 2010). Clinical manifestations of vaso-occlusion include acute episodes of severe pain (crises); acute chest syndrome (a life-threatening pneumonia-like illness); increased infections; joint necrosis; stroke; spontaneous abortion; and multi-organ failure (Ballas 2010; Ballas 2012; Ballas 2013; Inati 2009; Mousa 2010; Steinberg 1999). Chronic haemolysis manifests clinically as anaemia, cholelithiasis (presence of gall stones), pulmonary hypertension, priapism (painful persistent erections), leg ulceration, sudden death, and possibly stroke (Gladwin 2012; Inati 2009b). However, the severity of the clinical manifestations depends on the degree of haemolysis, and those with less haemolysis are predicted to have pain crises, acute chest syndrome, and osteonecrosis (Bunn 2010). According to Bunn and colleagues, pulmonary hypertension is usually minor and is confounded by several co-morbid conditions including high cardiac output, pulmonary vascular inflammation and occlusion (thrombosis in situ, fat embolism), as well as left ventricular failure (Bunn 2010). A comprehensive overview of clinical signs and symptoms is provided in a article by Ballas 2010, in which clinical manifestations are divided into three groups; haemolytic anaemia and its sequelae, pain syndromes and related issues and complications in major organs and related co-morbidities. Morbidity and mortality in people with SCD mainly result from tissue infarction (tissue death due to oxygen shortage) secondary to obstruction of the small blood vessels by sickle cells (Davies 2012).

 

Symptoms

Pain is the hallmark of SCD (Ballas 2013; de Montalembert 2008; Steinberg 2011). It can be acute or chronic and most often is located in joints, extremities, back or chest, but pain can occur anywhere and can last several days or weeks, or longer (de Montalembert 2008; Steinberg 2011). The frequency and severity of painful episodes vary widely within and between individual patients (de Montalembert 2008; Steinberg 2011). Acute chest syndrome is characterised by fever, cough, sputum production, tachypnoea (rapid breathing) and dyspnoea (breathing difficulties) and is the second most common reason for hospitalisation in this group of patients after pain (Ballas 2010; Ballas 2013; de Montalembert 2008; Steinberg 2011).

Patients are more susceptible to infection; in children the most prevalent agent is Streptococcus pneumoniae, and in adults gram-negative organisms are more common (de Montalembert 2008; Steinberg 2011). Fatigue and shortness of breath are symptoms of pulmonary hypertension, which is another frequent complication. Strokes occur in approximately 10% of children and adults with sickle cell anaemia but are much less common in other genotypes of the disease (Inati 2009; Steinberg 2011) and can lead to cognitive impairment as a result of neurological changes.

Anaemia manifests as fatigue, dizziness, headache, and cold hands and feet. Other complications associated with SCD include priapism in men leading to painful erections; leg ulcers, which can be both painful and disabling; sight problems due to retinopathy; and renal failure. But in fact all organs can be affected, resulting in organ-specific symptoms and complications (Ballas 2010; Ballas 2012; Ballas 2013; de Montalembert 2008; Steinberg 2011).

 

Epidemiology and causes

With estimates of approximately 300,000 babies born each year with documented SCD, this is one of the most common genetic inherited diseases worldwide (de Montalembert 2008; Mousa 2010; Rees 2010; WHO 2006). Prevalence is highest among people whose ancestors come from sub-Saharan Africa, India, Saudi Arabia and Mediterranean countries (Rees 2010; WHO 2006), but in our increasingly multi-ethnic world, the disease has become a global problem (de Montalembert 2008; Steinberg 2011; WHO 2006).

Sickle cell disease is caused by inheritance from both parents of a mutation in the beta-globin gene. As a result of this point mutation in the sixth position of the β-globin chain, valine is substituted for glutamic acid, leading to the production of a defective form of haemoglobin (haemoglobin S (HbS)) (De Franceschi 2011; Inati 2009b; Mousa 2010). Upon deoxygenation, HbS polymerises to the sickle form with distorted, sickle-shaped dehydrated red blood cells (Inati 2009b). Sickle erythrocytes occlude blood vessels of all sizes (Steinberg 2011), causing a spectrum of clinical manifestations, in addition to haemolysis and anaemia (Mousa 2010). It can cause severe pain crises and progressive organ damage to virtually every organ system in the body, and it is associated with a reduced life expectancy (Mousa 2010; Rees 2010; WHO 2006).

 

Description of the intervention

Low-molecular-weight heparins (LMWHs) act through the antithrombin inhibition of Factor Xa more than Factor IIa (thrombin) and have greater bioavailability and longer duration of action than unfractionated heparin (Hoy 2010) (see  Table 2 for the classes of anticoagulants). At a higher dose, LMWHs are used to treat active thrombotic diseases such as deep vein thromboses, pulmonary emboli, or both, and they are used at lower doses to prevent thrombosis. The LMWHs have a more predictable anticoagulant response than unfractionated heparin, allowing them to be administered in fixed, weight-based dosages without routine laboratory monitoring, thus facilitating outpatient therapy (Hoy 2010). Conducting a systematic review of the effectiveness and safety of LMWHs is warranted because hypercoagulability in SCD is a well-established pathogenic phenomenon (Ataga 2012).. Several studies have suggested the use of tinzaparin (one of the commonly used LMWHs) to control the hypercoagulable state of SCD, but none have provided solid evidence to support or discourage the use of LMWHs (De Franceschi 2009; Hirani 2011; Mousa 2010; Qari 2007).

 

How the intervention might work

The pathophysiology of SCD has many facets, and no single treatment addresses all consequences of the disease. Hence, for treatment of patients with SCD, a combination of several interventions, depending on the expression of disease-specific features and complications, is necessary. In addition to standardised pain management (de Montalembert 2008; Mousa 2010; Rees 2010; Steinberg 2011), alternative approaches to therapy that have anti-adhesion, anti-inflammatory and anticoagulant effects have been proposed (Mousa 2010).

The LMWHs exert their major anticoagulant effect by binding to antithrombin via a pentasaccharide, consequently inactivating Factor Xa and Factor IIa (Hirsh 1992; Hirsh 2001; Mousa 2003). Furthermore, LMWHs have anti-inflammatory properties in addition to their anticoagulant properties (Carr 2007), in part caused by suppression of tumour necrosis factor-α, which is released during blood clotting, and in part because of binding to P-selectin to inhibit leukocyte migration. Vaso-occlusion also leads to an altered nitric oxide (vasodilator) metabolism and contributes to vascular dysfunction (Mousa 2010), whereas LMWHs increase nitric oxide production and enhance vasodilating effects.

 

Why it is important to do this review

Management of vaso-occlusive crises is complicated and may require multiple strategies and interventions. However, we are unaware of the existence of a current systematic review undertaken to examine available evidence for the benefits and harms of LMWHs.

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

To assess the effects of LMWHs in managing vaso-occlusive crises in patients with SCD.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomised controlled clinical trials (RCTs) and controlled clinical trials (CCTs).

 

Types of participants

People with SCD SS, HbSC, Sβ0, and Sβ+ (confirmed by electrophoresis and sickle solubility test, with family studies or DNA tests as appropriate) of all ages and both sexes, in any setting.

 

Types of interventions

Any LMWH administered subcutaneously compared with placebo or standard care for a period of up to two years.

A post hoc change has been made to the protocol to include all LMWHs rather than just one (tinzaparin), as was previously included. This change is intended to provide a more comprehensive review of this treatment area.

 

Types of outcome measures

 

Primary outcomes

  1. Pain
    1. Intensity (expressed as scores obtained through any validated patient-reported outcomes instrument, either generic or SCD specific)
    2. Duration
  2. The requirement for opiate treatment
    1. Dose
    2. Type
    3. Frequency

 

Secondary outcomes

  1. Number of serious complications of SCD (e.g. stroke, acute chest syndrome, infection, acute splenic sequestration).
  2. Number of other sickle-related events (e.g. priapism, leg ulceration).
  3. Quality of life (e.g. absence from school, lost time at work, mobility) as assessed by any validated questionnaire, either generic or SCD specific.
  4. Hospitalisation (number and duration).
  5. Participant satisfaction with the medication as assessed by any appropriate and validated questionnaire (either generic or SCD specific).
  6. Adverse events associated with the use of anticoagulants (e.g. bleeding).

 

Search methods for identification of studies

 

Electronic searches

Authors identified relevant studies from the Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register using the terms (bemiparin* OR certoparin* OR nadroparin* OR parnaparin* OR reviparin* OR ardeparin* OR danaparoid OR tinzaparin* OR dalteparin* OR enoxaparin* OR fondaparinux) AND (sickle cell OR haemoglobinopathies general).

The Haemoglobinopathies Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of The Cochrane Library) and from quarterly searches of MEDLINE. Unpublished work is identified by searching the abstract books of five major conferences: the European Haematology Association conference; the American Society of Hematology conference; the British Society for Haematology Annual Scientific Meeting; the Caribbean Health Research Council Meetings; and the National Sickle Cell Disease Program Annual Meeting. For full details of all searching activities for the register, please see the relevant section of the Cochrane Cystic Fibrosis and Genetic Disorders Group Module.

Date of the last search of the Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 06 December 2012.

 

Searching other resources

The following additional resources were used:

  1. the bibliographical references of identified studies for citations to additional studies (EvZ, 4 January 2013);
  2. personal contact with corresponding authors of relevant trials or review authors and other experts (EvZ);
  3. clinical trials registries: ClinicalTrials.govCurrent Controlled Trials (across multiple registers) using the search terms (low-molecular-weight heparin OR sickle cell OR crises) AND trial (EvZ, 4 January 2013);
  4. conference proceedings of the International Society of Thrombosis and Hemostasis (ISTH) and of the Scientific Subcomittee of the ISTH (EvZ, 10 January 2013).

 

Data collection and analysis

 

Selection of studies

Two review authors (EvZ and ZF) independently assessed the abstracts of trials resulting from the searches. They obtained full-text copies of all relevant and potentially relevant trials, those appearing to meet the inclusion criteria and those for which details in the title and in the abstract were insufficient to allow a clear decision. The two review authors then independently assessed the full-text articles. Any disagreements on the eligibility of trials were resolved through discussion and consensus. All irrelevant records were excluded, and details of the trials and the reasons for their exclusion were noted in the Characteristics of excluded studies in RevMan 5.1 (RevMan 2011).

 

Data extraction and management

Two review authors (EvZ, ZF) entered details for the included trials into the tables in the 'Characteristics of included studies' in RevMan 5.1 (RevMan 2011) and collected outcome data using a pre-determined form designed for this purpose. Two review authors (EvZ, ZF) extracted data independently and in duplicate and included them if consensus was reached. Trial investigators were contacted and were asked to provide missing data or to clarify study details (see  Table 3).

The review authors extracted the following details.

  1. Trial methods
    1. sequence generation
    2. method of concealment of allocation
    3. masking of participants, trialists and outcome assessors
    4. exclusion of participants after randomisation and proportion and reasons for losses at follow-up
  2. Participants
    1. country of origin and study setting
    2. sample size
    3. age
    4. gender
    5. inclusion and exclusion criteria
  3. Intervention group
    1. type of LMWH
    2. dose and frequency
    3. duration of intervention and follow-up
  4. Control group
    1. dose and frequency
    2. duration of intervention and follow-up
  5. Outcomes: primary and secondary outcomes mentioned in the 'Types of outcome measures' section of this review and categorised and grouped accordingly: short-term data at 3, 6 and 12 months and medium- to long-term data (beyond one year).

If stated in the trial reports, the review authors recorded the sources of funding of all included studies and used this information to help in assessment of the clinical heterogeneity and external validity of all included trials.

 

Assessment of risk of bias in included studies

Two review authors (EvZ, ZF) independently assessed the selected trials using a simple contingency form and in accordance with the domain-based evaluation described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions 5.1 (Higgins 2011a). The review authors compared evaluations and discussed and resolved any inconsistencies in these evaluations.

The review authors assessed the following domains as having low, unclear or high risk of bias:

  1. sequence generation;
  2. allocation concealment;
  3. blinding (of participants, personnel and outcome assessors);
  4. incomplete outcome data addressed;
  5. free of selective outcome reporting;
  6. free of other bias.

The review authors reported these assessments for each trial in the 'Characteristics of included studies' tables and in the 'Assessment of risk of bias in included studies' section of this review.

The authors categorised and reported the overall risk of bias of each of the included studies according to the following:

  • low risk of bias (plausible bias unlikely to seriously alter the results) if all criteria met;
  • unclear risk of bias (plausible bias that raises some doubt about the results) if one or more criteria assessed as unclear; or 
  • high risk of bias (plausible bias that seriously weakens confidence in the results) if one or more criteria not met.

 

Measures of treatment effect

The review authors sought advice from the Cochrane Cystic Fibrosis and Genetic Diseases Group with regard to statistical analysis for data synthesis. They analysed the data using RevMan 5.1 and report the results according to Cochrane Collaboration criteria (RevMan 2011). The authors analysed binary data and report risk ratios (RRs) with corresponding 95% confidence intervals (CIs); they also analysed continuous outcomes and report mean differences (MDs) between treatment groups and their 95% CIs. For future updates, if different scales or different units are collected for continuous outcomes, the review authors will calculate and present the data using the standardised mean difference (SMD). In addition, for repeated observations for individual participants and for events that may recur, the authors will follow Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011c).

 

Unit of analysis issues

In future updates, if cluster-randomised or cross-over trials are included, they will be checked for unit of analysis errors based on the advice provided in Chapters 16.3.4 and 16.4.4 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011d). For repeated observations per participant and for events that may recur, the review authors will follow guidance provided in Chapters 9.3.4 and 9.3.5, respectively, of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011d).

 

Dealing with missing data

The review authors contacted principal investigators of included trials to request missing data and followed the advice provided in Chapter 16.1 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011d) (see  Table 3).

 

Assessment of heterogeneity

The review authors will assess in future updates (when more studies are included) clinical diversity between trials by examining trial characteristics, similarities between types of participants, the interventions and the outcomes as specified in the inclusion criteria.
They will explore statistical heterogeneity using a Chi2 test and the I2 statistic, where I2 values of 30% to 60% indicate moderate to high, 50% to 90% substantial, and 75% to 100% considerable heterogeneity. The review authors will consider heterogeneity to be significant when the P value is less than 0.10 for the Chi2 test (Higgins 2003).

 

Assessment of reporting biases

In view of the low number of trials included, this assessment was not undertaken. In future updates, and if a sufficient number of trials (at least 10) assessing similar interventions are identified for inclusion in this review, the review authors plan to assess publication bias according to the recommendations on testing for funnel plot asymmetry as described in Chapter 10 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). If asymmetry is identified, the review authors will attempt to assess other possible causes, and these will be explored in the discussion section of the review if appropriate.

 

Data synthesis

Two review authors (ZF, EvZ) analysed the data in RevMan 5.1 (RevMan 2011) and reported them as specified in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions 5.1 (Higgins 2011c). They used a fixed-effect model to analyse data from studies, unless in future updates they plan to identify moderate or higher heterogeneity (see classifications above), in which case they will use a random-effects model to analyse data.

 

Subgroup analysis and investigation of heterogeneity

In future updates, if a sufficient number of trials are included and if the authors identify moderate, substantial or considerable heterogeneity (see 'Assessment of heterogeneity'), they plan to carry out the following subgroup analyses based on:

  • type of LMWH;
  • type of SCD: sickle cell anaemia; haemoglobin SC disease; sickle cell β0-thalassaemia; sickle cell β+-thalassaemia;
  • different dosing schedules.

 

Sensitivity analysis

The review authors will undertake sensitivity analyses in future updates if a larger number of trials are included, to assess the robustness of their review results by repeating the analysis with the following adjustments:

  • exclusion of trials with an unclear or high risk of bias for allocation concealment;
  • exclusion of trials with an unclear or high risk of bias for blinding of outcome assessment;
  • exclusion of trials with an unclear or high risk of bias for completeness of follow-up;
  • exclusion of CCTs.

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Description of studies

 

Results of the search

Study selection was carried out independently by both review authors (EvZ and ZF), who retrieved two studies, one of which was a duplicate. The review authors also identified one ongoing trial (see Characteristics of ongoing studies). For further details, see the 'Study Flow Diagram' (Figure 1).

 FigureFigure 1. Study flow diagram.

 

Included studies

One study comprising 253 participants was included (Qari 2007, see the 'Characteristics of included studies' section).

 

Characteristics of the trial setting and methods

The study was a randomised placebo-controlled trial conducted in three hospitals in Saudi Arabia.

 

Characteristics of the participants

A total of 253 participants (men and women) of around 22 years of age with homozygous SCD and with painful vaso-occlusive crises, severe enough to require narcotic analgesia, were included.

 

Characteristics of the interventions

Tinzaparin at 175 IU/kg given subcutaneously versus placebo was evaluated over seven days. All participants received standard analgesic therapy consisting of morphine at 1 mg/h given by intravenous infusion and rehydration with normal saline.

 

Characteristics of the outcome measures

Seven outcome measures were assessed, including pain intensity and duration, as well as complications and adverse events of the therapy (see 'Characteristics of included studies' for further details).

 

Excluded studies

No studies were excluded; just one study and a duplicate remained after assessment of the titles and abstracts resulting from the searches.

 

Risk of bias in included studies

The review authors assessed the included study for risk of bias and reported the judgements for the individual domains in the risk of bias table associated with the study. The review authors have also presented these in the risk of bias graph in Figure 2 and in a summary of the risk of bias in Figure 3.

 FigureFigure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
 FigureFigure 3. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

 

Allocation

 

Sequence generation

The method used to generate the allocation sequence was not described, and the review authors judged this domain as having an unclear risk of bias.

 

Allocation concealment

The method used to conceal the allocation sequence was not reported, and a judgement of an unclear risk of bias was given for this domain.

 

Blinding

Reporting of the measures used to blind study participants and personnel from knowledge of which intervention a participant received was inadequate, as was information on blinding of the outcome assessment. Therefore, a clear judgement could not be made for these domains.

 

Incomplete outcome data

No losses to follow-up were reported, and this domain was therefore judged as having a low risk of bias.

 

Selective reporting

Athough the protocol was not available, all pre-specified outcomes appear to have been reported, and this domain was assessed as having a low risk of bias.

 

Other potential sources of bias

One of the investigators was employed by Leo Pharmaceutical Products (Athens, Greece), the manufacturer of tinzaparin, and a potential risk of bias cannot be excluded.

 

Effects of interventions

See:  Summary of findings for the main comparison Tinzaparin compared to placebo for people with sickle cell disease

 

Tinzaparin versus placebo

One single study provided data for this comparison (Qari 2007).

 

Primary outcomes

 
1. Pain
 
a. Intensity (expressed as scores obtained through any validated patient-reported outcomes instrument, either generic or SCD specific)

No precise data were reported; therefore, these were estimated from the graph-plot in the report. The authors indicated that at days two and three, the pain severity score was lower in the tinzaparin group than in the placebo group (P < 0.01 (ANOVA)), in addition to that at day 4 (P < 0.05 (ANOVA)), and thus that tinzaparin resulted in more rapid resolution of pain as measured by the numerical pain scale (NMS).

 
b. Duration

In the tinzaparin group, the duration of painful crises was 2.57 days (standard deviation (SD) 0.45) versus 4.35 days (0.78) for the placebo group; mean difference (MD) -1.78 days (95% CI -1.94 to -1.62), and this difference was statistically significant in favour of tinzaparin ( Analysis 1.1).

 
2. The requirement for opiate treatment

This outcome was inadequately reported, only that during the study all participants received standard analgesia therapy consisting of morphine at 1 mg/h given via intravenous infusion and rehydration with normal saline.

 

Secondary outcomes

 
1. Number of serious complications of SCD

Not assessed.

 
2. Number of other sickle-related events

Not assessed.

 
3. Quality of life (e.g. absence from school, lost time at work, mobility) as assessed by any validated questionnaire, either generic or SCD specific

Not assessed.

 
4. Hospitalisation (number and duration)

Participants treated with tinzaparin had statistically significantly fewer hospitalisation days compared with those in the group treated with placebo. The number of days in the tinzaparin group was 7.08 (SD 1.8), and in the placebo group, the number was 12.06 (2.2), MD -4.98 days (95% CI -5.48 to -4.48) ( Analysis 1.2).

 
5. Participant satisfaction with the medication assessed by any appropriate and validated questionnaire (either generic or SCD specific)

Not assessed.

 
6. Adverse events associated with the use of anticoagulants (e.g. bleeding)

Two minor bleeding events were reported in the tinzaparin group compared with none in the placebo group, RR 4.96 (95% CI 0.24 to 102.31); P value = 0.30). The difference was not statistically significant ( Analysis 1.3).

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Summary of main results

One study at unclear to high risk of bias, which examined 253 participants, was included. This study reported that tinzaparin reduced hospitalisation days and pain, as well as pain intensity, more rapidly when compared with placebo. The review authors identified an ongoing trial that, although it is investigating the effects of another LMWH dalteparin, will address several common outcome measures and may contribute to the body of evidence (NCT01419977).

For further details, see the ' Summary of findings for the main comparison'.

 

Overall completeness and applicability of evidence

Incomplete evidence was found to support or refute the effectiveness of LMWHs for the management of vaso-occlusive crises in individuals with SCD. Although adequately powered, the single trial included in this review failed to address the majority of clinically relevant secondary outcomes, not least of all change in 'quality of life' and patient satisfaction; this somewhat limits the applicability of the evidence generated. However, the low number of adverse events reported appeared to illustrate the relative safety of the use of tinzaparin, albeit only over a short period of treatment time. The single ongoing study that was identified may eventually help to fill in some of the gaps in evidence for the effectiveness of LMWHs in managing vaso-occlusive crises.

 

Quality of the evidence

 

Limitations in study design and implementation

Although the study design of the included study appeared to have been at best adequate, our assessment of the risk of bias for several domains in this study revealed some of the limitations in its implementation, which have been reported in the 'Risk of bias in included studies' section of this review. In particular, after unsuccessful attempts to contact the investigators in this study, the methods used to generate the sequence and to conceal the allocation and the measures taken to blind investigators and participants remained unclear. Pain intensity and duration are key outcomes and require accurate assessment with the use of a valid and reliable tool. The NMS pain scale used in the study did not appear to meet these criteria, making it difficult for the review authors to interpret the value of the reported outcomes and to further translate these into clinical practice.

 

Indirectness of the evidence

Participants in the included study in general constituted a clinically representative sample, matching the inclusion criteria; therefore, the review authors had no significant concerns about the appropriateness of including participants identified in the review.

Placebo-controlled rather than head-to-head trials are still required to evaluate whether LMWHs have any beneficial effect on vaso-occlusive crises. These trials should also consider evaluating other LMWHs.

The study addressed several of our predefined outcomes; however, evidence was lacking on a requirement of opiates for pain relief and of participants' assessed outcomes (e.g. health-related quality of life (HRQOL) and participants' level of' satisfaction). Patient-relevant outcomes are a pre-requisite for informing evidence-based clinical decision making, but the importance of patient-reported outcomes (PROs), specifically those used in evaluating the impact of the intervention on quality of life, appears to have been underestimated by the investigators in the included study.

 

Inconsistency of the results

As only one study was included, assessment of inconsistency was not feasible.

 

Imprecision of the results

Only one study was included.

 

Publication bias

Although our attempts to identify additional studies were unsuccessful, the possibility of unpublished research on this topic cannot be excluded. In future updates, and if further trials are identified for inclusion, we will assess publication bias as specified in the Assessment of reporting biases section of this review.

 

Potential biases in the review process

We made every attempt to limit bias in the review process by ensuring a comprehensive search for potentially eligible studies. The review authors' independent assessments of eligibility of studies for inclusion in this review minimised the potential for additional bias.

 

Agreements and disagreements with other studies or reviews

A number of literature reviews have described a range of management strategies for sickle cell disease-related vaso-occlusive crises; the most recent and relevant for our review is Mousa 2010, which referred to the only RCT (Qari 2007) identified in this systematic review and indicated that treatment with tinzaparin is "justified in the treatment of acute painful crisis in SCA based on that randomized controlled trial". The report specifies tinzaparin as adjuvant therapy in its "evidence based recommendations for pain management" but provides no indication of any systematic search of the literature, nor a critical appraisal of the cited references, but rather states that these recommendations are based on the "long term experience" of a panel of physicians and scientists.

Several studies have suggested the possible use of tinzaparin to control the hypercoagulable state occurring in SCD (De Franceschi 2009; Hirani 2011; Mousa 2010), but all were based on one study (Qari 2007). Whilst these investigators recognize its potential use in managing vaso-occlusive crises, they concur that it is still an experimental treatment option and provide no general recommendation as long as further studies have not been conducted.

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

 

Implications for practice

Current recommendations and practices for the management of vaso-occlusive crises in people with SCD continue to be largely based on clinicians' judgement. However, the results of this review demonstrate that at present, high-level objective evidence is insufficient to support reliable clinical decision making regarding the use of LMWHs in patients with SCD.

 
Implications for research

This review highlights the need for further randomised placebo-controlled trials to evaluate the effects of LMWHs in the management of vaso-occlusive crises in patients with SCD, which can ultimately provide reliable evidence to help inform clinical decision making.

Studies with other types of LMWHs, as well as in participants with different genotypes of SCD, still need to be carried out to confirm or dismiss the results reported by this single study.

Any future RCTs must be well designed, well conducted and adequately delivered with subsequent reporting, including high-quality descriptions of all aspects of methodology. Reporting should conform to the Consolidated Standards of Reporting Trials (CONSORT) statement (http://www.consort-statement.org/), which will enable appraisal and interpretation of results, as well as accurate judgements to be made about the risk of bias and the overall quality of the evidence.

Although it is uncertain whether reported quality mirrors actual study conduct, it is noteworthy that studies with unclear methodology have been shown to produce biased estimates of treatment effects (Schulz 1995).

For further research recommendations based on the EPICOT (evidence, population, intervention, comparison, outcomes and time) format (Brown 2006), see  Table 4.

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

The authors would like to thank Amani Al Hajeri, Moiz Bakhiet, Joel Beleno and Nilda Manansala for their contributions to the drafting of this protocol. The authors would also like to thank Tracey Remmington and Nikki Jahnke of the Cochrane Cystic Fibrosis and Genetic Disorders Group for their support in developing this review.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
Download statistical data

 
Comparison 1. Tinzaparin versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Duration of the pain1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 2 Number of hospitalisations days1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 3 Number of adverse events1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 

History

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

Protocol first published: Issue 10, 2012
Review first published: Issue 6, 2013


DateEventDescription

10 October 2012AmendedA post hoc change has been made to the protocol to include all LMWHs rather than just one (tinzaparin) as previously included. This is to provide a more comprehensive review of this treatment area.



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

EvZ and ZF are responsible for the following:

  • designing and co-ordinating the review (EVZ, ZF);
  • co-ordinating the review (EvZ);
  • organising the retrieval of papers (EvZ);
  • writing to authors of papers for additional information (EvZ);
  • screening search results (EvZ, ZF);
  • screening retrieved papers against inclusion criteria (EvZ, ZF);
  • appraising the quality of papers (EvZ, ZF);
  • data collection for the review (EvZ, ZF);
  • extracting data from papers (EvZ, ZF);
  • obtaining and screening data on unpublished trials (EvZ);
  • the analysis and interpretation of data (EvZ, ZF);

Both review authors contributed to development of the protocol.
ZF is the guarantor of the review.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

No financial conflicts of interest have been reported, and the authors declare that they do not have any associations with any parties who may have vested interests in the results of this review.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Internal sources

  • No sources of support, Bahrain.
  • No sources of support, Netherlands.

 

External sources

  • No sources of support, Netherlands.
  • No sources of support, Bahrain.

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

A post hoc change was made to the original protocol (before publication of the full review) to include all LMWHs rather than just one (tinzaparin), as was previously included. This was done in an effort to provide a more comprehensive review of this treatment area.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to ongoing studies
  20. Additional references
Qari 2007 {published data only}
  • Qari MH, Aljaouni SK, Alardawi MS, Fatani H, Alsayes FM, Zografos P, et al. Reduction of painful vaso-occlusive crisis of sickle cell anaemia by tinzaparin in a double-blind randomized trial. Thrombosis and Haemostasis 2007;98(2):392-6. [PUBMED: PMID: 17721622]
  • Qari MH, Mousa S, Alsaigh MA, Zografos P, Aljaouni SK, Fatani H, et al. Tinzaparin in the management of painful vaso-occlusive crisis of sickle cell anaemia. Blood 2005;106(11):Abstract no: 2340.

References to ongoing studies

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to ongoing studies
  20. Additional references
NCT01419977 {unpublished data only}
  • NCT01419977. Treatment of sickle cell patients hospitalized in pain crisis with prophylactic dose low-molecular-weight heparin (LMWH) versus placebo. www.clinicaltrials.gov/show/NCT01419977 (accessed 01 March 2013).

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to ongoing studies
  20. Additional references
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