Pro-coagulant haemostatic factors for the prevention and treatment of bleeding in patients without haemophilia

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effects and safety of pro-coagulant haemostatic factors and factor concentrates in the prevention and treatment of bleeding in patients without haemophilia.

Background

Description of the condition

Bleeding (the acute loss of intravascular volume) carries a risk of mortality and significant morbidity, which requires urgent medical and surgical management. Patients with on-going bleeding frequently develop a coagulopathy, either due directly to the bleeding or as a consequence of the resuscitation strategy employed, including the use of blood transfusions. Coagulopathy (dysfunctional clotting response) is typically defined by abnormalities of standard coagulation tests performed in haematology laboratories, including the prothrombin time or the activated partial thromboplastin time, both of which are in vitro tests of the time taken for a plasma sample to form a clot, although there are no clear definitions of what levels of abnormalities of these tests are clinically significant (Tripodi 2009).

Coagulopathy is common in critically ill patients, both in patients with and without bleeding, because of the nature of their illness. In a recent multi-centre prospective observational study in adult critical care, which evaluated just under 2000 intensive-treatment-unit (ITU) admissions, one third of patients, without active bleeding, were shown to develop coagulopathy during their ITU admission (Walsh 2009).

The commonest medical treatment for patients with coagulopathy remains the transfusion of plasma. Plasma is the liquid component of blood in which different cellular elements and macromolecules are suspended. Plasma contains pro-coagulant haemostatic proteins which are a key component of the haemostatic system. These pro-coagulant haemostatic proteins, known as blood clotting factors, interact with each other, platelets and tissues to form stable blood clots. Around one-third of the patients with coagulopathy received transfusions of plasma (termed fresh frozen plasma, FFP, in the UK), with around half of all FFP transfusions given to reduce a perceived risk of bleeding or prior to invasive procedures (Stanworth 2011; Walsh 2009).

Whilst the use of FFP has increased significantly in recent years, the optimal use of plasma transfusion in clinical practice is poorly defined and the risk-benefit profile of FFP remains unknown. As for all allogeneic blood components, FFP is a costly and scarce biological resource associated with risks. The theoretical benefit of FFP (correcting clotting factor deficiency, improving coagulopathy, reducing blood loss and decreasing bleeding complications) needs to be balanced against the risks associated with its use (fluid overload, transfusion-related acute lung injury, along with the generic risks associated with transfusion of allogeneic blood products). Whilst many of the risks are captured (and can be quantified) by national haemovigilance systems (e.g. Serious Hazards of Transfusion (SHOT) in the UK (SHOT 2011)), there are concerns about the actual effectiveness of FFP in improving abnormalities of coagulation tests. A national audit of 5000 FFP transfusion episodes to consecutive patients from 196 hospitals across England indicated very small median changes in levels of PT following FFP transfusion (Stanworth 2010). A recent systematic review of randomised controlled trials (RCTs) examining the use of FFP identified 80 trials but, despite the large number of trials, the evidence base for the effectiveness of plasma was very weak (Yang 2012).

Description of the intervention

Given concerns about the supply, safety and effectiveness of plasma transfusion, there is increasing interest in the targeted use of specific or purified intravenous pro-coagulant haemostatic factors. Many different intravenous pro-coagulant haemostatic factors exist, including those derived from plasma as concentrates, or those developed as specific recombinant factors. The advantages of plasma derived coagulation factor concentrates include greater standardisation (whether at the stage of production or during manufacture) and reduced infective and compatibility complications when compared with blood transfusions through the application of techniques such as pasteurisation, nanofiltration and adsorption to remove viruses. The advantages of recombinant derived factors include potentially unlimited supply, with reduced reliance on the availability of blood donors, as well as negligible infective risk. Finally, both recombinant and plasma-derived intravenous concentrates offer the potential advantage of providing specific pro-coagulant haemostatic factors more rapidly and at higher concentrations than is possible with the use of traditional plasma transfusion. 

Some of the plasma-derived coagulation factor concentrates contain multiple pro-coagulant haemostatic factors. Prothrombin complex concentrates are plasma-derived coagulation factor concentrates that contain three or four (vitamin K-dependent) factors at high concentration. In the UK, prothrombin complex concentrates are now increasingly being considered for use in patients with acquired coagulopathy, and may be given with cryoprecipitate (a blood component which is derived from plasma and transfused to patients as a concentrated source of fibrinogen). The combination of prothrombin complex concentrates and fibrinogen concentrate is being employed as first line therapy in some European countries for patients with severe bleeding following trauma. Two observational cohort studies have examined the use of prothrombin complex concentrates as an adjunct to fibrinogen concentrate in the management of bleeding following trauma. Whilst neither of these studies demonstrated reduced mortality in those receiving prothrombin complex concentrates, one of the studies demonstrated an association between receiving prothrombin complex concentrates and a reduced transfusion requirement (Görlinger 2011). Safety data on the use of prothrombin complex concentrates are limited. In particular, rates of thrombosis, both arterial and venous, and disseminated intravascular coagulation need to be fully assessed (Grottke 2011).

In contrast to concentrates containing multiple factors, single recombinant pro-coagulant haemostatic factors allow the treatment of individual clotting factor deficiencies to be specifically targeted. For example, recombinant factor VIIa (rVIIa; NovoSeven®) is a recombinant factor which has been extensively investigated in patients without haemophilia, although with uncertain benefit and potential risks of increased arterial thromboembolic events (Simpson 2012). A specific concentrate of the key pro-coagulant haemostatic factor fibrinogen (or factor I) is now available, although currently only licensed for use in patients with inherited hypofibrinogenaemia. There is increasing interest in its use in major obstetric haemorrhage, which is frequently associated with the development of disseminated intravascular coagulopathy and hypofibrinogenaemia. The observation that normal-to-high levels of fibrinogen (in the range 1.5 to 4.0 g/L) prior to the onset of major obstetric haemorrhage are associated with improved outcomes (Charbit 2007; de Lloyd 2011), has led clinicians to consider targeted therapy with concentrates of fibrinogen in this cohort of patients rather than the more traditional use of FFP or cryoprecipitate.

How the intervention might work

Specific coagulation factors and factor concentrates are presumed to stop or prevent bleeding, by providing a source of pro-coagulant haemostatic factors which, alongside contributions from platelets and the endothelium, interact to produce a stronger fibrin clot. The rationale for their use is based on either restoring or increasing levels of pro-coagulant haemostatic factors, or activating clotting systems by infusing recombinant activated complexes to initiate coagulation.

It is hypothesised that pro-coagulant haemostatic factors administered intravenously might work more effectively than plasma (either FFP or cryoprecipitate) to deliver a more concentrated source of factors which will raise factor levels more effectively and predictably using a standardised product. Given that the current processes for thawing and/or cross-matching of blood components would not apply to pro-coagulant haemostatic factors, it is also likely these agents would be more rapidly available for use in emergency situations.

However, as for all pro-coagulant haemostatic agents, adverse events are recognised. In particular, use of these agents might be expected to be associated with a greater rate of thromboembolic events. This has been clearly demonstrated in meta-analyses of RCTs of rFVIIa in patients without haemophilia (Levi 2010; Simpson 2012).

Why it is important to do this review

The optimal use of pro-coagulant haemostatic factors in the management of patients with bleeding, or at risk of bleeding, is unclear. In a relatively short period there has been a rapid shift in the clinician's approach to the management of coagulopathy and bleeding, with an increasing interest in the use of specific intravenous pro-coagulant haemostatic factors instead of the current standard of plasma transfusion. Because of the real uncertainties about the effectiveness and safety of FFP, wider use of the pro-coagulant haemostatic factors and evaluation in clinical trials are anticipated.

Pro-coagulant haemostatic factors and drugs are often very costly and lessons should be learned from the story of rFVIIa. rFVIIa was 'marketed' as a universal haemostatic agent but then was found to have uncertain benefit with potential harm (Levi 2010; Simpson 2012), emphasising the importance of a systematic review to identify and appraise the RCT literature as it evolves.

An up-to-date review of the evidence for the clinical use of these pro-coagulant haemostatic factors prior to their expansion in use would be timely. This Cochrane review will build on the experience gained from the rFVIIa Cochrane review (Simpson 2012), and is necessary to comprehensively identify and critically appraise all the RCT evidence assessing the use of intravenous pro-coagulant haemostatic factors, considering both their effectiveness and safety. This systematic review will also indicate where evidence is lacking, so informing health care professionals where more evidence is required before these expensive drugs are widely accepted into clinical practice.

Objectives

To assess the effects and safety of pro-coagulant haemostatic factors and factor concentrates in the prevention and treatment of bleeding in patients without haemophilia.

Methods

Criteria for considering studies for this review

Types of studies

We will only include RCTs.

Types of participants

We will include adults and children (with no age restriction) either at risk of bleeding or bleeding due to any cause. We will exclude patients with known congenital haemostatic disorders (e.g. haemophilia) unless any data in a trial is separately available for the patients without the congenital abnormality.

Types of interventions

We will assess separately whether a pro-coagulant haemostatic factor product is administered as a treatment or in a prophylactic manner for the following comparisons:

  1. The use of a pro-coagulant haemostatic factor product (either alone or in combination with another pro-coagulant haemostatic factor product) against either placebo or current best/standard treatment (e.g. plasma/FFP).

  2. The use of one pro-coagulant haemostatic factor product against another different pro-coagulant haemostatic factor product.

Each of the above combinations could be given in any dose.

We will include RCTs of the administration of prothrombin complex concentrates in any context, including that of warfarin (or a similar agent) reversal. We are only interested in pro-coagulant haemostatic factors that have been administered intravenously. Pro-coagulant haemostatic factors administered topically, e.g. thrombin or fibrin glue, will be excluded and are the subject of a previous Cochrane review (Carless 2009). RCTs of desmopressin, tranexamic acid and aminocaproic acid will also be excluded due to their different mechanisms of action to other pro-coagulant haemostatic agents.

Studies exclusively administering rFVIIa will be excluded from this review as they have been the subject of a recent Cochrane review (Simpson 2012). However, studies incorporating rFVIIa as well as other intravenous pro-coagulant haemostatic factors (i.e. in separate comparator arms or co-administration of rFVIIa and another factor/reagent) will be included.

Types of outcome measures

We will present outcome data from all identified RCTs by prophylactic and therapeutic indications for use. In prophylactic use, the agent was given to prevent bleeding which may be anticipated such as during an operation; in therapeutic use, the agent was given to treat bleeding which is already established.

We anticipate variation in the time points at which each outcome is measured due to the nature of the participants and condition in the trial and we will take this into account when reporting and analysing the outcome data for the identified studies. The majority of studies report outcomes acutely post- and twenty-four hours following any given intervention or procedure, compared to baseline measures. These will form our main outcome time point comparators.

Primary outcomes
  • Mortality (all-cause)

  • Arterial and venous thromboembolic events

Secondary outcomes
  • Mortality due to bleeding

  • Red blood cell transfusion requirement

  • Blood loss

  • Allergy

  • Change to laboratory measures of coagulation, both standard laboratory tests and global measurements of coagulation

Search methods for identification of studies

The Systematic Review Initative's Information Specialist (CD) will formulate the search strategies used in collaboration with the Cochrane Injuries Group.

Electronic searches

We will search for RCTs in the following electronic databases between the following dates:

  • Cochrane Injuries Group Specialised Register (recent version);

  • CENTRAL (The Cochrane Library, latest issue) (Appendix 1);

  • MEDLINE (OvidSP) (1946 to present) (Appendix 2);

  • EMBASE (1974 to present) (Appendix 3);

  • CINAHL (1982 to present) (Appendix 4);

  • PubMed (current e-publications only) (Appendix 5);

  • UKBTS SRI Transfusion Evidence Library (www.transfusionevidencelibrary.com) (from 1980 to present) (Appendix 6);

  • LILACS (from 1982 to present) (Appendix 7);

  • Conference Proceedings Citation Index, Web of Science (from 1990 to present) (Appendix 7).

We will also search for ongoing trials in the following databases (all years): 

  • ISRCTN Register (Appendix 8);

  • ClinicalTrials.gov (Appendix 9);

  • EU Clinical Trials Register (EUDRACT) (Appendix 9);

  • WHO International Clinical Trials Registry Platform (ICTRP) (Appendix 10);

  • UMIN-CTR Japanese Clinical Trials Registry and the Hong Kong Clinical Trials Registry (Appendix 10).

Searches in MEDLINE, EMBASE and CINAHL will be combined with adaptations of the Cochrane RCT search filter as detailed in chapter 6 of the Cochrane Handbook (Higgins 2011). Please see the appendices for search strategies.

Searching other resources

We will augment database searching by:

  • handsearching of reference lists - we will check references of all identified trials, relevant review articles, and current treatment guidelines for further literature. We will limit these searches to the 'first generation' reference lists;

  • personal contacts - we will contact authors of relevant studies, study groups and experts worldwide who are known to be active in the field for unpublished material or further information on ongoing studies.

Data collection and analysis

Selection of studies

One author (CD) will initially screen all search results for relevance against the eligibility criteria and discard all those that are clearly irrelevant. Thereafter, two authors (JF, NC) will independently screen all the remaining results (titles, abstracts and full text) for relevance against the full eligibility criteria. Full text papers will be retrieved for all references for which a decision of eligibility cannot be made from the title and abstract alone. If necessary, further information will be sought from the authors where articles contain insufficient data to make a decision about eligibility. Differences of opinion will be resolved through discussion and consensus, where necessary with reference to a fourth author (SS). Studies that do not meet our eligibility criteria will be detailed in the 'Characteristics of excluded studies' table.

Data extraction and management

Two authors (JF, GS) will independently extract data onto standardised forms. These forms will be piloted by the two authors on two included RCTs and changes made to the data extraction form where appropriate and agreed upon. Throughout the data extraction process any disagreements will be resolved by consensus. If agreement cannot be reached, a third author (SS) will be consulted. The review authors will not be blinded to names of authors, institutions, journals or the outcomes of the trials. If indicated, copies of trial protocols will be requested from researchers. The following data will be extracted for each trial:

  1. general information (review author's name, date of data extraction);

  2. trial details (first author of the trial report, year, contact address, citation, country, city, start and end dates, overlap of data, trial design, setting, methods of treatment allocation, randomisation and blinding, inclusion and exclusion criteria, initial number, reason for sample size, comparability of groups, length of follow up, whether intention to treat analysis was employed and funding source);

  3. characteristics of participants (age, gender, total number recruited, total number randomised, total number analysed for endpoints, losses to follow-up and drop outs (percentage in each arm) with reasons and protocol violations;

  4. interventions (experimental and control interventions, timing dosage and route of intervention, compliance to interventions e.g. not receiving full dose or schedule, additional interventions given, any differences between co-interventions e.g. transfusion protocols);

  5. outcomes (as per primary and secondary outcomes set out above, and whether the outcomes were treated as continuous or binary data, with justification of cut offs. Data extraction will include appropriate time point data for all outcomes).

Assessment of risk of bias in included studies

Two authors (JF, SB) will independently assess all included studies for possible risk of bias as described in chapter 8 of the Cochrane Handbook (Higgins 2011). Studies will be classified as being at low risk of bias, high risk of bias or unclear. To assess risk of bias, the authors will include the following questions in the risk of bias table for each included study.

  1. Was the allocation sequence adequately generated?

  2. Was allocation adequately concealed?

  3. Was knowledge of the allocated intervention adequately prevented (i.e. blinded) throughout the study for participants, study personnel and outcome assessors?

  4. Were incomplete outcome data adequately addressed for the main outcome?

  5. Are reports of the study free of selective outcome reporting?

  6. Was the study apparently free of other problems that could put it at risk of bias?

Risk of bias dimensions 2, 3, 4 and 5 above will be reported separately for each of the two main outcomes and where data allows for the secondary outcomes as well.

It is anticipated that knowledge of the allocated intervention will be difficult to blind from clinicians and participants. However we believe that it would be possible to blind knowledge of the allocated intervention from outcome assessors. We will bear these considerations in mind when assessing risk of bias for dimension 3 above, and will record all quotes from studies separately from our judgement in the risk of bias table.

Measures of treatment effect

We will present dichotomous outcomes as relative risks (RRs) with 95% confidence intervals (CIs). If we identify a small number of events, then we will explore presenting the results using Peto odds ratios (ORs) with 95% CIs. We will present continuous outcomes as mean differences (MDs) with 95% CIs.

Unit of analysis issues

In the included studies the patient is the unit of analysis.

We do not expect to encounter unit of analysis issues, as cluster-randomised trials are unlikely to be included in this review, but if any arise we will treat these in accordance with the advice given in the Cochrane Handbook (Higgins 2011).

Dealing with missing data

We will contact study authors in order to obtain information that is missing or unclear in the published report. Of particular concern will be missing outcome data and data that does not allow an assessment of risk of bias for the domains of allocation concealment, knowledge of allocation concealment (i.e. blinding) for outcome assessors and data on the number of patients lost to follow-up for each trial. Our preferred analysis will be by intention-to-treat (ITT), but if insufficient data are presented in the included studies then per protocol analyses will be presented.

Assessment of heterogeneity

We will assess clinical heterogeneity based on the data extracted about the characteristics of the included studies. Possible explanations for the observed heterogeneity will be discussed within the review.

If studies are considered to be clinically homogeneous, meta-analysis will be conducted and statistical heterogeneity of treatment effects between trials will be assessed by using a Chi2 test with a significant level at P < 0.1. The I2 index will be used to quantify the amount of possible heterogeneity (I2 > 30% as moderate heterogeneity and I2 > 75% as considerable heterogeneity). Potential causes of heterogeneity will be explored according to pre-specified subgroup and sensitivity analyses.

Assessment of reporting biases

Although it is believed that every effort will have been made to identify unpublished studies, we will assess publication bias using funnel plots if more than 10 studies are identified for inclusion. It is acknowledged that asymmetry, of which publication bias is one cause, is difficult to detect with the small numbers of studies (i.e. less than 10) often encountered in systematic reviews.

Data synthesis

We will undertake meta-analysis where studies are sufficiently homogeneous in terms of clinical setting and study design and there is sufficient data of a suitable type. We will use the Cochrane Collaboration's statistical software, Review Manager 2013. A fixed-effect model will be used for combining data in the first instance. If substantial heterogeneity is identified in a fixed-effect meta-analysis, this will be noted and the analysis repeated using a random-effects model.

For the purpose of the meta-analysis, blood loss outcome data will be log transformed and the analysis conducted using the transformed values. The formulae used for the transformations are available from the review authors. A meta-analysis (using arithmetic means) of the differences in means using the transformed blood loss data corresponds to a meta-analysis (using geometric means) of the ratio of means in the original scale. The pooled estimates will be back-transformed to give the blood loss ratios and 95% confidence intervals on the original scale.

As well as quantitative synthesis, the overall interpretation of the data will also incorporate insights from qualitative summary. Conclusions will be based on patterns of results identified across clearly tabulated results of included studies as well as summary measures. Both the direction and magnitude of any effect will be considered. Individual trial results will be presented in the 'Additional Tables' section of the review.

We will group outcome data into the outcomes listed earlier in the Types of outcome measures section. Specifically for changes in coagulation, outcome data from different time points will be analysed separately in this review.

We will create a 'Summary of Findings' table as suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The following outcomes will be included in this table:

  • All-cause mortality;

  • Mortality due to bleeding;

  • Total blood loss;

  • Red cell transfusion requirement;

  • Any complication of transfusion;

  • Total thromboembolic complications.

The quality of the evidence for each outcome will be assessed based on the GRADE system (Schünemann 2011) taking into account the risk of bias of each study, as discussed above.

Subgroup analysis and investigation of heterogeneity

We will perform a subgroup analysis if data are available to evaluate the following:

  1. children vs. adults (because different definitions of coagulopathy apply). Adults defined as 18 or older at time of recruitment.

  2. studies of patients with brain/neurological injuries. e.g. acute intracranial injury vs. no acute intracranial injury (in view of the added effect of central nervous system injury on coagulopathy and therefore the different possible efficacy of interventions in this patient group).

Sensitivity analysis

We will assess the robustness of our findings by performing sensitivity analyses (where appropriate), including only those trials:

  1. where allocation concealment is adequate; and

  2. in which 25% of participants or fewer were lost to follow up.  

Acknowledgements

None known.

Appendices

Appendix 1. CENTRAL (The Cochrane Library) search strategy

#1   MeSH descriptor Factor XIII explode all trees
#2   MeSH descriptor Fibrinogen explode all trees
#3   MeSH descriptor Thrombin, this term only
#4   MeSH descriptor Prothrombin, this term only
#5   MeSH descriptor Fibrin Foam, this term only
#6   MeSH descriptor Fibrin Tissue Adhesive, this term only
#7   (coagulation NEXT factor* or factor NEXT concentrate* or clotting NEXT factor* or recombinant NEXT factor* or plasma NEXTderived NEXT concentrate*):ti
#8 ((procoagulant* or pro NEXT coagulant* or prohaemostatic or prohemostatic* or pro NEXT haemostatic* or pro NEXT hemostatic*) NEAR/2 (factor* or agent*))
#9   (fibrinogen NEXT concentrate* or Haemocomplettan* or Clottagen* or Fibroraas*)
#10 prothrombin NEXT complex NEXT concentrate* or Beriplex* or Octaplex* or Cofact or Prothrombinex* or Proplex-T* or Prothroraas* or Haemosolvex* or Profiline* or Prothromplex* or Bebulin* or "HT Defix*" or Facnyne* or "PPSB-Human*" or "UMAN Complex*" or Kaskadil*
#11  factor NEXT XIII NEXT concentrate* or rFXIII or Fibrogammin or recombinant NEXT factor NEXT XIII
#12  (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11)
#13  MeSH descriptor Hemorrhage explode all trees
#14  (haemorrhag* or hemorrhag* or bleed* or bloodloss* or (blood NEAR/2 los*))
#15  (#13 OR #14)
#16  (#12 AND #15)

Appendix 2. MEDLINE (Ovid) search strategy

1. exp Hemorrhage/
2. (haemorrhag* or hemorrhag* or bleed* or bloodloss* or (blood adj3 los*)).tw.
3. 1 or 2
4. exp Factor XIII/
5. *Fibrinogen/
6. Prothrombin/
7. (coagulation factor* or factor concentrate* or clotting factor* or recombinant factor* or plasma-derived concentrate*).ti.
8. ((procoagulant* or pro-coagulant* or prohaemostatic or prohemostatic* or pro-haemostatic* or pro-hemostatic*) adj (factor* or agent*)).tw.
9. (fibrinogen concentrate* or Haemocomplettan* or Clottagen* or Fibroraas*).tw.
10. (prothrombin complex concentrate* or Beriplex* or Octaplex* or Cofact or Prothrombinex* or Proplex-T* or Prothroraas* or Haemosolvex* or Profiline* or Prothromplex* or Bebulin* or "HT Defix*" or Facnyne* or "PPSB-Human*" or "UMAN Complex*" or Kaskadil*).tw.
11. (factor XIII concentrate* or rFXIII or Fibrogammin or recombinant factor XIII).tw.
12. 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11
13. 3 and 12
14. ((haemophilia* or hemophilia*) not (non or without)).ti.
15. 13 not 14

Appendix 3. EMBASE (Ovid) search strategy

1. exp Bleeding/
2. (haemorrhag* or hemorrhag* or bleed* or bloodloss* or (blood adj3 los*)).tw.
3. 1 or 2
4. Blood Clotting Factor 13/
5. *Fibrinogen/
6. Prothrombin Complex/
7. (coagulation factor* or factor concentrate* or clotting factor* or recombinant factor* or plasma-derived concentrate*).ti.
8. ((procoagulant* or pro-coagulant* or prohaemostatic or prohemostatic* or pro-haemostatic* or pro-hemostatic*) adj2 (factor* or agent*)).tw.
9. (fibrinogen concentrate* or Haemocomplettan* or Clottagen* or Fibroraas*).tw.
10. (prothrombin complex concentrate* or Beriplex* or Octaplex* or Cofact or Prothrombinex* or Proplex-T* or Prothroraas* or Haemosolvex* or Profiline* or Prothromplex* or Bebulin* or "HT Defix*" or Facnyne* or "PPSB-Human*" or "UMAN Complex*" or Kaskadil*).tw.
11. (factor XIII concentrate* or rFXIII or Fibrogammin or recombinant factor XIII).tw.
12. 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11
13. 3 and 12
14. ((haemophilia* or hemophilia*) not (non or without)).ti.
15. 13 not 14

Appendix 4. CINAHL (NHS Evidence) search strategy

1. exp Hemorrhage/
2. (haemorrhag* or hemorrhag* or bleed* or bloodloss* or (blood adj3 los*)).ti,ab
3. 1 or 2
4. Fibrinogen/
5. (coagulation factor* or factor concentrate* or clotting factor* or recombinant factor* or plasma-derived concentrate*).ti
6. (procoagulant* or pro-coagulant* or prohaemostatic or prohemostatic* or pro-haemostatic* or pro-hemostatic*).ti,ab
7. (fibrinogen concentrate* or Haemocomplettan* or Clottagen* or Fibroraas*).ti,ab
8. (prothrombin complex concentrate* or Beriplex* or Octaplex* or Cofact* or Prothrombinex* or Proplex-T* or Prothroraas* or Haemosolvex* or Profiline* or Prothromplex* or Bebulin* or HT Defix* or Facnyne* or PPSB-Human* or UMAN Complex* or Kaskadil*).ti,ab
9. (factor XIII concentrate* or rFXIII or Fibrogammin or recombinant factor XIII).ti,ab
10. 4 or 5 or 6 or 7 or 8 or 9
11. 3 and 10
12. ((haemophilia* or hemophilia*) not (non or without)).ti.
13. 11 not 12

Appendix 5. PUBMED search strategy

1. haemorrhag*[TIAB] OR hemorrhag*[TIAB] OR bleed*[TIAB] OR bloodloss*[TIAB] OR blood los*[TIAB] OR “loss of blood” [TIAB]
2. coagulation factor*[TI] OR factor concentrate*[TI] OR clotting factor*[TI] OR recombinant factor*[TI] OR plasma-derived concentrate*[TI]
3. procoagulant*[TIAB] OR pro-coagulant*[TIAB] OR prohaemostatic[TIAB] OR prohemostatic*[TIAB] OR pro-haemostatic*[TIAB] OR pro-hemostatic*[TIAB]
4. fibrinogen concentrate*[TIAB] OR Haemocomplettan*[TIAB] OR Clottagen*[TIAB] OR Fibroraas*[TIAB]
5. prothrombin complex concentrate*[TIAB] OR Beriplex*[TIAB] OR Octaplex*[TIAB] OR Cofact*[TIAB] OR Prothrombinex*[TIAB] OR Proplex-T*[TIAB] OR Prothroraas*[TIAB] OR Haemosolvex*[TIAB] OR Profiline*[TIAB] OR Prothromplex*[TIAB] OR Bebulin*[TIAB] OR HT Defix*[TIAB] OR Facnyne*[TIAB] OR PPSB-Human*[TIAB] OR UMAN Complex*[TIAB] OR Kaskadil*[TIAB]
6. factor XIII concentrate*[TIAB] OR rFXIII[TIAB] OR Fibrogammin[TIAB] OR recombinant factor XIII[TIAB]
7. #2 OR #3 OR #4 OR #5 OR #6
8. #1 AND #7
9. ((haemophili*[TI] OR hemophili*[TI]) NOT (non[TI] OR without[TI]))
10. #8 NOT #9
11. publisher[SB] NOT pubstatusnihms
12. #10 AND #11
13. (random*[TIAB] OR blind*[TIAB] OR trial*[TIAB] OR prospective*[TIAB] OR allocat*[TIAB] OR assign*[TIAB] OR  control group*[TIAB] OR crossover[TIAB] OR cross-over[TIAB] OR systematic*[TIAB] OR metaanalys*[TIAB] OR meta-analys*[TIAB] OR search*[TIAB] OR literature review[TIAB] OR study[TIAB] OR studies[TIAB])
14. #12 AND #13

Appendix 6. TRANSFUSION EVIDENCE LIBRARY search strategy

1. haemorrhag* OR hemorrhag* OR bleed* OR bloodloss* OR blood los* OR "loss of blood"
2. coagulation factor* OR factor concentrate* OR clotting factor* OR recombinant factor* OR plasma-derived concentrate* OR procoagulant* OR pro-coagulant* OR prohaemostatic OR prohemostatic* OR pro-haemostatic* OR pro-hemostatic*
3. fibrinogen concentrate* OR Haemocomplettan* OR Clottagen* OR Fibroraas* OR prothrombin complex concentrate* OR Beriplex* OR Octaplex* OR Cofact* OR Prothrombinex* OR Proplex-T* OR Prothroraas* OR Haemosolvex* OR Profiline* OR Prothromplex* OR Bebulin* OR HT Defix* OR Facnyne* OR PPSB-Human* OR UMAN Complex* OR Kaskadil*
4. factor XIII concentrate* OR rFXIII OR Fibrogammin OR recombinant factor XIII
5. 2 OR 3 OR 4
6. 1 AND 5

Appendix 7. LILACS & Web of Science search strategy

1. (haemorrhag$ OR hemorrhag$ OR bleed$ OR bloodloss$ OR blood los$ OR "loss of blood")
2. (factor$ OR plasma-derived concentrate$ OR procoagulant$ OR pro-coagulant$ OR prohaemostatic OR prohemostatic$ OR pro-haemostatic$ OR pro-hemostatic$ OR fibrinogen concentrate$ OR Haemocomplettan$ OR Clottagen$ OR Fibroraas$ OR prothrombin complex concentrate$ OR Beriplex$ OR Octaplex$ OR Cofact$ OR Prothrombinex$ OR Proplex-T$ OR Prothroraas$ OR Haemosolvex$ OR Profiline$ OR Prothromplex$ OR Bebulin$ OR HT Defix$ OR Facnyne$ OR PPSB-Human$ OR UMAN Complex$ OR Kaskadil$ OR factor XIII concentrate$ OR rFXIII OR Fibrogammin OR recombinant factor XIII)
3. 1 AND 2

Appendix 8. ISRCTN search strategy

((hemorrhage OR haemorrhage OR haemorrhaging OR hemorrhaging OR bleed OR bleeding) AND (coagulation factor OR factor concentrate OR clotting factor OR recombinant factor OR plasma-derived concentrate OR procoagulant))
((hemorrhage OR haemorrhage OR haemorrhaging OR hemorrhaging OR bleed OR bleeding) AND (progcoagulants OR pro-coagulant OR prohaemostatic OR prohemostatic OR pro-haemostatic OR pro-hemostatic OR fibrinogen OR Haemocomplettan OR Clottagen OR Fibroraas))
((hemorrhage OR haemorrhage OR haemorrhaging OR hemorrhaging OR bleed OR bleeding) AND (prothrombin complex concentrate OR Beriplex OR Octaplex OR Cofact OR Prothrombinex OR Proplex OR Prothroraas OR Haemosolvex OR Profiline OR Prothromplex))
((hemorrhage OR haemorrhage OR haemorrhaging OR hemorrhaging OR bleed OR bleeding) AND (Bebulin OR Facnyne OR Kaskadil OR rFXIII OR Fibrogammin))

Appendix 9. ClinicalTrials.gov & EUDRACT search strategy

(hemorrhage AND (coagulation factor OR factor concentrate OR clotting factor OR recombinant factor OR plasma-derived concentrate OR procoagulant OR pro-coagulant OR prohaemostatic OR prohemostatic OR pro-haemostatic OR pro-hemostatic OR fibrinogen OR Haemocomplettan OR Clottagen OR Fibroraas OR prothrombin complex concentrate OR Beriplex OR Octaplex OR Cofact OR Prothrombinex OR Proplex OR Prothroraas OR Haemosolvex OR Profiline OR Prothromplex OR Bebulin OR Facnyne OR Kaskadil OR rFXIII OR Fibrogammin OR recombinant factor XIIi))

Appendix 10. ICTRP, UMIN-CTR Clinical Trials and HK Clinical Trials search strategy

Condition: (hemorrage OR haemorrhage OR bleeding)
AND
Title/Keywords: (factor OR concentrate OR prohemostatic OR prohaemostatic or fibrinogen)

Contributions of authors

Graham Barker led the development of the protocol, prepared the first draft of the protocol and will prepare the final draft of the protocol.

Jez Fabes has contributed to subsequent drafts of the protocol and will prepare the final draft of the protocol.

Gemma Simons has contributed to subsequent drafts of the protocol and will prepare the final draft of the protocol.

Nikki Curry is a content advisor for this review and has contributed to the protocol in this capacity.

Susan Brunskill is a methodological advisor for this review and has contributed to the protocol in this capacity.

Carolyn Doree is an information specialist and developed the 'Search Methods' section of the protocol.

Yulia Lin is a content advisor for this review and has contributed to the protocol in this capacity.

Simon Stanworth is a content advisor for this review and has contributed to the protocol in this capacity.

Declarations of interest

Yulia Lin: The author is a study site investigator for a registry on the off-label use of rFVIIa in Canada funded by an unrestricted educational grant from Novo Nordisk but receives no personal financial payments for participation in the registry.

All other authors: None known.

Sources of support

Internal sources

  • NHS Blood & Transplant, Research and Development, UK.

External sources

  • No sources of support supplied

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