Introduction
Prothrombin complex concentrates (PCCs) are an important plasma-derived therapeutic option for the rapid correction of deficiency of vitamin-K dependent clotting factors1. PCCs are produced by ion-exchange chromatography from the cryoprecipitate supernatant of large plasma pools after removal of antithrombin and factor (F) XI2. Different processing techniques involving ion exchangers permit the production of either three- (i.e., FII, FIX and FX) or four-factor (i.e., FII, FVII, FIX and FX) concentrates with a final overall clotting factor concentration approximately 25 times higher than in normal plasma (Tables I and II)3. To prevent activation of these factors, most PCCs contain heparin. In addition, they may also contain the physiological inhibitors of coagulation protein C and protein S. PCCs are standardised according to their FIX content and are subjected to viral inactivation processes, both by physical (vapour, heating) and chemical (solvent detergent treatment) methods.
Table I.
Three-factors prothrombin complex concentrates brief fact sheet.
| ATCa | B02BD |
| Definition | Three-factors prothrombin complex concentrates |
| U/Mb | I.U. |
| Therapeutic indications | Prophylaxis or treatment of bleeding in patients with congenital deficiencies, either single or multiple, of factor IX (Haemophilia B or Christmas disease), II (Prothrombin deficiency) or X (Stuart-Prower Factor deficiency); in patients with single or multiple acquired prothrombin complex factor deficiency. |
| NHS classc | A |
| Management information | - |
Anatomical Therapeutic Chemical Classification System. The World Health Organization system classifies all therapeutic medicinal products (MP). The purpose is to serve as a tool for MP utilisation research in order to improve the quality of MPs use. MPs are classified into five different levels;
Unit of Measure;
National Health Service Class.
All medicinal products are divided in classes according to the level of reimbursement by the NHS. Class A includes all medicinal products at the expense of the NHS; class H includes all medicinal products distributed only by hospital pharmacies within the Regional Healthcare Services; class C refers to all medicinal products at the private out-of-pocket expense.
Table II.
Four-factors prothrombin complex concentrates brief fact sheet.
| ATCa | B02BD01 |
| Definition | Four-factors prothrombin complex concentrates |
| U/Mb | I.U. |
| Therapeutic indications | Bleeding and perioperative prophylaxis of bleeding in patients with prothrombin complex coagulation factors deficiency, after treatment with vitamin K antagonists or in case of vitamin K antagonist overdose, the prompt correction of the deficiency is needed. Bleeding and perioperative prophylaxis in patients with congenital deficiencies of vitamin K-dependent coagulation factor II and X, when the specific purified clotting factor is not available. |
| NHS classc | H |
| Management information | - |
Anatomical Therapeutic Chemical Classification System. The World Health Organization system classifies all therapeutic medicinal products (MP). The purpose is to serve as a tool for MP utilisation research in order to improve the quality of MPs use. MPs are classified into five different levels;
Unit of Measure;
National Health Service Class.
All medicinal products are divided in classes according to the level of reimbursement by the NHS. Class A includes all medicinal products at the expense of the NHS; class H includes all medicinal products distributed only by hospital pharmacies within the Regional Healthcare Services; class C refers to all medicinal products at the private out-of-pocket expense.
Various preparations are commercially available in Italy, as reported in Tables III4 and IV4.
Table III.
Products containing three-factors prothrombin complex concentrates currently available on the Italian market.
Source: Farmadati (www.farmadati.it, accessed on 01/03/2012), processed and adapted by the Italian National Blood Centre.
| AIC codea | Name of medicinal product | I.U.b | Manufacturer | NHS classc |
|---|---|---|---|---|
| 023309103 | UMANCOMPLEX D.I.*FL 500UI+F20M | 500 | Kedrion SpA | A |
| 023288032 | PROTROMPLEX TIM3*F 600UI+20ML | 600 | Baxter SpA | A |
AIC, Autorizzazione Immissione in Commercio, Marketing authorisation. The Italian Medicine Agency (Agenzia Italiana del Farmaco, AIFA) is in charge of releasing the AIC code, which identifies each medicinal products package on the national market4;
International units of prothrombin complex concentrates contained in the medicinal product;
National Health Service Class.
All medicinal products are divided in classes according to the level of reimbursement by the NHS. Class A includes all medicinal products at the expense of the NHS; class H includes all medicinal products distributed only by hospital pharmacies within the Regional Healthcare Services; class C refers to all medicinal products at the private out-of-pocket expense.
Table IV.
Products containing four-factors prothrombin complex concentrates currently available on the Italian market.
Source: Farmadati (www.farmadati.it, accessed on 01/03/2012), processed and adapted by the Italian National Blood Centre.
| AIC codea | Name of medicinal product | I.U.b | Manufacturer | NHS classc |
|---|---|---|---|---|
| 038844015 | CONFIDEX*500 1FL+1FL SOLV 20ML | 500 | CSL Behring GmbH | H |
| 039240015 | PRONATIV*500UI FL+FL SOLV 20ML | 500 | Octapharma Italy | H |
AIC, Autorizzazione Immissione in Commercio, Marketing authorisation. The Italian Medicine Agency (Agenzia Italiana del Farmaco, AIFA) is in charge of releasing the AIC code, which identifies each medicinal products package on the national market4;
International units of alternative therapies prothrombin complex concentrates contained in the medicinal product;
National Health Service Class.
All medicinal products are divided in classes according to the level of reimbursement by the NHS. Class A includes all medicinal products at the expense of the NHS; class H includes all medicinal products distributed only by hospital pharmacies within the Regional Healthcare Services; class C refers to all medicinal products at the private out-of-pocket expense.
Clinical indications of prothrombin complex concentrates
PCCs were originally developed for the treatment of haemophilia B patients; however, due to the availability in recent years of plasma-derived high purity FIX concentrates and, more recently, of a recombinant FIX product, they have progressively shifted from this clinical indication towards the replacement of vitamin K-dependent clotting factors. The current indications for the clinical use of PCCs are mostly based on retrospective or observational studies, as very few controlled randomised clinical trials have been conducted so far in this setting3.
Therefore, PCCs are used for prophylaxis or treatment of bleeding in patients with a documented inherited deficiency of FII or FX; if PCCs are not available, fresh frozen plasma (FFP) can be used as an alternative. However, solvent/detergent plasma should be preferred in patients with inherited coagulation disorders who need replacement therapy when virus-inactivated single-factor concentrates are not available5. Similarly, in patients with congenital deficiency of FVII or FIX, PCCs can be used only when the specific clotting factor concentrate is not available. In patients with acquired deficiencies of factors of the prothrombin complex (due to severe liver disease, blood loss or dilution), PCCs could be administered, as a second choice alternative to FFP, taking into account that the potential utility of PCCs in (bleeding) patients not being treated with vitamin K antagonist (VKA) is only based on limited evidence from retrospective studies involving few patients6 and that the risk of thrombosis is higher with PCC than with plasma7–10.
Thus, the current clinical indications for PCC use include:
- patients on VKA therapy requiring emergency reversal in case of bleeding or need for urgent surgery (grade of recommendation: 1B)7,9,11–19. PCCs are able to completely reverse the warfarin-induced anticoagulation within 10 minutes but the infused clotting factors have a finite half-life. Therefore, intravenous vitamin K (10 mg) should be given with the PCC. The recently published ACCP (American College of Chest Physicians) guidelines suggest, for patients with VKA-associated major bleeding, rapid reversal of anticoagulation with four-factor PCCs, due to the presence of FVII (Grade of recommendation: 2C)19;
- prophylaxis or treatment of bleeding in patients with a documented inherited deficiency of FII or FX (grade of recommendation: 2C)7,9,20,21;
- prophylaxis or treatment of bleeding in patients with congenital deficiency of FVII or FIX if the specific clotting factor concentrate is not available (grade of recommendation: 2C)7,9,20,21;
- patients with acquired deficiencies of factors of the PCCs and limitations to the use of FFP, such as those at a risk of circulatory overload or with the need for urgent restoration of normal haemostasis (grade of recommendation: 2C)6,7,9,22.
Quantification and characterisation of the three-factors prothrombin complex concentrates demand
Tables V and VI show both the absolute and standardised demand (expressed in I.U. and per capita I.U., respectively) for three-factors PCCs in the period 2007–2011, at the national and regional level, according to medicinal products traceability data23.
Table V.
Quantification of total (public and private) demand for three-factors prothrombin complex concentrates (expressed in international units) in Italy and Italian regions, from 2007 to 2011.
Source: medicinal product traceability, processed and adapted by the Italian National Blood Centre.
| Region | 2007 | 2008 | 2009 | 2010 | 2011 |
|---|---|---|---|---|---|
| Abruzzo | 152,000 | 184,000 | 280,000 | 192,000 | 330,400 |
| Aosta Valley | 65,000 | 118,500 | 172,500 | 170,000 | 225,000 |
| AP Bolzano | 449,500 | 500,000 | 725,000 | 450,000 | 553,500 |
| AP Trento | 20,000 | 85,000 | 164,000 | 254,000 | 163,500 |
| Apulia | 1,036,600 | 1,253,300 | 1,074,500 | 1,716,700 | 1,866,000 |
| Basilicata | 199,500 | 163,700 | 254,400 | 261,000 | 241,000 |
| Calabria | 315,900 | 325,300 | 363,400 | 592,100 | 247,400 |
| Campania | 1,877,100 | 2,138,600 | 994,500 | 1,522,100 | 1,576,900 |
| ER | 1,529,700 | 1,874,900 | 1,871,000 | 2,960,600 | 3,472,600 |
| FVG | 359,500 | 135,000 | 101,500 | 307,500 | 500,000 |
| Latium | 911,200 | 617,900 | 998,900 | 1,534,100 | 1,325,000 |
| Liguria | 285,200 | 281,000 | 332,000 | 458,500 | 649,900 |
| Lombardy | 1,416,100 | 2,009,200 | 2,957,000 | 3,251,500 | 4,279,500 |
| Marche | 706,000 | 908,000 | 711,000 | 934,500 | 1,143,500 |
| Molise | 79,200 | 218,000 | 245,500 | 97,500 | 244,700 |
| Piedmont | 1,562,500 | 1,642,500 | 1,487,500 | 1,596,500 | 1,388,000 |
| Sardinia | 299,400 | 429,600 | 405,000 | 564,500 | 855,400 |
| Sicily | 1,171,500 | 1,621,600 | 1,139,800 | 1,252,400 | 1,442,800 |
| Tuscany | 1,313,300 | 1,585,000 | 1,613,100 | 1,604,000 | 2,744,800 |
| Umbria | 312,800 | 291,500 | 429,000 | 461,000 | 400,000 |
| Veneto | 1,244,500 | 1,222,200 | 1,505,000 | 1,917,200 | 2,129,900 |
| Other* | 338,600 | 170,900 | 40,000 | 37,500 | 2,400 |
|
| |||||
| Italy | 15,645,100 | 17,775,700 | 17,864,600 | 22,135,200 | 25,782,200 |
Legend AP: Autonomous Province; ER: Emilia-Romagna; FVG: Friuli-Venezia Giulia; Other*: movements of medicinal products not univocally defined.
Table VI.
Quantification of total (public and private) standardised demand for three-factors prothrombin complex concentrates (expressed in per capita international units) in Italy and Italian regions, from 2007 to 2011.
Source: medicinal product traceability, processed and adapted by the Italian National Blood Centre.
| Region | 2007 | 2008 | 2009 | 2010 | 2011 |
|---|---|---|---|---|---|
| Abruzzo | 0.1 | 0.1 | 0.2 | 0.1 | 0.3 |
| Aosta Valley | 0.5 | 0.9 | 1.4 | 1.3 | 1.8 |
| AP Bolzano | 0.9 | 1.0 | 1.5 | 0.9 | 1.1 |
| AP Trento | 0.0§ | 0.2 | 0.3 | 0.5 | 0.3 |
| Apulia | 0.3 | 0.3 | 0.3 | 0.4 | 0.5 |
| Basilicata | 0.3 | 0.3 | 0.4 | 0.4 | 0.4 |
| Calabria | 0.2 | 0.2 | 0.2 | 0.3 | 0.1 |
| Campania | 0.3 | 0.4 | 0.2 | 0.3 | 0.3 |
| ER | 0.4 | 0.4 | 0.4 | 0.7 | 0.8 |
| FVG | 0.3 | 0.1 | 0.1 | 0.3 | 0.4 |
| Latium | 0.2 | 0.1 | 0.2 | 0.3 | 0.2 |
| Liguria | 0.2 | 0.2 | 0.2 | 0.3 | 0.4 |
| Lombardy | 0.2 | 0.2 | 0.3 | 0.3 | 0.4 |
| Marche | 0.5 | 0.6 | 0.5 | 0.6 | 0.7 |
| Molise | 0.3 | 0.7 | 0.8 | 0.3 | 0.8 |
| Piedmont | 0.4 | 0.4 | 0.3 | 0.4 | 0.3 |
| Sardinia | 0.2 | 0.3 | 0.2 | 0.3 | 0.5 |
| Sicily | 0.2 | 0.3 | 0.2 | 0.3 | 0.3 |
| Tuscany | 0.4 | 0.4 | 0.4 | 0.4 | 0.7 |
| Umbria | 0.4 | 0.3 | 0.5 | 0.5 | 0.4 |
| Veneto | 0.3 | 0.3 | 0.3 | 0.4 | 0.4 |
| Other* | na | na | na | na | na |
|
| |||||
| Italy | 0.3 | 0.3 | 0.3 | 0.4 | 0.4 |
Legend AP: Autonomous Province;
Values marked as “0.0” do not identify the absence of handled quantities but consumptions that would have needed an excessive number of decimal places to be quantified.
ER: Emilia-Romagna; FVG: Friuli-Venezia Giulia; Other*: movements of medicinal products not univocally defined; na: not assessable.
The three-factors PCCs national demand showed an increase of about 65%, from 15,645,100 I.U. in 2007 to 25,782,200 I.U. in 2011 (Table V), with a per capita consumption of 0.4 I.U. in 2011 (Table VI).
Regions with the highest per capita demand are Aosta Valley and Emilia-Romagna, as well as the Autonomous Province (AP) of Bolzano with about 2 and 1 I.U., respectively (Figure 1), with a percentage change from the national mean demand of +313%, +84%, and +156%, respectively (Figure 2).
Figure 1.
Quantification of total (public and private) standardised demand for three-factors prothrombin complex concentrates (in per capita international units), in Italy and Italian regions, year 2011.
Source: medicinal product traceability, processed and adapted by the Italian National Blood Centre.
Figure 2.
Percentage change from the national mean value of standardised regional demand of prothrombin complex concentrates (per capita international units) in 2011.
Source: medicinal product traceability, processed and adapted by the Italian National Blood Centre.
Legend AP: Autonomous Province; ER: Emilia-Romagna; FVG: Friuli-Venezia Giulia.
Regions with the lowest observed demand are Calabria, Latium and Abruzzo with 0.1, 0.2, and 0.3 per capita I.U., with a percentage departure of −71%, −46%, and −42% from the national mean value (Figure 2).
The distribution of PCCs takes place almost exclusively through the public health facilities distribution channel23. Aosta Valley, the AP of Bolzano and Emilia-Romagna have the largest demand through this channel, i.e. about 2 per capita I.U. for the first Region and about 1 I.U. for the latter two, respectively (Figure 3).
Figure 3.
Demand for three-factors prothrombin complex concentrates (per capita international units), in Italy and Italian regions, by public health facilities channel, year 2011.
Legend AP: Autonomous Province; ER: Emilia-Romagna; FVG: Friuli-Venezia Giulia.
It is also necessary to underline the use of the pharmacies open to the public channel in Latium and Campania, which represents on average of about 6% of the total demand of both Regions (data reported elsewhere)24.
Quantification and characterisation of four-factors prothrombin complex concentrates demand
In 2011, the national demand for four-factors PCCs was 2,433,000 I.U. (Table VII) with a percentage increase over the previous year of 71%. Molise and the AP of Bolzano recorded the highest use of these products with 474 e 411 I.U. per 1,000 population, respectively, compared to a significantly lower national mean demand of 40 I.U. per 1,000 population. In Aosta Valley, AP of Trento, Friuli-Venezia Giulia and Umbria no utilisation have been traced (Table VII).
Table VII.
Quantification of total (public and private) and total standardised demand for four-factors prothrombin complex concentrates (expressed in international units and per capita international units) in Italy and Italian regions, from 2010 to 2011.
Source: medicinal product traceability, processed and adapted by the Italian National Blood Centre.
| Region | 2010 | 2011 | ||
|---|---|---|---|---|
| Abruzzo | 40,000 | 29.9 | 38,000 | 28.3 |
| Aosta Valley | - | na | - | na |
| AP Bolzano | 260,000 | 516.5 | 208,500 | 410.7 |
| AP Trento | - | na | - | na |
| Apulia | 188,000 | 46.0 | 283,500 | 69.3 |
| Basilicata | 92,500 | 157.1 | 113,500 | 193.2 |
| Calabria | 31,500 | 15.7 | 92,000 | 45.7 |
| Campania | 119,000 | 20.4 | 232,000 | 39.8 |
| Emilia-Romagna | 26,000 | 5.9 | 42,500 | 9.6 |
| Friuli-Venezia Giulia | 2,000 | 1.6 | - | na |
| Latium | 181,500 | 31.9 | 362,000 | 63.2 |
| Liguria | 6,000 | 3.7 | 31,000 | 19.2 |
| Lombardy | 33,500 | 3.4 | 44,500 | 4.5 |
| Marche | - | na | 7,000 | 4.5 |
| Molise | 31,000 | 96.8 | 151,500 | 473.8 |
| Piedmont | 94,000 | 21.1 | 124,000 | 27.8 |
| Sardinia | 153,000 | 91.5 | 172,000 | 102.7 |
| Sicily | 51,500 | 10.2 | 274,000 | 54.2 |
| Tuscany | 107,500 | 28.8 | 247,500 | 66.0 |
| Umbria | - | na | - | na |
| Veneto | 2,500 | 0.5 | 9,500 | 1.9 |
| Other* | - | na | - | na |
|
| ||||
| Italy | 1,419,500 | 23.5 | 2,433,000 | 40.1 |
Legend AP: Autonomous Province; -: absence of utilisation; Other*: movements of medicinal products not univocally defined; na: not assessable.
International demand and evidence-based recommendations
The international comparisons of demand for PCCs (as well as antithrombin) are complex and probably not reliable because difficulties of classification are still present at national level. In particular, these plasma-derived medicinal products show different applications within the clinical practice in different national contests. However, this does not prevent the definition of the world demand as 400 million I.U.25 of which about 30 million are used in Italy.
It also seems very appropriate to point out that there is still insufficient evidence to establish whether three- or four-factors PCCs differ in efficacy and safety in the reversal of antivitamin K anticoagulation6. In fact, it was suggested that patients with INR <4.5 may have FVII levels adequate to permit an effective action by three-factors PCCs, whereas patients with INR >4.5 not having sufficient levels of FVII need to be treated with four-factors PCCs. However, this hypothesis is yet to be confirmed by clinical evidence.
Also worthy of note, is the different degree of recommendation and level of evidence concerning the use of PCCs for the urgent reversal of anticoagulation by VKAs adopted by recent international guidelines, also for the management of patients with intracerebral non-traumatic haemorrhage26.
In fact, as can be noted from Table VIII9,16,18,19,27–32, the degree of recommendation and level of evidence vary from quite high (1B - British Committee for Standards in Haematology19, European Society of Anaesthesiology29, Task Force for Advanced Bleeding Care in Trauma32) to very low (ASTH, Australasian Society of Thrombosis and Haemostasis31). Furthermore, according to the ASTH, supporting evidence is insufficient to meet even the lowest grade of evidence and therefore their recommendation is based on the consensus opinion of the ASTH writing panel.
Table VIII.
Recent guideline recommendations for the use of prothrombin complex concentrates in the reversal of vitamin K antagonist overdose.
| Name | Year | Country | Grade of recommendation/Level of evidence |
|---|---|---|---|
| SIMTI9 | 2009 | Italy | 2C+ |
| AFSSAPS and several specialist medical societies16 | 2010 | France | C3 |
| AHA§27 | 2010 | USA | Class IIa, level B |
| STS, STA28 | 2011 | USA | Class IIa, level B |
| BCSH19 | 2012 | UK | 1B |
| ACCP18 | 2012 | USA | 2C |
| ESA29 | 2013 | Europe | 1B |
| Seville Document30 | 2013 | Spain | 2A |
| ASTH31 | 2013 | Australia | GPP# |
| Task Force for Advanced Bleeding Care in Trauma32 | 2013 | Europe | 1B |
Legend SIMTI: Società Italiana di Medicina Trasfusionale e Immunoematologia, Italian Society of Transfusion Medicine and Immunohaematology; AFSSAPS: Agence Française de Sécurité Sanitaire des Produits de Santé, The French Agency for the Safety of Health Products; AHA: American Heart Association;
Intracerebral haemorrhage in the presence of vitamin K antagonist;
STS: Society of Thoracic Surgeons; STA: Society of Cardiovascular Anaesthesiologists; BCSH: British Committee for Standards in Haematology; ACCP: American College of Chest Physician; ESA: European Society of Anaesthesiology; ASTH: Australasian Society of Thrombosis and Haemostasis; GPP: Good Practice Point;
Supporting evidence is insufficient to meet even the lowest grade of evidence. Recommendation is therefore based on consensus opinion of the ASTH writing panel.
Conclusions
In conclusion, the uncertainty in the possible differences in efficacy and safety between three- or four-factors PCCs, as well as the heterogeneity of the classification of recent evidence-based recommendations concerning their use for the urgent reversal of anticoagulation by VKAs, could, at least in part, be the reason for non-homogeneous therapeutic approaches in clinical practice and could justify a variability, also at international level, of the utilisation of PCCs.
Footnotes
The Authors declare no conflicts of interest.
References
- 1.Santagostino E, Mannucci PM. Guidelines on replacement therapy for haemophilia and inherited coagulation disorders in Italy. Haemophilia. 2000;6:1–10. doi: 10.1046/j.1365-2516.2000.00361.x. [DOI] [PubMed] [Google Scholar]
- 2.Hellstern P. Production and composition of prothrombin complex concentrates: correlation between composition and therapeutic efficiency. Thromb Res. 1999;95:S7–12. doi: 10.1016/s0049-3848(99)00078-x. [DOI] [PubMed] [Google Scholar]
- 3.Franchini M, Lippi G. Prothrombin complex concentrates: an update. Blood Transfus. 2010;8:149–54. doi: 10.2450/2010.0149-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Legislative Decree 219/2006. Implementation of Directive 2001/83/EC (and subsequent amendment directives) on a Community code relating to medicines for human use, as well as Directive 2003/94/EC. [Accessed on 13/08/2013]. Available at: http://www.agenziafarmaco.gov.it/it/content/normativa-di-riferimento-registrazione.
- 5.Santagostino E, Mancuso ME, Morfini M, et al. Solvent/detergent plasma for prevention of bleeding in recessively inherited coagulation disorders: dosing, pharmacokinetics and clinical efficacy. Haematologica. 2006;91:634–9. [PubMed] [Google Scholar]
- 6.Rodgers GM. Prothrombin complex concentrates in emergency bleeding disorders. Am J Hematol. 2012;87:898–902. doi: 10.1002/ajh.23254. [DOI] [PubMed] [Google Scholar]
- 7.Società Italiana di Medicina Trasfusionale e Immunoematologia. Raccomandazioni SIMTI sul corretto utilizzo degli emocomponenti e dei plasmaderivati. Milano: Edizioni SIMTI; 2008. [Google Scholar]
- 8.Hellstern P, Halbmayer WM, Kohler M, et al. Prothrombin complex concentrates: indications, contraindications, and risks: a task force summary. Thromb Res. 1999;95:S3–6. doi: 10.1016/s0049-3848(99)00077-8. [DOI] [PubMed] [Google Scholar]
- 9.Liumbruno G, Bennardello F, Lattanzio A, et al. on behalf the Italian Society of Transfusion Medicine and Immunohematology (SIMTI) Recommendations for the use of antithrombin concentrates and prothrombin complex concentrates. Blood Transfus. 2009;7:325–34. doi: 10.2450/2009.0116-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Sorensen B, Spahn DR, Innerhofer P, et al. Clinical review: protrhombin complex concentrates - evaluation of safety and thrombogenicity. Crit Care. 2011;15:201. doi: 10.1186/cc9311. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Schulman S, Bijsterveld NR. Anticoagulants and their reversal. Transfus Med Rev. 2007;21:37–48. doi: 10.1016/j.tmrv.2006.08.002. [DOI] [PubMed] [Google Scholar]
- 12.Leissinger CA, Blatt PM, Hoots WK, Ewenstein B. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: a review of the literature. Am J Hematol. 2008;83:137–43. doi: 10.1002/ajh.21046. [DOI] [PubMed] [Google Scholar]
- 13.Baglin T, Keeling DM, Watson HG British Committee for Standards in Haematology. Guidelines on oral anticoagulation (warfarin): third edition--2005 update. Br J Haematol. 2006;132:277–85. doi: 10.1111/j.1365-2141.2005.05856.x. [DOI] [PubMed] [Google Scholar]
- 14.Dentali F, Ageno W, Crowther M. Treatment of coumarin-associated coagulopathy: a systematic review and proposed treatment algorithms. J Thromb Haemost. 2006;4:1853–63. doi: 10.1111/j.1538-7836.2006.01986.x. [DOI] [PubMed] [Google Scholar]
- 15.Viguè B. Bench-to-bedside review: Optimising emergency reversal of vitamin K antagonists in severe haemorrhage – from theory to practice. Crit Care. 2009;13:209. doi: 10.1186/cc7701. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Pernod G, Godiér A, Gozalo C, et al. French clinical practice guidelines on the management of patients on vitamin K antagonists in at-risk situations (overdose, risk of bleeding, and active bleeding) Thromb Res. 2010;126:e167–74. doi: 10.1016/j.thromres.2010.06.017. [DOI] [PubMed] [Google Scholar]
- 17.Keeling D, Baglin T, Tait C, et al. British Committee for Standards in Haematology. Guidelines on oral anticoagulation with warfarin - fourth edition. Br J Haematol. 2011;154:311–24. doi: 10.1111/j.1365-2141.2011.08753.x. [DOI] [PubMed] [Google Scholar]
- 18.Holbrook A, Schulman S, Witt DM, et al. American College of Chest Physicians. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e152S–84S. doi: 10.1378/chest.11-2295. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Makris M, Van Veen JJ, Tait CR, et al. British Committee for Standards in Haematology. Guideline on the management of bleeding in patients on antithrombotic agents. Br J Haematol. 2013;160:35–46. doi: 10.1111/bjh.12107. [DOI] [PubMed] [Google Scholar]
- 20.Bolton-Maggs PHB, Perry DJ, Chalmers EA, et al. The rare coagulation disorders - review with guidelines for management from the United Kingdom Haemophilia Centre Doctors’ Organization. Haemophilia. 2004;10:593–628. doi: 10.1111/j.1365-2516.2004.00944.x. [DOI] [PubMed] [Google Scholar]
- 21.Acharya SS, Coughlin A, Dimichele DM North American Rare Bleeding Disorder Study Group. Rare Bleeding Disorder Registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias. J Thromb Haemost. 2004;2:248–56. doi: 10.1111/j.1538-7836.2003.t01-1-00553.x. [DOI] [PubMed] [Google Scholar]
- 22.Lorenz R, Kienast J, Otto U, et al. Efficacy and safety of a prothrombin complex concentrate with two virus inactivation steps in patients with severe liver damage. Eur J Gastroenterol Hepatol. 2003;15:15–20. doi: 10.1097/00042737-200301000-00004. [DOI] [PubMed] [Google Scholar]
- 23.Lanzoni M, Biffoli C, Candura F, et al. Plasma-derived medicinal products in Italy: information sources and flows. Blood Transfus. 2013;11(Suppl 4):s13–7. doi: 10.2450/2013.004s. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Calizzani G, Lanzoni M, Candura F, et al. Anni 2007–2011. Roma: Istituto Superiore di Sanità; 2012. [Accessed on 24/08/2012]. Analisi della Domanda dei Principali Medicinali Plasmaderivati in Italia. (Rapporti ISTISAN 12/53). Available at: http://www.iss.it/binary/publ/cont/dodici53web.pdf. [Google Scholar]
- 25.Robert P The Marketing Research Bureau (MRB) The Worldwide Plasma Fractions Market 2008. Orange, CT: The Marketing Research Bureau, Inc; 2010. April 2010 Ed. [Google Scholar]
- 26.Degos V, Westbroek EM, Lawton MT, et al. Perioperative Management of Coagulation in Nontraumatic Intracerebral Hemorrhage. Anesthesiology. 2013;119:218–27. doi: 10.1097/ALN.0b013e318297c18a. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Morgenstern LB, Hemphill JC, III, Anderson C, et al. American Heart Association Stroke Council and Council on Cardiovascular Nursing. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2010;41:2108–29. doi: 10.1161/STR.0b013e3181ec611b. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Society of Thoracic Surgeons Blood Conservation Guideline Task Force. Ferraris VA, Brown JR, Despotis GJ, et al. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg. 2011;91:944–82. doi: 10.1016/j.athoracsur.2010.11.078. [DOI] [PubMed] [Google Scholar]
- 29.Kozek-Langenecker SA, Afshari A, Albaladejo P, et al. Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology. Eur J Anaesthesiol. 2013;30:270–382. doi: 10.1097/EJA.0b013e32835f4d5b. [DOI] [PubMed] [Google Scholar]
- 30.Leal-Noval SR, Muñoz M, Asuero M, et al. Spanish Consensus Statement on alternatives to allogeneic blood transfusion: the 2013 update of the “Seville Document”. Blood Transfus. 2013 doi: 10.2450/2013.0029-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Tran HA, Chunilal SD, Harper PL, et al. An update of consensus guidelines for warfarin reversal. Med J Aust. 2013;198:198–9. doi: 10.5694/mja12.10614. [DOI] [PubMed] [Google Scholar]
- 32.Spahn DR, Bouillon B, Cerny V, et al. Management of bleeding and coagulopathy following major trauma: an updated European guideline. Crit Care. 2013;17:R76. doi: 10.1186/cc12685. [DOI] [PMC free article] [PubMed] [Google Scholar]