Table of Contents

HK J Paediatr (New Series)
Vol 11. No. 1, 2006

HK J Paediatr (New Series) 2006;11:50-54

Personal Practice

Haemophilia B: Should We Stop Using Prothrombin Complex Concentrates in Hong Kong?

The Hong Kong Paediatric Haematology & Oncology Study Group: ACW Lee, MMK Shing, SC Ling, GCF Chan, HL Yuen


The use of coagulation factor concentrates remains the mainstay treatment for haemophilias. Prothrombin complex concentrates, plasma-derived products that contain other vitamin K-dependent factors additional to factor IX, have been used for treatment of haemophilia B since 1959. However, they carry a small but significant risk of thromboembolic complications, and fatalities subsequent to myocardial infarction have been reported. We recommend that highly purified plasma-derived or recombinant products of factor IX concentrates should be the treatment of choice for patients with haemophilia B, especially those who are at higher risk for thromboembolism.

Keyword : Coagulation factor concentrate; Haemophilia B; Prothrombin complex concentrate; Thromboembolism

Abstract in Chinese


Haemophilia B, also known as Christmas disease, is an inherited form of bleeding diathesis due to deficiency or defective synthesis of circulating factor IX. It is usually transmitted as an X-linked recessive condition, but up to one-third of new cases may be due to sporadic mutations.1 Factor IX is one of the vitamin K-dependent serine proteases synthesised in the liver, and has a half-life of about 24 hours in the circulation. The gene for factor IX is located at the long arm of the X chromosome, and more than 2,000 mutations have been described.2 Clinically, haemophilia B is classified into three categories of severity depending on the residual clotting factor procoagulant activities (mild, >5-40%; moderate, 1-5%; and severe, < 1%). Although remarkable progress in gene therapy has been made in the laboratory,3 and an occasional patient may reconstitute his plasma factor IX activity at puberty due to specific mutations4 or liver transplantation,5 haemophilia B remains an incurable condition. To date, the treatment of hereditary factor IX deficiency consists of replacement of the clotting factor, either on demand in the presence of bleeding complications or prophylactically.6

Development of Replacement Therapy for Haemophilia B

In the middle of the twentieth century, transfusion of whole blood or fresh frozen plasma became the mainstay treatment for haemophilias. The large volume of plasma needed to stop bleeding sometimes resulted in circulatory overload and thus heart failure, as exemplified in a previously reported patient with severe factor VII deficiency before purified clotting factor concentrates were available locally.7 In 1959, a factor concentrate was manufactured from the cryoprecipitate supernatant of the plasma.6 Factor IX, together with other vitamin K-dependent clotting factors such as factors II, VII and X, was available for therapeutic use in a pharmaceutical product known as prothrombin complex concentrate (PCC) or factor IX complex concentrate. Treatment of haemophilias was revolutionised with the introduction of clotting factor concentrates, but the association of thrombotic complications with PCC was soon observed.6 In the 1990s, highly purified factor IX concentrates that were devoid of other vitamin K-dependent clotting factors became available.8 Because of the concerns of blood-borne infectious complications, recombinant factor IX concentrates that were free of human plasma were introduced towards the end of the twentieth century.9

Blood-borne Infections Associated with Plasma-derived Products

Each lot of plasma-derived factor IX products is collected from as many as 10,000 persons, and the use of such initially minimally treated concentrates had been linked to the development of chronic hepatitis B, hepatitis C, and human immunodeficiency virus infection during the 1970s and 1980s. Since 1984, factor IX concentrates derived from human plasma have been subjected to various virus inactivation processes such as dry heat treatment, pasteurisation, moist heating in organic solvent, hot vapour treatment, solvent-detergent treatment, chemical disinfection, membrane ultrafiltration, and nanofiltration.10 The latter methodology has been developed to eliminate hepatitis A and parvovirus B19 which tend to elude from other treatment processes.11 Safety monitorings have documented that none of the haemophilic patients born after 1985, 1992, and 1993 has been infected with human immunodeficiency virus, hepatitis C virus, and hepatitis B virus, respectively, due to treatment with plasma-derived factor concentrates in the United States.12,13 However, none of these methodologies of viral inactivation has been proven to be completely safe, and the risk of transmission of blood-borne infections is greatly minimised, though not completely absent.6

Thromboembolic Complications

The occurrence of disseminated intravascular coagulation after treatment with PCC has been noted as early as 1959,6 the year when PCC was available for clinical use. Other reported complications include myocardial infarction, deep vein thrombosis, and pulmonary embolism.14 The strong association of PCC with thromboembolic complications was first established in a 5-year observation study when Kasper reported postoperative thrombophlebitis, thrombosis, and pulmonary embolism in 6 of 13 (46%) haemophilia B patients, but in none of 72 haemophilia A patients treated with factor VIII concentrate or cryoprecipitate.14 The repeated occurrence of fatal myocardial infarction in young haemophilic subjects, including the findings of previously unrecognised subclinical infarcts at postmortem, was particulary worrying.15 Between 1987 and 1990, 72 incidents of thromboembolic complications were reported to the International Committee on Thrombosis and Haemostasis from an international registry.16 Seven of these were fatal. In Germany, a PCC product had been withdrawn from the market in 1994 when three fatalities associated with thromboembolic complications were observed.17 In addition, Kohler also quoted the occurrence of arterial thrombosis and disseminated intravascular coagulation in 8 premature neonates after treatment with PCC.14 The thrombogenic potential of PCC has not been clearly understood but the presence of activated clotting factors during the production process and overloading of factors II and X, the serine proteases with the longer circulating half lives, have been implicated as the causative mechanisms for the thromboembolic complications observed.18 Patients who have prothrombotic tendency such as pre-existing liver diseases, immobilisation, and patients who require large infusions of PCC such as those who undergo surgeries, especially orthopaedic surgeries, are at the highest risks. The Factor IX Task Force of the International Society on Thrombosis and Haemostasis (ISTH) once recommended the addition of 5-10 iu of heparin to each milliliter of reconstituted PCC, while others advocated using fresh frozen plasma or antithrombin III concentrates prior to elective surgical procedures.6,17 The effectiveness of each of these manoeuvres remains unproven, and there is a theoretical risk of heparin-induced thrombocytopenia,19 an immunological reaction to unfractionated heparin that leads to thrombosis paradoxically.

PCCs are also used for the treatment of bleeding associated other rarer congenital clotting factor (II, VII and X) deficiencies,20 excessive oral anticoagulation,21 and hepatic dysfunction associated with liver failure or liver transplantation.22,23 Nevertheless, thromboembolic complications have been specifically linked to their use under such circumstances.24

Because of its thrombogenicity, PCCs are not generally recommended for treatment of haemophilia B when purified factor IX concentrates are available.25 Indeed, highly purified or recombinant factor IX concentrates are now recommended for treatment of haemophilia B in Australia,26 Germany,27 Canada,28 Italy,29 New Zealand,30 the United Kingdom,31 and the United States of America.32 These newer generations of factor IX concentrates have been shown to be equally efficacious when compared with PCC for management of haemophilia B.33-36 They are of comparable or superior safety in terms of transmission of viral pathogens.18,36 Most importantly, laboratory markers of thrombogenicity were consistently reduced after the use of highly purified or recombinant products.18,34,35,37,38

Current Treatment of Haemophilia B in Hong Kong

ProthrombinexTM-HT (CSL Bioplasma Division, CSL Limited, Broadmeadows, Australia), the most commonly used product for treatment of haemophilia B in Hong Kong, is a form of PCC containing factors II, IX and X (with low level factor VII).25 Heparin and in 1992, antithrombin III and a high temperature viral inactivation step (and the product was renamed from ProthrombinexTM), have also been added according to the recommendations of the ISTH. The factor concentrate is manufactured from plasma collected from voluntary blood donors by means of a contract fractionation between the Hong Kong Red Cross and Blood Transfusion Service and the manufacturer.39 The viral inactivation procedures involves dry heat treatment at 80°C for 72 hours. There is limited published data on its safety with respect to viral inactivation and published results from similar products are only available prior to 1990. Thirty-two patients with haemophilia A or B treated with similar products in the United Kingdom had no laboratory features of hepatitis over a 4-month period.40 In a subsequent Scottish study, none of the 13 patients developed hepatitis after 6 months of treatment.41 However, because of the small number of patients enrolled in these two studies, the 95% confidence intervals for viral infectivity were wide and ranged from 0-9% and 0-30%, respectively. The risk of transmission of parvovirus B19 has not been eliminated,42 and a recent study suggests that haemophilia A patients who have serological evidence of parvovirus infection have worse outcomes in term of arthropathy when compared with those who do not.43 There has been one report of thrombotic complication observed after the use of ProthrombinexTM prior to 1992.44 According to the data of CSL Bioplasma, there have been no reported incidences of thrombotic complications associated with ProthrombinexTM-HT in Australasia where over 100,000,000 units have been distributed (personal communication with CSL Bioplasma).

Conclusions and Recommendations

Prothrombin complex concentrates are efficacious pharmaceutical products for the treatment of bleeding manifestations of haemophilia B. Thromboembolic complications, though uncommon, represent a potentially lethal threat to their recipients. With the availability of highly purified and recombinant factor IX concentrates, there has been a global trend of substituting prothrombin complex concentrates with the newer and safer products for the treatment of haemophilia B. Following the experience of most developed countries, patients with haemophilia B in Hong Kong should receive either highly purified or recombinant factor IX concentrates as the treatment of choice for bleeding complications. Alternatively, a selective approach may be adopted in the presence of cost limitations (see Table 1 for price comparison) where purified factor IX concentrates are given in certain high-risk individuals such as neonates, patients undergoing surgery, patients with crush injuries, those with liver dysfunction, patients with a history of thrombotic complications, or patients requiring prophylactic treatment.

Table 1 Factor IX concentrates currently available in Hong Kong
Products (Manufacturer) Clotting factor content Source Cost (HKD/USD per unit)

ProthrombinexTM-HT (CSL)

Factors II, IX, X Plasma-derived product $ 0.80/$ 0.10
MonoFix-VF (CSL) Pure Factor IX Plasma-derived product $ 1.28/$ 0.16
BeneFix (Wyeth) Pure Factor IX Recombinant product $ 4.70/$ 0.60
Information provided by the Hong Kong Red Cross & Blood Transfusion Service.


1. Roberts HR, Liles DK. The molecular biology of hemophilia B. In: Forbes CD, Aledort L, Madhok R (eds.). Hemophilia. London: Chapman & Hall Medical, 1997; pp. 35-50.

2. Bolton-Maggs PH, Pasi KJ. Haemophilias A and B. Lancet 2003;361:1801-9.

3. Nathwani AC, Davidoff AM, Tuddenham EG. Prospects for gene therapy of haemophilia. Haemophilia 200410:309-18.

4. Coyle TE, Spicer T, Michalovic D, Poiesz BJ. Moderate hemophilia B Leyden: identification by polymerase chain reaction, sequencing, and oligomer restriction. Am J Hematol 1994;46:234-40.

5. Wilde J, Teixeira P, Bramhall SR, Gunson B, Mutimer D, Mirza DF. Liver transplantation in haemophilia. Br J Haematol 2002;117:952-6.

6. Lusher JM. Factor IX concentrates. In: Forbes CD, Aledort L, Madhok R (eds.). Hemophilia. London: Chapman & Hall Medical, 1997; pp. 203-11.

7. Lee AC, Wong KW, Szeto SC, Tong KS, So KT. Treating factor VII deficiency: fresh frozen plasma or factor VII concentrate? HK J Paediatr (new series) 1998;3:68-70.

8. Berntorp E. Why prescribe highly purified factor VIII and IX concentrates? Vox Sang 1996;70:61-8.

9. Pipe SW. The promise and challenges of bioengineered recombinant clotting factors. J Thromb Haemost 2005;3:1692-701.

10. Seitz R, Dodt J. Virus safety of prothrombin complex concentrates and factor IX concentrates. Thromb Res 1999;95(4 Suppl 1):S19-23.

11. Yokoyama T, Murai K, Murozuka T, et al. Removal of small non-enveloped viruses by nanofiltration. Vox Sang 2004;86:225-9.

12. Soucie JM, Richardson LC, Evatt BL, et al. Risk factors for infection with HBV and HCV in a largecohort of hemophiliac males. Transfusion 2001;41:338-43.

13. Centers for Disease Control and Prevention (CDC). Blood safety monitoring among persons with bleeding disorders--United States, May 1998-June 2002. MMWR Morb Mortal Wkly Rep 2003;51(51-52):1152-4.

14. Kohler M. Thrombogenicity of prothrombin complex concentrates. Thromb Res 1999;95(4 Suppl 1):S13-7.

15. Sullivan DW, Purdy LJ, Billingham M, Glader BE. Fatal myocardial infarction following therapy with prothrombin complex concentrates in a young man with hemophilia A. Pediatrics 1984;74:279-81.

16. Lusher JM. Thrombogenicity associated with factor IX complex concentrates. Semin Hematol 1991;28(3 Suppl 6):3-5.

17. Kohler M, Hellstern P, Lechler E, Uberfuhr P, Muller-Berghaus G. Thromboembolic complications associated with the use of prothrombin complex and factor IX concentrates. Thromb Haemost 1998;80:399-402.

18. Herring SW, Abildgaard C, Shitanishi KT, Harrison J, Gendler S, Heldebrant CM. Human coagulation factor IX: assessment of thrombogenicity in animal models and viral safety. J Lab Clin Med 1993;121:394-405.

19. Menajovsky LB. Heparin-induced thrombocytopenia: clinical manifestations and management strategies. Am J Med 2005;118 Suppl 8A:21S-30S.

20. Kouides PA, Kulzer L. Prophylactic treatment of severe factor X deficiency with prothrombin complex concentrate. Haemophilia 2001;7:220-3.

21. Pindur G, Morsdorf S. The use of prothrombin complex concentrates in the treatment of hemorrhages induced by oral anticoagulation. Thromb Res 1999;95(4 Suppl 1):S57-61.

22. Bohrer H. Prothrombin complex concentrate substitution during liver transplantation. Thromb Res 1999;95(4 Suppl 1):S71-4.

23. Stuklis RG, O'Shaughnessy DF, Ohri SK. Novel approach to bleeding in patients undergoing cardiac surgery with liver dysfunction. Eur J Cardiothorac Surg 2001;19:219-20.

24. Mariani G, Herrmann FH, Schulman S, et al. Thrombosis in inherited factor VII deficiency. J Thromb Haemost 2003;1:2153-8.

25. Anon. Datasheet: ProthrombinexTM-HT, human prothrombin complex, freeze-dried. Parkville: CSL Limited, 2002.

26. Evans G, Collett M, Came N, Lloyd J, Powell L, Street A. MonoFIX-VF, a new mono-component factor IX concentrate: a single-centre continuous-infusion study. Haemophilia 2002;8:635-8.

27. Hellstern P, Halbmayer WM, Kohler M, Seitz R, Muller-Berghaus G. Prothrombin complex concentrates: indications, contraindications, and risks: a task force summary. Thromb Res 1999;95(4 Suppl 1):S3-6.

28. Hemophilia and von Willebrand's disease: 2. Management. Association of Hemophilia Clinic Directors of Canada. CMAJ 1995;153:147-57.

29. Santagostino E, Mannucci PM, Bianchi Bonomi A. Guidelines on replacement therapy for haemophilia and inherited coagulation disorders in Italy. Haemophilia 2000;6:1-10.

30. Medical Advisory Committee of Haemophilia Foundation of New Zealand. Management of haemophilia: treatment protocols. Christchurch: Haemophilia Foundation of New Zealand, 2004.

31. United Kingdom Haemophelia Centre Doctors' Organisation. Guidelines on the selection and use of therapeutic products to treat haemophilia and other hereditary bleeding disorders. Haemophilia 2003;9:1-23.

32. Hemophilia of Georgia. Monograph No. 14. Protocols for the treatment of hemophilia and von Willebrand disease: revised edition. Montreal: World Federation of Hemophilia, 2004.

33. Benny AG, Ockelford PA, Johns AS, Woodfield DG, Berry EW. Heat treated New Zealand factor IX concentrate: comparison with Prothrombinex in patients with haemophilia B. N Z Med J 1986;99:408-9.

34. Kim HC, McMillan CW, White GC, Bergman GE, Horton MW, Saidi P. Purified factor IX using monoclonal immunoaffinity technique: clinical trials in hemophilia B and comparison to prothrombin complex concentrates. Blood 1992;79:568-75.

35. Roth DA, Kessler CM, Pasi KJ, et al. Human recombinant factor IX: safety and efficacy studies in hemophilia B patients previously treated with plasma-derived factor IX concentrates. Blood 2001;98:3600-6.

36. Shapiro AD, Di Paola J, Cohen A, et al. The safety and efficacy of recombinant human blood coagulation factor IX in previously untreated patients with severe or moderately severe hemophilia B. Blood 2005;105:518-25.

37. Galan AM, Reverter JC, Bozzo J, Hernandez MR, Escolar G, Aznar-Salatti J. Assessment of potential thrombogenicity of coagulation factor IX concentrates in an in vitro model of human thrombogenesis. Thromb Res 1999;96:383-9.

38. Gray E, Tubbs J, Thomas S, et al. Measurement of activated factor IX in factor IX concentrates: correlation with in vivo thrombogenicity. Thromb Haemost 1995;73:675-9.

39. World Federation of Hemophilia. Facts and Figures No. 5. Contract fractionation: revised edition. Montreal: World Federation of Hemophilia, 2004.

40. Effect of dry-heating of coagulation factor concentrates at 80 degrees C for 72 hours on transmission of non-A, non-B hepatitis. Study Group of the UK Haemophilia Centre Directors on Surveillance of Virus Transmission by Concentrates. Lancet 1988;2:814-6.

41. Bennett B, Dawson AA, Gibson BS, et al. Study of viral safety of Scottish National Blood Transfusion Service factor VIII/IX concentrate. Transfusion Med 1993;3:295-8.

42. Blumel J, Schmidt I, Effenberger W, et al. Parvovirus B19 transmission by heat-treated clotting factor concentrates. Transfusion 2002;42:1473-81.

43. Soucie JM, Siwak EB, Hooper WC, Evatt BL, Hollinger FB; Universal Data Collection Project Working Group. Human parvovirus B19 in young male patients with hemophilia A: associations with treatment product exposure and joint range-of-motion limitation. Transfusion 2004;44:1179-85.

44. Anderson BJ, Keeley SR, Johnson ND. Prothrombinex-induced thrombosis and its management with regional plasminogen activator in hepatic failure. Med J Aust 1990;153:352, 355-6.


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