Factor IX concentrate versus prothrombin complex concentrate for the treatment of hemophilia B during surgery J.M. BARDIN AND Y. SULTAN Hemophilia B patients are usually treated for the prevention and control of bleeding episodes with a plasma derivative containing the four vitamin K-dependent clotting factors (PPSB). Prothrombin complex concentrate and the French PPSB concentrate are known to be thrombogenic when used in long-term treatment of surgical patients. The present study reports two cases of thrombotic episodes following surgery in PPSB-treated hemophilia B patients. Since 1986, there has been available a factor IX (FIX) concentrate depleted of the other vitamin K-dependent clotting factors and virally inactivated by the solvent-detergent method. This preparation has been used as replacement therapy in six patients with severe hemophilia B who were to undergo orthopedic surgery. The management of the patients before and after operation was without any thrombotic complication or undesirable side effects. The present study suggests that there is a need for an FIX preparation devoid of the other vitamin Kde endent clotting factors for long-term therapy of hemophilia B patients. TRANSF&ON 1990;30:441-443.
THE PREVENTION AND TREATMENT of bleeding episodes in hemophilia B patients are usually achieved with a plasma-derived preparation containing the four vitamin K-dependent clotting factors (prothrombin, proconvertin, Stuart factor, and antihemophilic B factor). Such a preparation, called PPB or PPSB, has been available in France since 1958.'.* Other countries have developed similar prothrombin complex concentrates (PCCs). Since 1958, hemophilia B patients have been treated with this preparation containing 20 to 40 times the concentration of factor IX (FIX) than in plasma. In 1959, the thrombogenicity of PPB was reported in a patient with liver d i ~ e a s e During .~ the following years, other thromboembolic episodes occurring in hemophilia B patients treated with PCC were reported in the l i t e r a t ~ r e . ~However, .~ hemophilia B patients in most countries are still treated with PCC, and very few modifications have been made in its manufacturing process. The addition of heparin in the vials of PCC did not eliminate thromboembolic events in hemophilia B patients on long-term therapy. In 1974, we observed a pulmonary embolism in a 42-year-old hemophilia B gastrectomy patient treated with PPSB.5 Between 1980 and 1986, four hemophilia B patients from our center underwent major surgery under PPSB coverage; two experienced severe thrombotic complications. Since 1986, a high-purity preparation of FIXGw7 virus-inactivated by the solvent-detergent method8 has been available in it has been used in six patients with hemophilia B who underwent major surgery.
The follow-up after surgery was uneventful, and no thromboembolic manifestations were observed, which suggests the efficacy and safety of the preparation. Materials and Methods
Therapeutic products We used PPSB, a preparation containing the four vitamin K-dependent clotting factors, which is manufactured by the Centre National de Transfusion Sanguine (CNTS) and prepared according to the technique of Steinbuch and Soulier,' and heattreated PPSB, which has been manufactured by CNTS since 1985. We also used a preparation of FIX concentrate depleted of the other vitamin K-dependent clotting factors according to described techniquehs7and virally inactivated by the solventdetergent (SD) method of Horowitz et aL8 (FIX SD HP, Biotransfusion, Lille, France)
Patients Between November 1981 and October 1988, eight patients with hemophilia B (7 severe and 1 moderate) underwent surgery under replacement therapy. Two of these patients (one severe and one moderate) underwent surgery under PPSB or heat-treated PPSB coverage. The six remaining patients were transfused with FIX SD HP.6m7 Patients were assigned sequential identification numbers'according to the date of surgery. Patient 1 had surgery in 1981; it is not known whether he was infected with human immunodeficiency virus type 1 (HIV-1) at that time, but he was found seropositive in 1984. The seven other patients were seronegative for HIV-1 at the time of surgery and remain seronegative at this writing.
Procedures On the day of surgery, we transfused 40 units of FIX per kg of body weight 1 hour preoperatively. During the postoperative period, patients were given 20 units per kg of FIX twice a day. We assayed FIX activity in each patient's plasma collected the morning before the transfusion of concentrate. T h e daily dose was adjusted according to the results to achieve a circulating level of 30- to 40-percent FIX.
From thc Centrc d'Accueil et de Traitemcnt dcs Htmophiles, HBpital Cochin, Paris, France. Supported by INSERM granf No. 865014. Rcceived for publicafion June 3, 1989; revision received November 8, 1989, and acceptcd Novcmber 11, 1989.
441
442
TRANSFUSION
BARDIN AND SULTAN
We collected blood into 129 mM sodium citrate (1 vol anticoagulant/9 vol blood) from the forearm not used for the transfusion. We measured activated partial thromboplastin time with human brain partial thromboplastin and kaolin ( 5 mg/mL) and prothrombin time with commercial reagents (Organon Teknika, Durham, NC). We used a one-stage assay with commercial FIX-depleted plasma (Boehringer, Ingelheim, FRG), partial thromboplastin of human origin, and kaolin to determine FIX. Factors 11, VII, and X were determined in a onestage assay using plasma depleted of the respective factor. We determined fibrogen levels by the weight of the dried clot and measured fibrin and fibrinogen degradation products with an agglutination test' or an enzyme immunoassay.'" We used an immunodiffusion method (M partigen, Behringwerke, Marburg, FRG) for antithrombin 111 determination. We used an enzyme-linked immunosorbent assay (Vironostika, Organon) to detect antibodies to HIV-1 and confirmed reactive samples by Western blot (DuPont, Wilmington, DE). Results Patient 1, a 28-year-old man with severe hemophilia B, underwent a rotational osteotomy of the leg. The patient was given 3200 units of FIX (80 mL of PPSB) 1 hour preoperatively. During the postoperative period, we transfused 3000 units every 12 hours. FIX activity in the pretransfusion samples varied between 30 and 55 percent. On Day 14, after receiving ii total of 92,000 FIX units, the patient developed headache and photophobia. Neurologic examination and scan demonstrated a thrombosis of the sylvian artery. Replacement therapy was reduced to 1500 units of FIX twice a day. We transfused a therapeutic preparation of antithrombin I11 (20 unitskg) before each dose of PPSB. Biologic abnormalities detected at the time of the thrombotic episode included increased levels of FII (180%), FVII and FX (140%). Antithrombin 111 and fibrinogen were in the normal range; no fibrin degradation products were detected. The fear of a hemorrhage in the brain around the thrombosis led us to prolong the coverage with PPSB (1000 FIX units twice a day) until Day 27. The total dose of FIX transfused was 135,000 units. Patient 2, a 4-year-old boy with moderate hemophilia B (FIX = 4%), underwent circumcision. Replacement therapy employed heat-treated PPSB. The patient was given 400 units of FIX preoperatively. After surgery, 200 units were given twice a day. On Day 2, the level of FIX in the circulation was 12 percent; two transfusions of 500 units were given the third diiy. On Day 4, oozing of the wound, epistaxis, and subcutaneous hemorrhage were the first clinical symptoms of disseminated intravascular coagulation (DIC) seen with the decline of fibrinogen. PPSB was discontinued and replaced with 30 mL of fresh-frozen plasma (FFP) every hour for 2 days and 15 mL per hour during the next 5 days. Healing was achieved after 15 days and the boy was discharged on Day 17. The total dose of FIX transfused was 2500 units. Patient 3, a 22-year-old man with severe hemophilia B, had a total knee replacement. The patient received 2400 units of FIX SD HP preoperatively and 1500 units twice a day from Day 1 to Day 5. On Day 5, a progressive decrease of the hemoglobin and a FIX level of 19 percent dictated the transfusion of 3 units of packed red cells, as well as the transfusion of 1500 units of FIX three times a day to bring the FIX level to between 30 and 49 percent. No other complications were noted. The total dose of FIX transfused was 62,760 units. Patient 4, a 30-year-old man with severe hemophilia B, underwent an osteotomy of the tibia. The patient received 2500
Val. 30, Na. 5-1'390
units of FIX SD HP before surgery and 1500 units twice a day during the 12 postoperative days. The FIX level in the circulation was maintained between 20 and 38 percent. The total dose of FIX transfused was 37,600 units. Hemostasis was achieved and maintained, and no complications were noted. Patient 5, a 31-year-old man with severe hemophilia B, underwent an osteotomy of the leg. He received a transfusion of 2500 units of FIX SD HP before surgery and 1500 units twice a day postoperatively. On Day 3, the dosage of FIX was decreased to 1200 units twice a day. The circulating FIX level ranged between 20 and 36 percent. Hemostasis was achieved and maintained. No complications were noted and the patient was discharged on Day 8. The total dose of FIX transfused was 19,030 units. Patient 6, a 30-year-old man with severe hemophilia B, underwent an osteotomy of the femur. We gave one preoperative dose of 2400 units of FIX SD HP and two 1500-unit doses a day for 11 postoperative days. Healing was uneventful and the patient was discharged on Day 11. The total dose of FIX transfused was 32,730 units. Patient 7, a 47-year-old man with severe hemophilia B, had a total hip replacement. We gave him 4000 units of FIX SD HP preoperatively and two doses of 2500 units per day postoperatively until Day 7. From Day 8 to Day 15, we transfused 2000 units twice a day. The level of circulating FIX was between 33 and 52 percent in the pretransfusion sample. Hemostasis was achieved and maintained, and no complications were noted. The total dose of FIX transfused was 61,275 units. Patient 8, a 47-year-old multiply transfused man with severe hemophilia B, underwent a total hip replacement. Before surgery, 2500 units of FIX were transfused (at 40 unitskg body weight); after surgery, 1700 units were transfused twice a day for 15 days. The circulating level of FIX in the pretransfusion plasma sample was between 25 and 42 percent. The patient was discharged on Day 15. Hemostasis was achieved and maintained, and no complications were noted. The total dose of factor FIX transfused was 39,065 units.
Discussion First reported in patients with liver diseaseY3 the thrombogenicity of P C C is now well recognized. Episodes of thrombosis have been reported in hemophilia B patients following replacement therapy with PCC.4J It was suggested that the thrombogenicity of these products w a s related to the presence of activated clotting factors such as factors Xa or VIIa, although no thrombin had been detected in any of the preparations tested." The addition of heparin to PCC or to PPSB2 did not reduce the thromboge'nicity of these products in hemophilia B patients on long-term therapy. T h e occurrence of thrombotic episodes in these patients is well documented. I 2 - l a In the present study, we report two major complications that occurred in two hemophilia B surgical patients on replacement therapy with PCC. In the first case, occlusion of the sylvian artery secondary to thrombosis occurred after 14 days of PPSB therapy. At that time, the patient had received a total of 92,000 FIX units. Laboratory test results indicated a significant shortening of the prothrombin time and increased levels of factors 11, VII, and X. In the second case, D I C occurred on the
TRANSFUSION t99O-Vol. 30. No. 5
FACXOR IX CONCENTRATE IN HEMOPHILA B
third day of therapy with heat-treated PPSB and after the transfusion of a total of 2500 units of FIX. To prevent thrombotic complications, we developed on the basis of the above observation, a new strategy of replacement therapy in hemophilia B patients undergoing surgery. When we detected a shortening of the prothrombin time coupled with increased levels of vitamin K-dependent clotting factors, we reduced the PPSB dose by one-half and administered either antithrombin I11 or FFP until the prothrombin time and factors 11, VII, and X returned to normal levels. Two hemophilia B patients, not reported in this study, safely underwent surgery with this protocol. Starting in 1986, an FIX concentrate depleted of the other vitamin K-dependent clotting factors, FIX SD HP, has been available in France. In this study, we used this product for major surgery in six hemophilia B patients without inducing thromboembolic complications. One patient (Patient 3) experienced a bleeding complication because the circulating FIX did not reach the expected level; the bleeding resolved after the administration of additional FIX, and the outcome was uneventful. Surgical procedures in the other five patients were uneventful. There was no shortening of the prothrombin times nor any increase of factors 11, VII, or X during the days of postoperative therapy. The lower protein content of such a preparation might also be beneficial to multiply transfused hemophiliacs, as several authors have suggested'"-?' that repeated transfusions of high doses of plasma proteins might have a deleterious effect on the immune system. For years, efforts have been made to obtain preparations of highly purified factor VIII (FVIII) for the treatment of FVIII-deficient patients.22 In contrast, except for such a preparation as that described by MenachC et which is not yet available commercially, hemophilia B patients are still being transfused with a mixture of vitamin K-dependent clotting factors. The experience we are beginning to gain with the French preparation of FIX depleted of the other vitamin K-dependent clotting factors is highly promising and indicates that this therapy could be extended to the usual treatment of hemophilia B y as was suggested by Smith.24 Preliminary encouraging results have begun to establish the efficacy and safety of the French preparation. Acknowledgments Thc authors thank Doctor D. MCnachC for many helpful discussions during the prcparation of thc manuscript and F. Kostas for sccrctarial hclp.
References I . Soulicr JP, Stcinbuch M. [Thc P.P.S.B. coagulant fraction.] Nouv Prcsse Mcd 1975;4:2581-4. 2. Goudcmand M. Lcs fractions coagulantcs. Encycl Mid Chir Sang 1987;3:12-6.
443
3. McnachC D, Fauvcrt R, Soulicr JP. [Utilization in hcpatology of a fraction containing prothrombin, the proconvcrtin-Stuart factor complex and antihcmophilic factor B (PPB)]. Pathol Biol (Paris) 1959;7:2515-23. 4. Kasper CK. Postoperative thromboscs in hemophilia B (lettcr). N Engl J Mcd 1973;289:160. 5. Kaspcr CK. Thrombocmbolic complications. Thromb Diafh Hacmorrh 1975;33:640-4. 6. Michalski C, Bal F, Burnouf T, Goudcmand M. Largc-scalc production and propcrties of a solvent-detcrgent-trcatcd facfor IX concentrate from human plasma. Vox Sang 1988;55:202-10. 7. Burnouf T, Michalski C, Goudemand M, Huart JJ. Propertics of a highly purified human plasma factor IX:c thcrapcutic conccnIrate prepared by conventional chromatography. Vox Sang 1989;57:225-32. 8. Horowitz B, Wicb ME, Lippin A, Strykcr MH. Inactivation of viruscs in labilc blood derivativcs. I. Description of lipid-cnvcloped viruscs by tri(n-buty1)phosphate dctergcnt combinations. Transfusion 1985;25:516-22. 9. Merskcy C, Lalczari P, Johnson AJ. A rapid, simplc, scnsifive mcthod for measuring fibrinolytic split products in human serum. Proc SOCExp Biol Mcd 1969;131:871-5. 10. Nieuwcnhuizcn W. Plasma assays for dcrivativcs of fibrin and of fibrinogen, based on monoclonal anfibodies. Fibrinolysis 1988;Z: 1-5. 1. Pepper DS, Banhegyi D. Howie A, Cash JD. In vitro thrombogenicity tests of factor IX concentrates. Br J Hacmatol 1977;36:57383. 2. Steinberg M, Brciling BJ. Vascular Icsions in hemophilia B (Ictter). N Engl J Med 1973;289:592. 3. Marchcsi SL, Burncy R. Prothrombin complcx concentratcs and thromboses (lettcr). N Engl J Med 1974;290:403. 4. Damus PS. Prothrombin complex conccntratcs and thromboscs (letter). N Engl J Med 1974;290:404. 5. Campbell EM', Neff S, Bowdlcr AJ. Thcrapy with factor IX concentrate resulting in DIC and thromboembolic phenomena. Transfusion 1978;18:94-7. 16. Fucrth JH, Mahrcr P. Myocardial infarction after factor IX therapy (letter). JAMA 1981;245:1455-6. 17. Agrawal BL, Zclkowitz L, Hlctko P. Acutc myocardial infarction in a young hemophiliac patient during therapy with Factor IX concentrate and cpsilon aminocaproic acid (Icttcr). J Pcdiatr 1981;98:931-3. 18. Sullivan DW, Purdy U,Billingham M, Gladcr BE. F d t d myocardial infarction following therapy with prothrombin conccnirate in a young man with hcmophilia A (lcttcr). Pcdiatrics 1984;74:279. 19. Mannhalter JW, Zlabinger GJ, Ahmad R, Ziclinski CC, Schranim W, Eibl MM. A functional dcfcct in the early phasc of thc immunc rcsponsc observcd in patients with hcmophilia A. Clin lmmunol lmmunopathol 1986;38:390-7. 20. Brettlcr DB, Brewstcr F, Lcvinc PH, Forsbcrg A, Bakcr S, Sullivan JL. Immunologic aberrations, HIV scropositivity and seroconversion rates in paticnts with hemophilia B. Blood 1987;70:27681. 21. Madhok R, Gracie A, Lowe GDO, ct al. lmpaircd cell mcdiatcd immunity in haemophilia in thc abscncc of infection with liuman immunodeficiency virus. Br Med J 1986; 193:978-80. 22. Jorpes JE, Blomback B, Blomback M, Magnusson S. A pilot plant for the preparation of a human plasma fraction confaining the human antihacrnophilic factor A (factor VIII) and von Willebrands factor. Acta Mcd Scand 1962;171 (suppl 379):7-19. 23. Mcnachd D, Behre HE, Orthncr CL, ct al. Coagulation facfor IX conccntratc: method of prcparation and asscssment of potcntial in vivo thrombogcnicity in animal modcls. Blood 1984;64:1220-7. 24. Smith KJ. Immunoaffinity purification of factor IX from commercial conccnhates and infusion studies in animals. Blood 1988;72:1269-77. J.M. Bardin, MD, Hcmobiologist, Ccntre dcs HCmophilcs, Hdpital Cochin, 27 ruc du Fg. St. Jaques, 75014 Paris, France. [Rcprint rcquests]
Y. Sultan, MD, Coordinator, Ccntre des HEmophilcs.
THE PREVENTION AND TREATMENT of bleeding episodes in hemophilia B patients are usually achieved with a plasma-derived preparation containing the four vitamin K-dependent clotting factors (prothrombin, proconvertin, Stuart factor, and antihemophilic B factor). Such a preparation, called PPB or PPSB, has been available in France since 1958.'.* Other countries have developed similar prothrombin complex concentrates (PCCs). Since 1958, hemophilia B patients have been treated with this preparation containing 20 to 40 times the concentration of factor IX (FIX) than in plasma. In 1959, the thrombogenicity of PPB was reported in a patient with liver d i ~ e a s e During .~ the following years, other thromboembolic episodes occurring in hemophilia B patients treated with PCC were reported in the l i t e r a t ~ r e . ~However, .~ hemophilia B patients in most countries are still treated with PCC, and very few modifications have been made in its manufacturing process. The addition of heparin in the vials of PCC did not eliminate thromboembolic events in hemophilia B patients on long-term therapy. In 1974, we observed a pulmonary embolism in a 42-year-old hemophilia B gastrectomy patient treated with PPSB.5 Between 1980 and 1986, four hemophilia B patients from our center underwent major surgery under PPSB coverage; two experienced severe thrombotic complications. Since 1986, a high-purity preparation of FIXGw7 virus-inactivated by the solvent-detergent method8 has been available in it has been used in six patients with hemophilia B who underwent major surgery.
The follow-up after surgery was uneventful, and no thromboembolic manifestations were observed, which suggests the efficacy and safety of the preparation. Materials and Methods
Therapeutic products We used PPSB, a preparation containing the four vitamin K-dependent clotting factors, which is manufactured by the Centre National de Transfusion Sanguine (CNTS) and prepared according to the technique of Steinbuch and Soulier,' and heattreated PPSB, which has been manufactured by CNTS since 1985. We also used a preparation of FIX concentrate depleted of the other vitamin K-dependent clotting factors according to described techniquehs7and virally inactivated by the solventdetergent (SD) method of Horowitz et aL8 (FIX SD HP, Biotransfusion, Lille, France)
Patients Between November 1981 and October 1988, eight patients with hemophilia B (7 severe and 1 moderate) underwent surgery under replacement therapy. Two of these patients (one severe and one moderate) underwent surgery under PPSB or heat-treated PPSB coverage. The six remaining patients were transfused with FIX SD HP.6m7 Patients were assigned sequential identification numbers'according to the date of surgery. Patient 1 had surgery in 1981; it is not known whether he was infected with human immunodeficiency virus type 1 (HIV-1) at that time, but he was found seropositive in 1984. The seven other patients were seronegative for HIV-1 at the time of surgery and remain seronegative at this writing.
Procedures On the day of surgery, we transfused 40 units of FIX per kg of body weight 1 hour preoperatively. During the postoperative period, patients were given 20 units per kg of FIX twice a day. We assayed FIX activity in each patient's plasma collected the morning before the transfusion of concentrate. T h e daily dose was adjusted according to the results to achieve a circulating level of 30- to 40-percent FIX.
From thc Centrc d'Accueil et de Traitemcnt dcs Htmophiles, HBpital Cochin, Paris, France. Supported by INSERM granf No. 865014. Rcceived for publicafion June 3, 1989; revision received November 8, 1989, and acceptcd Novcmber 11, 1989.
441
442
TRANSFUSION
BARDIN AND SULTAN
We collected blood into 129 mM sodium citrate (1 vol anticoagulant/9 vol blood) from the forearm not used for the transfusion. We measured activated partial thromboplastin time with human brain partial thromboplastin and kaolin ( 5 mg/mL) and prothrombin time with commercial reagents (Organon Teknika, Durham, NC). We used a one-stage assay with commercial FIX-depleted plasma (Boehringer, Ingelheim, FRG), partial thromboplastin of human origin, and kaolin to determine FIX. Factors 11, VII, and X were determined in a onestage assay using plasma depleted of the respective factor. We determined fibrogen levels by the weight of the dried clot and measured fibrin and fibrinogen degradation products with an agglutination test' or an enzyme immunoassay.'" We used an immunodiffusion method (M partigen, Behringwerke, Marburg, FRG) for antithrombin 111 determination. We used an enzyme-linked immunosorbent assay (Vironostika, Organon) to detect antibodies to HIV-1 and confirmed reactive samples by Western blot (DuPont, Wilmington, DE). Results Patient 1, a 28-year-old man with severe hemophilia B, underwent a rotational osteotomy of the leg. The patient was given 3200 units of FIX (80 mL of PPSB) 1 hour preoperatively. During the postoperative period, we transfused 3000 units every 12 hours. FIX activity in the pretransfusion samples varied between 30 and 55 percent. On Day 14, after receiving ii total of 92,000 FIX units, the patient developed headache and photophobia. Neurologic examination and scan demonstrated a thrombosis of the sylvian artery. Replacement therapy was reduced to 1500 units of FIX twice a day. We transfused a therapeutic preparation of antithrombin I11 (20 unitskg) before each dose of PPSB. Biologic abnormalities detected at the time of the thrombotic episode included increased levels of FII (180%), FVII and FX (140%). Antithrombin 111 and fibrinogen were in the normal range; no fibrin degradation products were detected. The fear of a hemorrhage in the brain around the thrombosis led us to prolong the coverage with PPSB (1000 FIX units twice a day) until Day 27. The total dose of FIX transfused was 135,000 units. Patient 2, a 4-year-old boy with moderate hemophilia B (FIX = 4%), underwent circumcision. Replacement therapy employed heat-treated PPSB. The patient was given 400 units of FIX preoperatively. After surgery, 200 units were given twice a day. On Day 2, the level of FIX in the circulation was 12 percent; two transfusions of 500 units were given the third diiy. On Day 4, oozing of the wound, epistaxis, and subcutaneous hemorrhage were the first clinical symptoms of disseminated intravascular coagulation (DIC) seen with the decline of fibrinogen. PPSB was discontinued and replaced with 30 mL of fresh-frozen plasma (FFP) every hour for 2 days and 15 mL per hour during the next 5 days. Healing was achieved after 15 days and the boy was discharged on Day 17. The total dose of FIX transfused was 2500 units. Patient 3, a 22-year-old man with severe hemophilia B, had a total knee replacement. The patient received 2400 units of FIX SD HP preoperatively and 1500 units twice a day from Day 1 to Day 5. On Day 5, a progressive decrease of the hemoglobin and a FIX level of 19 percent dictated the transfusion of 3 units of packed red cells, as well as the transfusion of 1500 units of FIX three times a day to bring the FIX level to between 30 and 49 percent. No other complications were noted. The total dose of FIX transfused was 62,760 units. Patient 4, a 30-year-old man with severe hemophilia B, underwent an osteotomy of the tibia. The patient received 2500
Val. 30, Na. 5-1'390
units of FIX SD HP before surgery and 1500 units twice a day during the 12 postoperative days. The FIX level in the circulation was maintained between 20 and 38 percent. The total dose of FIX transfused was 37,600 units. Hemostasis was achieved and maintained, and no complications were noted. Patient 5, a 31-year-old man with severe hemophilia B, underwent an osteotomy of the leg. He received a transfusion of 2500 units of FIX SD HP before surgery and 1500 units twice a day postoperatively. On Day 3, the dosage of FIX was decreased to 1200 units twice a day. The circulating FIX level ranged between 20 and 36 percent. Hemostasis was achieved and maintained. No complications were noted and the patient was discharged on Day 8. The total dose of FIX transfused was 19,030 units. Patient 6, a 30-year-old man with severe hemophilia B, underwent an osteotomy of the femur. We gave one preoperative dose of 2400 units of FIX SD HP and two 1500-unit doses a day for 11 postoperative days. Healing was uneventful and the patient was discharged on Day 11. The total dose of FIX transfused was 32,730 units. Patient 7, a 47-year-old man with severe hemophilia B, had a total hip replacement. We gave him 4000 units of FIX SD HP preoperatively and two doses of 2500 units per day postoperatively until Day 7. From Day 8 to Day 15, we transfused 2000 units twice a day. The level of circulating FIX was between 33 and 52 percent in the pretransfusion sample. Hemostasis was achieved and maintained, and no complications were noted. The total dose of FIX transfused was 61,275 units. Patient 8, a 47-year-old multiply transfused man with severe hemophilia B, underwent a total hip replacement. Before surgery, 2500 units of FIX were transfused (at 40 unitskg body weight); after surgery, 1700 units were transfused twice a day for 15 days. The circulating level of FIX in the pretransfusion plasma sample was between 25 and 42 percent. The patient was discharged on Day 15. Hemostasis was achieved and maintained, and no complications were noted. The total dose of factor FIX transfused was 39,065 units.
Discussion First reported in patients with liver diseaseY3 the thrombogenicity of P C C is now well recognized. Episodes of thrombosis have been reported in hemophilia B patients following replacement therapy with PCC.4J It was suggested that the thrombogenicity of these products w a s related to the presence of activated clotting factors such as factors Xa or VIIa, although no thrombin had been detected in any of the preparations tested." The addition of heparin to PCC or to PPSB2 did not reduce the thromboge'nicity of these products in hemophilia B patients on long-term therapy. T h e occurrence of thrombotic episodes in these patients is well documented. I 2 - l a In the present study, we report two major complications that occurred in two hemophilia B surgical patients on replacement therapy with PCC. In the first case, occlusion of the sylvian artery secondary to thrombosis occurred after 14 days of PPSB therapy. At that time, the patient had received a total of 92,000 FIX units. Laboratory test results indicated a significant shortening of the prothrombin time and increased levels of factors 11, VII, and X. In the second case, D I C occurred on the
TRANSFUSION t99O-Vol. 30. No. 5
FACXOR IX CONCENTRATE IN HEMOPHILA B
third day of therapy with heat-treated PPSB and after the transfusion of a total of 2500 units of FIX. To prevent thrombotic complications, we developed on the basis of the above observation, a new strategy of replacement therapy in hemophilia B patients undergoing surgery. When we detected a shortening of the prothrombin time coupled with increased levels of vitamin K-dependent clotting factors, we reduced the PPSB dose by one-half and administered either antithrombin I11 or FFP until the prothrombin time and factors 11, VII, and X returned to normal levels. Two hemophilia B patients, not reported in this study, safely underwent surgery with this protocol. Starting in 1986, an FIX concentrate depleted of the other vitamin K-dependent clotting factors, FIX SD HP, has been available in France. In this study, we used this product for major surgery in six hemophilia B patients without inducing thromboembolic complications. One patient (Patient 3) experienced a bleeding complication because the circulating FIX did not reach the expected level; the bleeding resolved after the administration of additional FIX, and the outcome was uneventful. Surgical procedures in the other five patients were uneventful. There was no shortening of the prothrombin times nor any increase of factors 11, VII, or X during the days of postoperative therapy. The lower protein content of such a preparation might also be beneficial to multiply transfused hemophiliacs, as several authors have suggested'"-?' that repeated transfusions of high doses of plasma proteins might have a deleterious effect on the immune system. For years, efforts have been made to obtain preparations of highly purified factor VIII (FVIII) for the treatment of FVIII-deficient patients.22 In contrast, except for such a preparation as that described by MenachC et which is not yet available commercially, hemophilia B patients are still being transfused with a mixture of vitamin K-dependent clotting factors. The experience we are beginning to gain with the French preparation of FIX depleted of the other vitamin K-dependent clotting factors is highly promising and indicates that this therapy could be extended to the usual treatment of hemophilia B y as was suggested by Smith.24 Preliminary encouraging results have begun to establish the efficacy and safety of the French preparation. Acknowledgments Thc authors thank Doctor D. MCnachC for many helpful discussions during the prcparation of thc manuscript and F. Kostas for sccrctarial hclp.
References I . Soulicr JP, Stcinbuch M. [Thc P.P.S.B. coagulant fraction.] Nouv Prcsse Mcd 1975;4:2581-4. 2. Goudcmand M. Lcs fractions coagulantcs. Encycl Mid Chir Sang 1987;3:12-6.
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Y. Sultan, MD, Coordinator, Ccntre des HEmophilcs.
