Catarino, C

Cruz, C

Diniz, MJ

Falcão, MT

Galvão, M

Tavares, A

Vieira, A

English

Repository of the Hospital Center of Central Lisbon

The Use of Recombinant Activated FVII (rFVIIa, Novoseven®) in the Treatment of Patients with Haemophilia and Inhibitors

Repositório do Centro Hospitalar de Lisboa Central, EPE

INTRODUCTION  The development of inhibitors to factor VIII (FVIII) has become one of the most serious complications in the treatment of haemophilia patients, occurring in 15-30% of haemophilia A (HA) patients and 1-3% of haemophilia B (HB) patients. (1) The management of acute bleeding episodes may use different approaches: human factor VIII or factor IX (2), porcine factor VIII (3), prothrombin complex concentrates (PCC), activated prothrombin complex concentrates (aPCC) (4-6) and more recently recombinant activated factor VII (rFVIIa, Novoseven) (7). rVIIa is a potent by-passing agent which mechanism of action is most probably to provide a full thrombin burst, in the absence of FVIII/FIX, on the activated platelets and represents a major therapeutic advance in the treatment of haemophilia patients with high-titter inhibitor (8). Its safety and efficacy in the treatment of haemophiliacs with inhibitors to FVIII or IX has been investigated in clinical studies since 1989 (9).  RFVIIa has been used in our country for the first time, in Compassionate Use Program, in November 1994. Since 1996 foi comercializado em Portugal e utilizado no tratamento dos doentes com hemofilia e inibidores. The aim of this study is to evaluate, retrospectively, the efficacy and safety of rFVIIa in the treatment of acute bleeding episodes and prophylactic, in surgical procedures, in the period between Nov.1994-Dec1999, in the patients followed in Hospital S. José and Hospital de Santa Maria in Lisbon.   PATIENTS AND METHODS The patient population consisted of 15 patients, 14 had hemophilia A (13 severe, 1 mild) and 1 had severe hemophilia B; mean age 25,7 years (range: 4-50), mean weight 56.4 Kg (range :22-100). RFVIIa was used in the treatment of 90 acute bleeding episodes. (Table 1) 2 patients have been treated on a compassionate use basis, in two lifethreatening bleeding episodes. In the treatment of acute hemarthroses rFVIIa was administered by intravenous bolus injection in the dose range 80-90mcg/Kg. The initial dose was given every 2 h, in a total of 3 injections or until clinical improvement was observed.  O tratamento dos hematomas intramusculares, (including psoas-iliac hematomas), dos hematomas retroperitoneais e do subdural hematoma foi efectuado com rFIIa em Bolus Intermitent Injections (BII), na dosagem de 80-100mcg/Kg, de 2/2 h nas primeira 24 horas, com alargamento dos intervalos para 3/3, 4/4 e 6/6 horas, de acordo com a sintomatologia clínica e  os exames de controlo. Quando usado em profilaxia em casos de cirurgia urgente o procedimento foi idêntico, variando o nº de dias de tratamento.   The efficacy was assessed as: an excellent/effective (E) response was defined when the bleeding ceased or decreased substantially, or when there was a significant relief of pain and swelling within 8-12 hours; a partially effective (PE) response was defined as some relief of symptoms, or an improvement of mobility but the bleeding continued; no clinical improvement or if bleeding remained or worsened, there was an ineffective response (IR). Epsilon aminocaproic acid, 100 mg/Kg, every 6 h, foi utilizado como terapêutica adjuvante, nos casos de cirurgia, hemorragias das mucosas e na extracção dentária. Laboratory monitoring included platelet count, estimations of  prothrombin time (PT/INR) and levels of factor VII:C. Both FVII:C and PT/INR were performed by a one-stage assay, using a rabbit brain thromboplastin. Case nº Hem. type Age Type of bleed 1 A 23 Subdural haematoma* (1) 2 A 40 Post-nefrectomy abdom.haematoma(1) 3 A 15 Joint bleed (3) Muscle bleed(2) Respiratory tract bleed (1) Prophylatic of lumbar puncture (1) 4 A 23 Oral cavity bleed (1) Nose bleed (1) 5 A 18 Joint bleed (3) Muscle bleed (4) Retroperitoneal hemorrhage (2) Dental bleed (2) Tongue bleed (1) 6 A 14 Joint bleed (5) Gastrointestinal bleed (1) 7 A 29 Joint bleed (17) Gastrointestinal bleed (1) 8 A 41 Circumcision (1) Joint bleed (2) 9 A 35 Neck Muscle bleed (1) 10 A 50 Muscle bleed (3) 11 A 31 Retroperitoneal hemorrhage (1) 12 A 29 Joint bleed (3) Muscle bleed (1) 13 A 6 Radioactive synoviorthesis (2) Central catheter removal (1) Joint bleed (9) 14 B 4 Subdural haematoma/craniotomy* (1) 15 A 27 Joint bleed (19) RESULTS EFFICACY Joint bleeds (Fig.1): an excellent/effective response to treatment was observed in 48 (79%) episodes. In 8 (13%) episodes the response was evaluated as partially effective and in 5 (8%) ineffective. Mean treatment/episode: 3,2 (range:1-9). Partially effective and ineffective responses are related to target joints (knee, elbow) assim como o maior nº de tratamentos por episódio. In one patient (pte. 15) in home treatment, all the joint bleeds were evaluated as effective, and  the mean treatment per episode was 2,6 (range: 1-6). Muscle bleeds (Fig 1): In this group of 11 episodes we included one ilio-psoas haematoma and 10 other intramuscular haematomas (thigh, calf, lombar, neck). The response to treatment was evaluated as excellent/effective in 9 (82%) episodes, partially effective in one case (4%) and ineffective in one case (4%). Mean treatment/episode -  15,5 (range:3-45). THE USE OF RECOMBINANT ACTIVATED FVII (rFVIIa, NOVOSEVEN®) IN THE TREATMENT OF PATIENTS WITH HAEMOPHILIA AND INHIBITORS M. J. DINIZ*, M. GALVÃO**, A. TAVARES**, A. VIEIRA*, M. T. FALCÃO*, C. CATARINO**, M. CRUZ* S. IMUNO-HEMOTERAPIA – *HOSPITAL DE  S. JOSÉ. **HOSPITAL DE  STA. MARIA. LISBOA. PORTUGAL Prophylactic (Table 2) - rFVIIa proved to be very effective in five (83%) episodes, with an excellent recovery of the child (pte. 14) with the subdural haematoma, with complete recovery of the neurological symptoms. In one case (pte.5) satisfactory haemostasis was not achieved, for dental extraction, with subsequent oozing, probabilly because of suboptimal rFVIIa and/or antifibrinolytic therapy (Table 2). Other hemorrhages  Doses/treat.  Efficacy  Post-circumcision  8  E  Gastrointestinal  5-6  E  Oral cavity  2-20  E  Tongue  27  PE  Nasal  36  E  Respiratory tract  3  E  PROPHYLATIC  Doses/treat.  Efficacy  Surgery  Craniotomy for subdural  hematoma  100  E  Post-nefrectomy abdominal hematoma   114  E  Other Procedures  Lumbar puncture  14  E  Dental extraction  13  PE  Central Catheter removal  31  E  Bilateral Synoviortesis  31  E  Table 2 – Novoseven use in prophylaxis, number of doses per episode  and efficacy  Table 1 – Characteristics of the patients given rFVIIa and bleeding episodes. Table 3- Novoseven use in other hemorrhages, number of  treatments per episode and efficacy. Figure 1- Joint and muscle bleeds treatment efficacy. Partially effective (13.11%)Ineffective (8.20%)Effective (78.69%)JOINTPartially effective (9.09%)Ineffective (9.09%)Effective (81.82%)MUSCLEEfficacyRetroperitoneal hematomas – an excellent response was observed in all cases, with evident relief of pain, less than 24 hours after the beginning of the treatment. Other haemorrhages (Table 3) - an excellent/effective response was observed in 7 episodes (87,5%) and a partially effective response in the case of the tongue haemorrhage. The patient had a dental spicule that caused trauma and after dental correction the haemorrhage stopped.  Mean treatment/episode: 13,4 (range: 2-36). Partially effective (13.33%)Ineffective (6.67%)Effective (80.00%)Global EfficacyLABORATORY MONITORING- Although the therapeutic level of rFVII:C is not yet well established, our target was to maintain plasma FVII:C level above 10U/mL. The levels of post-infusion FVII:C had been determined in 5 cases. The highest FVII:C level recorded in each individual range from 8,7 to 23,4U/mL. These differences may be related to differences in individual recovery of rFVIIa.  ADVERSE EVENTS- A total of 4 non-serious adverse events were recorded: local thrombophlebitis (3  cases) and fever and cutaneous erythema (1 case).  RESULTS AND CONCLUSIONS        References 1-Ehrenfoth S, Kreuz W, Scharrer I, Linda R, Funk M, Gungor T, Krackhardt B, Kornhuber B: Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339:594-598 2-Kasper CK. Treatment of factor VIII inhibitors. Prog Hemost Thromb 1989; 9:57-86 3-Brettler DB, Forsberg AD, Levine PH, Buttler DB, Aledort LM, Hilgartner MW, Kasper CK, Lusher JM, McMillan C, Roberts H. The use of porcine factor VIII concentrate (Hyate C) in the treatment of patients with inhibitor antibodies to factor VIII:A multicenter US experience. Arch Intern Med 1989;149:1381-5 4-Lusher JM, Shapiro SS, Palascak JE et al. Efficacy of prothrombin-complex concentrates in hemophilics with antibodies to factor VIII. N Engl J Med 1980;303:421-5 5-Sjamsoedin LJM, Heijnen L, Mauser-Bunschoten EP, Van Geijlswijk JL, Van Houwelingen H, Van Asten P, Sixma JJ. The effect of activated prothrombin-complex concentrate (FEIBA) on joint and muscle bleeding in patients with hemophilia A and antibodies to factor VIII. N Engl J Med 1981;305:717-21 6-Lusher JM, Blatt PM, Penner JA, Aledort LM, Levine PH, White GC, Warrier AI, Whitehurst DA. Autoplex versus proplex: a controlled, double blind study of effectiveness in acute hemarthroses in hemophiliacs with inhibitors to factor VIII. Blood 1983;62:1135-8 7-Hoffman M, Monroe DM, Oliver JA, Roberts HR. Platelet activity of high dose factor VIIa is independent of tissue factor. Br.J Haematol, 1997; 99:542-547. 8-Lusher J, Ingerslev J, Roberts H, Hedner U. Clinical experience with recombinant VIIa. Blood Coagulation and Fibrinolysis.1998; 9:119-128 9-HR Roberts- Clinical experience with activated factor VII: focus on safety aspects. Blood Coagulation and Fibrinolysis.1998,9 (Suppl 1): S115-118. 

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The Use of Recombinant Activated FVII (rFVIIa, Novoseven®) in the Treatment of Patients with Haemophilia and Inhibitors

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