Blood Coagulation and Fibrinolysis, 6, 31-34 The successful removal of a bleeding intracranial tumour in a severe haemophiliac using an adjusted dose continuous infusion of monoclonal factor VIII H. A. Doughty, J. Coles, K. Parmar, P. Bullock and G. F. Savidge (Received 27 July 1994; accepted in revised form 23 November 1994) Ten per cent of patients with haemophilia A develop intracranial haemorrhage (ICH) with a mortality rate of 30% and an incidence of psycho-neurological sequelae in 50% of survivors. {CH may be spontaneous or in association with trauma and other pathology. The generally recommended management is conservative replacement therapy using bolus injections of factor VIII and no neurosurgical intervention. Adjusted dose continuous infusion therapy provides an alternative method of factor VIII administration that is simple, more cost effective and safer through the maintenance of stable plasma VIII:C levels. This method has been successfully used to cover general surgery and the conservative treatment of subarachnoid haemorrhage but is not widely used due to unfamiliarity with the technique. This paper describes the use of continuous infusion of factor VIII concentrates to cover the successful neurosurgical manage- ment of a young man with severe haemophilia A who presented with an ICH associated with a bleeding choroid plexus tumour. Surgery was complicated by the development of a factor VIII inhibitor which disappeared following treatment with an immune-tolerance induc- tion programme. Key words: Haemophilia A, continuous infusion, factor VUI, neurosurgery. Introduction One of the major causes of death in haemophilia is intracranial haemorrhage (ICH). About 10% of hae- mophilic patients develop objective evidence of ICH and the majority of these patients are aged less than 20 years.’ In severe haemophilia, 85% of the ICH are spontaneous. The overall mortality rate is high at 30% and is related to the site of the bleed with intracerebral haemorrhage carrying the worst prognosis. If the patient survives, the incidence of psycho-neurological sequelae is 50%.? The recognized management of ICH is factor VIII replacement given by bolus injection, bedrest and no neurosurgical intervention as surgery within the cranium has always been considered too dangerous to undertake. Adjusted dose continuous infusion provides a simple, cost effective and a safer method of factor replacement during surgery and major bleeds in hae- mophilia. This approach has not been widely used in the UK due to unfamiliarity with the technique. Con- tinuous infusion has been used successfully for the conservative management of subarachnoid haemor- rhage’ but the authors have found no description of this method used to cover intracranial surgery. This paper presents the case of a young man with severe haemo- philia A who presented with an ICH associated with a choroid plexus tumour. The tumour was successfully resected under the stable haemostatic cover of factor VIII given by continuous infusion. Drs Doughty, Savidge and Mrs Parmar are with the Haemophilia Reference Centre, St Thomas’s Hospital, Lambeth Palace Road, London SE1. Drs Cole and Bullock are with The Neurosurgical Unit, The Maudsley Hospital, DeCrespigny Park, London SES 8AZ, UK. Address correspon- dence to Dr G. F, Savidge, Reference Centre for Haemostatic and Thrombotic Disorders, St Thomas’s Hospital, Lambeth Palace Road, London SE17EH, UK. Tel: (+44) 71-922-8035; Fax (+44) 71401-3125. © 1995 Rapid Communications of Oxford Ltd Blood Coagulation and Fibrinolysis, Vol 6, 1995 31 H. A. Doughty et al. Case report Presentation and initial management An 18-year-old Greek-Cypriot student presented to his local emergency department with a 2-day history of left-sided headache, generalized weakness and vomit- ing. He was a known severe haemophilic (factor VIII level <1 iu./dl) and had suffered frequent spon- taneous muscle and joint bleeds. Bleeding episodes were treated on demand with 1-2 000 i.u. of intermedi- ate purity factor VIII (8Y, BPL). He was known to be Hepatitis B and HIV sero-negative with no previously recorded factor VII] inhibitor. On examination he was partially obtunded but responsive with a right full VII nerve weakness and a right hemiparesis; CT scanning demonstrated a large intraventricular haemorrhage with modest ventricular dilatation and an underlying calcified intrinsic tumour. He was initially managed with intermediate purity factor VIII (8Y, BPL), requiring a total of 8000 i.u. to reach a plasma VIIL:C of 98%, before transfer to a regional neurosurgical unit. After assessment, a de- cision was made to delay surgery and to treat conserva- tively with bedrest and 3 000 i.u. bd high purity factor VII (Monoclate P, Armour Pharmaceutical Com- pany, Collegeville, PA). Interval CT scans at 1,3 and 9 days showed no progression -of the bleed and a reduction in cerebral oedema. An angiogram was per- i , Infusion rate iu./kg/h formed to exclude an arteriovenous malformation be- fore surgery to evacuate the haematoma and remove the tumour. Factor VIII therapy and surgery Factor VIII levels using intermittent boluses of factor VIII during the pre-operative period had resulted in low factor VIII troughs despite high post-treatment peaks (Figure 1) and a half-life (71/2) of 7.2 h. Twelve hours before surgery, a continuous infusion of factor VIII was established following a bolus dose of 50 icu./kg. The infusion rate was initially set using a syr- inge driver pump to deliver 5 i.u./kg/h with the aim of achieving a target level of > 100i.u./dl. A simultaneous infusion of 0.9% saline was given to prevent thrombo- phlebitis. The infusion of factor VIII was increased to 8.2 iu/kg/h until the target factor VIII level was achieved. The plasma factor VIII was maintained be- tween 100 and 130 i.u./dl until after the ventricular drain had been removed on day 6. Figure 2 shows the plasma factor VIII levels and treatment during the peri- operative and early post-operative period. The infusion was stopped 13 days after the operation. The dosage and plasma levels of VIII:C were analysed using standard and extended single compartment pharmaco- kinetic models.* The pharmacokinetics of the infused factor VIII during the pre-, peri- and post-operative periods are shown in the Table 1. The 71/2 of factor 270 | 260 250 240 Factor Vill ectivity iu. /di 24 Time (h) infusion rate . Target factor Vili level Key: 72 Observed factor Vili level Predicted factor Vill level Bolus Figure 1. Treatment and factor VIII levels during first 5 days of the pre-operative period. Factor VIII levels were measured before and after the morning bolus. High doses of factor VIII were used in an attempt to ensure an adequate haemostatic level as measured by the next pre-treatment factor VIII level. 32 Blood Coagulation and Fibrinolysis, Vol 6, 1995 Infusion rote iu./kg/h Infusion of FVIII covering intracranial surgery 260 250 240 230 220 210 200 190 _ 180 y 170 Fp 160 = N 150 = 2 140 3 & 1390 2 3 120 7 8 10 2 8 100 2 90 80 70 60 50 40 30 20 0 T 1 t 1 rt 0 0 24 48 lofusion rate Target factor Vill level Time (h) . Observed foctor Vill level Predicted factor Vill level 72 96 120 | Bolus Figure 2. Treatment and factor VIII levels during the peri-operative and early post-operative period. A bolus dose is shown at the beginning of the period followed by a standard infusion rate of 5 i.u./kg/h aiming for a target factor VIII level of 100 i-u./dl. The immediate post-bolus dose was satisfactory but the steady-state factor VIII level pre-surgery was unexpectedly low at 86 i.u./dl. The infusion rate was increased to 8.2 i.u./kg/h achieving a factor VIII level of 120 i.u./dl. This dose was continued for a further 24 h before reducing the dose to 6 i.u./kg/h. VIII fell substantially at the time of operation to 3 hbut returned to the pre-operative values of 7 h in the immediate post-operative period. A choroid plexus tumour was excised via a left par- ietal craniotomy using the transcalosal approach. Hae- mostasis was satisfactory throughout the procedure and during removal of the ventricular drain. The tumour histology was a choroid plexus papilloma with abundant calcification. These vascular and histologi- cally benign tumours are closely related to the ependy- momas and characteristically present in the young with ICH. The patient was discharged a fortnight after sur- gery with a full resolution of his hemiparesis. Table 1. Pharmacokinetic data using the fitted model shown in Figure 2 Period Elimination Clearance Half-life Volume of rate (hr) (I/h/kg) (h) distribution (I/kg) Pre-operative 0.0933 0.00467 7.43 0.0501 Peri-operative 0.2318 0.00919 2.99 0.0396 Immediate post-op 0.1101 00.0437 6.29 0.0396 End of infusion —_0,0511 0.00390 13.57 0.0764 Post-operative period After discharge the patient was maintained on prophy- lactic factor VIII three times a week (2000/2 000/4 000 i.u.). However, 2 weeks later he presented with bruis- ing on his legs following minimal trauma and was shown to have a developed a low titre human factor VIII inhibitor (7 BU/ml). He did not respond to large doses of his factor VIII and was then treated with a single dose of FEIBA (Immuno). The inhibitor was then successfully eradicated using an immune-toler- ance induction programme based on a modified ‘Bonn Protocol” using an alternative high purity factor VIII (ALPHA VIII, Alpha Therapeutic UK Ltd; 100 i.u./ kg/day = 6000 iu.). The inhibitor initially rose to 12 BU/ml and then slowly decreased to <0.2 BU/ml at 3 months. However, at this time the 7'1/2 of infused fac- tor VIII was only 2.5 h; therefore, daily factor VIII was continued for a further 2 months before returning to prophylaxis as before. Discussion The procedure was successful, demonstrating that intracranial surgery can be considered in individuals with factor VIII deficiency. Surgery was necessary in this case to remove the cause of bleeding however the Blood Coagulation and Fibrinolysis, Vol 6, 1995 33 H. A. Doughty et al. option of surgery for the treatment of spontaneous ICH has the potential to reduce morbidity and mor- tality. Surgery can only be contemplated if adequate haemostasis can be secured during the procedure and the post-operative period. Adjusted dose continuous infusion offers the best method of factor replacement. Continuous infusion was first reported as a safer method of replacing factor VIII by McMillan et al. in 1970 with five cases of classic haemophilia undergoing surgery using infusions of cryoprecipitate and glycine precipitated fractions. The advent of purified factor VIII was associated with greater solubility and stability in solution. Recent papers”? have described continu- ous infusion in the treatment of patients with and with- out inhibitors, requiring replacement therapy for haemorrhage and surgery. The most recent and largest study? describes 24 patients undergoing a wide variety of procedures. Recommended doses of factor VIII given by continuous infusion are 2-4 i.u./kg/h for adults and 4-5 i.u./kg/h for children. Inhibitors, infec- tion and active bleeding including surgery lead to increased clearance. In this case report, a high infusion rate of 8 iu./kg/h was required to achieve levels in excess of 100 i.u./dl during the operation when the T1/2 was reduced. The T1/2 rapidly returned to the preoperative level. In this case an inhibitor became evi- dent after treatment with large amounts of a monoclo- nally immunopurified product. The patient had never been exposed to this product before. Approximately 10-20% of haemophiliacs develop inhibitors, ie. VHI:C neutralizing antibodies and these are most com- monly seen in the young with severe haemophilia. What triggers inhibitor production is largely unknown; however, there are anecdotal reports of patients who have developed late onset inhibitors fol- lowing a change in factor VIII concentrate.'*!! Such case reports imply that occasional patients may dis- tinguish different forms of the factor VIII molecule and respond on exposure to a new product or batch in which the processing is different. Inhibitors once formed usually persist for life and treatment should be aimed at eradication. The approach to these patients is controversial; however, the ‘Bonn Protocol’ as used in this report was the first to consistently achieve elimin- ation of inhibitors. 34 Blood Coagulation and Fibrinolysis, Vol 6, 1995 In conclusion, patients with haemophilia A can suc- cessfully undergo intracranial surgery. Continuous infusion of high purity factor VIII is the replacement treatment of choice. Acknowledgements—We would like to thank Dr D. O. Chanter of Brookwood Statistics Ltd for preparing the pharmacokinetic modelling and Dr G. Cowing of Armour Pharmaceutical Co. Ltd for his technical advice. References 1. Kerr CB. Intracranial haemorrhage in hemophilia. J Neurol Neurosurg Psychiatry 1964; 27: 166. 2. De Tezanos Pinto M, Fernandez J, Perz Bianco PR. Update of 156 episodes of central nervous system bleed- ing in hemophiliacs. Haemostasis 1992; 22: 259-267. 3. Martinowitz U, Schulman S, Gitel $, Horozowski H, Heim M, Varon D. 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