Effective management of intracranial haemorrhage with continuous infusion of highly purified von Willebrand factor/factor VIII complex concentrate in an adult with severe haemophilia A

Dear Sir,

Intracranial haemorrhage (ICH) affects 3.5–4.0% of all haemophilic neonates¹ which is a rate 40–80 times higher than that in the normal population. After the neonatal period ICH occurs in 3–10% of haemophilic patients, who are mainly treated on demand. Elderly patients and those with uncontrolled hypertension, not undergoing a prophylactic regimen, are at particularly high risk of life-threatening ICH. Continuous infusion of factor VIII (FVIII) was originally developed as an alternative to bolus infusion for situations requiring intensive clotting factor concentrate administration, such as peri-operative haemostatic control, with the aim of maintaining more stable FVIII levels. Continuous infusion avoids the deep troughs that accompany bolus infusion, which expose the patient to the risk of bleeding, and the unnecessary peak with a considerable reduction of the need for clotting factor concentrate². We here report the case of an adult with severe haemophilia not undergoing prophylaxis who developed ICH and was effectively treated with a continuous infusion of highly purified von Willebrand factor (VWF)/FVIII complex concentrate.

A 55-year old male smoker, 80 kg body weight, with severe haemophilia A and hypertension, treated on demand with recombinant FVIII, presented to our hospital with left hemiplegia, dysarthria, and confusion. His blood pressure was 140/100 mmHg. The patient was admitted to the intensive care unit and a computed tomography (CT) scan was performed immediately, showing a right nucleocapsular haemorrhage with a slight mass effect on the ipsilateral ventricle (Figure 1A). Anti-oedema and vasodilating treatment was started promptly and two boluses of 3,500 IU of doubly virus-inactivated highly purified VWF/FVIII complex concentrate (Fanhdi^®, Instituto Grifols S.A., Barcelona, Spain) was infused. No change was observed in the CT scan repeated 4 hours later. The patient was moved to the neurology department and a further CT performed 12 hours after admission to hospital showed more extensive bleeding with signs of compression of the median line and left peduncular displacement (Figure 1B). The lesion was considered inoperable. As previously reported in children³, adjusted-dose continuous infusion of highly purified VWF/FVIII complex concentrate was started, with the aim of keeping plasma levels of FVIII stable and high. Daily monitoring of FVIII and consequent dose adjustments, from the initial 4 IU/Kg/h to 3 IU/Kg/h, were used to maintain FVIII levels consistently around 100% (Table I). The patient was continuously hydrated by a parallel saline infusion to prevent potential thromboembolic events. The comparative method using the standard FVIII deficient plasma device BCS coagulation instrument (BCS, Siemens) was used to assess FVIII levels in the plasma. Factor VIII levels were measured every 24 hours while the patient was receiving a continuous infusion and every 12 hours after each bolus infusion (just before the next one) when treated by bolus infusion. The continuous infusion was given for 7 days followed by intermittent daily boluses dosed in order to keep FVIII levels always above 100% for a further 11 days (Table I).

Figure 1.

A: Cerebral CT scan at admission; B: Cerebral CT scan 12 hours after admission to hospital; C: Cerebral CT scan 16 days after starting treatment.

Table I.

Administration schedule of highly purified VWF/FVIII complex concentrate and FVIII levels during hospital stay.

Day from admission	Dose	Total 24 h dose	Mode of administration	FVIII level
1	44 IU/Kg	7,000 IU	Bid (3,500 IU)	119%
2	4 IU/Kg/h	8,000 IU	CI	126%
3	4 IU/Kg/h	8,000 IU	CI	129%
4	4 IU/Kg/h	8,000 IU	CI	137%
5	4 IU/Kg/h	8,000 IU	CI	138%
6	3.5 IU/Kg/h	7,500 IU	CI	138%
7	3 IU/Kg/h	6,000 IU	CI	90%
8	3 IU/Kg/h	6,000 IU	CI	125%
9	44 IU/Kg	7,000 IU	Bolus	211%
10	44 IU/Kg	7,000 IU	Bolus	160%
11	38 IU/Kg	6,000 IU	Bolus	111%
12	38 IU/Kg	6,000 IU	Bolus	97%
13	38 IU/Kg	6,000 IU	Bolus	147%
14	31 IU/Kg	5,000 IU	Bolus	122%
15	25 IU/Kg	4,000 IU	Bolus	118%
16	25 IU/Kg	4,000 IU	Bolus	118%
17	25 IU/Kg	4,000 IU	Bolus	82%
18	25 IU/Kg	4,000 IU	Bolus	70%
19	25 IU/Kg	4,000 IU	Bolus	60%
Rehabilitation	30 IU/Kg 3 times/week	2,500 IU	Bolus

ND= not detected, CI=continuous infusion.

The clinical picture consistently improved beginning from day 3 after starting treatment, with progressive improvement of the level of consciousness, hemiplegia and dysarthria. At day 11 after admission to hospital, CT scans showed no change but a slight increase of the hyperdense perilesional area due to cell suffering, whereas at day 16 a reduction in the density of haematoma and of the signs of compression was observed (Figure 1C). After 18 days, the patient was discharged and transferred to a rehabilitation unit for physiotherapy. He was well oriented in time and space, but his dysarthria and hemiparesis remained. During rehabilitation, long-term secondary prophylaxis with intermittent boluses of highly purified VWF/FVIII complex concentrate, 30 IU/kg three times weekly, was introduced to be continued lifelong. Two weeks after discharge, a control CT scan showed significant reductions in the size and density of the haematoma, with disappearance of the surrounding oedema and normalization of the ventricular system. At completion of the rehabilitation programme, the patient was in a stable clinical condition, with mild residual paresis of the left lower limb and full recovery of language. At the time of writing this report, he is still receiving the prophylactic regimen that he started 10 months previously.

No local thrombotic complications, reported by other authors⁴ to occur with continuous infusion, were observed despite the fact that no heparin prophylaxis was given because of the high purity of the concentrate. With 10 months of administration (>130 CEDS), no FVIII inhibitor has been detected.

Up to 10% of patients with haemophilia A develop intracranial bleeding with significant mortality and neuro-psychological sequelae¹. Treatment of intracranial bleeding is based on the infusion of clotting factor concentrate. These life-threatening bleeds require FVIII levels to be maintained consistently within the normal range. In order to keep the trough FVIII plasma concentrations above the minimum haemostatic level, frequent bolus injections are required, often resulting in the peak levels being too high. Replacement therapy by continuous infusion in haemophilia has been shown to be a safe, effective and practical approach in case reports and open-label trials involving the use of FVIII and recombinant activated FVII for a variety of indications including surgical prophylaxis, acute bleeding, primary prevention, and management of inhibitors^4,5. This method prevents peaks and troughs in plasma FVIII levels, thereby reducing the risk of breakthrough haemorrhage. Further, by avoiding the unnecessary high peaks of bolus infusion, a considerable reduction of requirement of clotting factor concentrate may be achieved by continuous infusion, especially if using “adjusted” doses. In our patient, the administration of a highly purified VWF/FVIII complex concentrate by continuous infusion in the acute phase maintained the FVIII levels stable and consistently above 100%, and was effective in controlling the haemorrhage. Since our patient was hypertensive and the previously administered recombinant FVIII contained a large amount of sodium as a stabiliser, the use of a low-sodium VWF/FVIII product was considered more adequate. The patient began to recover as early as 3 days after treatment initiation and improved consistently during the maintenance phase with intermittent boluses. Relevant neurological improvement was further observed when the patient was put under VWF/FVIII prophylaxis.

It has been reported that continuous infusion can induce local phlebitis³, but that this can be avoided by concomitant heparin administration.

Our patient had no local phlebitis or other adverse effects, even though he was not given heparin because of the high purity of the VWF/FVIII concentrate.

In case of life-threatening events, such as ICH, clotting factor concentrate replacement therapy by continuous infusion may be the treatment of choice. We believe that lifelong secondary prophylaxis is feasible and should be strongly recommended.