Inhibitors During and After Continuous Infusion of Different Factor Concentrates Given During and After Surgical

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First Data of a Prospective Study About Incidence of

Inhibitors During and After Continuous Infusion of Different Factor Concentrates Given During and After Surgical

Procedures in Hemophilia A or B and von Willebrand Disease

G. Auerswald, T. Spranger and S. Meister

Introduction

Inhibitor development against F VIII / IX or VWF is one of the most severe compli- cation in treatment of patients with hemophilia A, B or von Willebrand disease (VWD). There are publications about increased inhibitor development in patients treated with continuous infusion (C.I.) during surgery or after severe bleeding epi- sodes. In an earlier retrospective study with 118 children and young adults with hemophilia A or B and von Willebrand disease treated with C.I. for surgical reasons we could show about 30–50% less use of factor concentrate compared to bolus in- fusions.

In addition the factor level could can be kept within the target range without unnecessary high peaks or dangerous low levels. There was no evidence for increa- sed inhibitor development during this study. In a new prospective study we investi- gated weather there is any increased risk for inhibitor development (especially low titre inhibitors) in patients treated with C.I. for surgical procedures.

Patients and Investigations

All included patients of our pediatric hospital and associated departments (ENT, oral surgery, urology, orthopedics and gynecology) with hemophilia A, B and VWD were treated with continuous infusion during surgical therapy. Inclusion criteria were: negative history for inhibitors, at least 50 exposure days prior inclusion and a surgical procedure requiring a C.I. for at least 3 days. Patients and / or parents gave informed consent to the study. In patients with hemophilia A or B the molecular defect was considered. 29 patients were included into the study so far: 18 patients with hemophilia A, 4 patients with hemophilia B and 7 patients with VWD.

Coagulation tests and estimation of hemoglobin, hematocrit and platelets were done before every surgical procedure. Specific coagulation tests included pro- thrombin time, APTT, thrombin time, fibrinogen, residual activity of F VIII or IX as well as a inhibitor test.

In patients with VWD additionally the bleeding time,VWF activity and VWF:Ag were measured. Recovery and half life was done in all patients.

I. Scharrer/W. Schramm (Ed.)

34

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Hemophilia Symposium Hamburg 2003

” Springer Medizin Verlag Heidelberg 2005

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Surgical Procedures and Therapy

The kind of surgery in patients with hemophilia A and B and VWD can be seen in Table 1–3. The age of the patients at the moment of surgery was 2,6 to 24 years for hemophilia A and 2,9 to 16,3 for hemophilia B. 8 patients with hemophilia A were treated with high purity pd concentrates and 3 patients with pd VWF containing concentrates. In 5 patients therapy was done with full molecule rFVIII concentrates and in 2 with B-domain deleted FVIII concentrate. All hemophilia B patients were treated with pd FIX concentrates. Therapy was started with a bolus dose of 30–50 IU/kg followed by continuous infusion with 3–4 IU/kg/h. The dose of C.I. was adap- ted to the factor levels which were measured minimum once a day.

6 patients with VWD were treated with Haemate HS, 1 patient was treated with Immunate.

Table 1. Surgical procedures in Hemophilia A

앫 abdominal surgery (3 patients) 앫 oto-laryngeal surgery (7 patients) 앫 orthopedic surgery (1 patient)

앫 neurosurgery (1 patient)

앫 Port-a-Cath-implantation (1 patient) 앫 oral surgery (3 patients) 앫 accident surgery (2 patients)

Table 2. Surgical procedures in Hemophilia B

앫 abdominal surgery (1 patient) 앫 oto-laryngeal surgery (1 patient) 앫 oral surgery (1 patient) 앫 accident surgery (1 patient)

Table 3. Surgical procedures in VWD

앫 abdominal surgery (1 patient) 앫 oto-laryngeal surgery (2 patients) 앫 oral surgery (2 patients) 앫 accident surgery (2 patients)

Results

All 29 patients underwent the surgical procedures without a major blood loss. The

time of continuous infusion was between 3 and 9 days (median 5.8 days). The con-

sumption with continuos infusion was up to 48 % lower compared to the calculated

consumption of factor concentrates with bolus doses. No thrombotic events or

postoperative wound infection was seen. The determination of the inhibitor activi-

First Data of a Prospective Study About Incidence of Inhibitors 265

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ty as well as the half-life was done latest before demission from the hospital. We found values within the estimated range for all patients also the inhibitor activity at that time was negative. A follow-up examination was done in all patients after 2–4 weeks after finishing continuous infusion. At this time again there was no inhibitor development detectable. 6 patients with hemophilia A had an intron 22 inversion, 4 patients had a large and 3 patients had a small deletion in the F VIII gene. The mole- cular diagnosis of the other patients is not available at the moment.

The group of investigated patients is still to small and heterogeneous to make a clear statement about incidence of inhibitor development during surgical procedu- res done under continuous infusion of factor con1es. This study will be continued.

References

1. Schulman S (2003) Continuous infusion. Haemophilia 9: 368–75

2. Tagariello G et al. (1999) Safety and efficacy of high-purity concentrates in haemophiliac patients undergoing surgery by continuous infusion. Haemophilia 5: 426–30

3. White B et al. (2000) High responding factor VIII inhibitors in mild haemophilia – is there a link with recent changes in clinical practice? Haemophilia 6: 113–5

Inhibitors During and After Continuous Infusion of Different Factor Concentrates Given During and After Surgical

First Data of a Prospective Study About Incidence of