Case report: 58-Year-Old Hemophilia A Patient with High-Titer Inhibitor Development and Introduction of a Multicenter PTP-Inhibitor Study

Case report: 58-Year-Old Hemophilia A Patient with High-Titer Inhibitor Development

and Introduction of a Multicenter PTP-Inhibitor Study

Ch. von Auer, M. Krause, W. Miesbach, G. Asmelash, I. Scharrer and PTP Study Group/Germany

Background

Today the development of inhibitors to FVIII or FIX is the most serious complicati- on in hemophilia treatment. The risk for inhibitor development is highest after the first exposure to factor concentrate and in young children (< 5 years). After 20 days of exposure and in children between 6–10 years of age the risk is levelling off [1].

Older patients with more than 50-100 exposure days (ED) are at low risk for inhibi- tor development. If such a patients develops an inhibitor, other influences such as immunogenicity or way of factor application should be considered [2].

In July 2003 a 58-year-old patient with hemophilia A developed a high-titer in- hibitor against FVIII in our centre.

Case history

58-year-old patient, normal body weight, severe hemophilia A, severe hemo- philic arthropathy in all main joints with resulting immobility in a wheelchair, chronic hepatitis C-infection, tooth decay with bad dental status, cholecystectomy 9/01. Previous hemophilia treatment (not done in a hemophilia treatment centre):

6 ED with plasma or whole blood samples, 14 ED with Beriate for cholecystectomy.

Gene mutation: Large deletion (Exon 23-24). Risk for inhibitor development: 35 %.

Case report

The patient was admitted to a regional hospital with spontaneous hematoma of the right thorax. He was treated with two boli of FVIII concentrate (Beriate, 2 x 3500 IU) and transferred to our centre. A CT-scan revealed a soft tissue hemorrhage of the right thorax and back muscles. Hemoglobin was 13.7 g/dl, FVIII:C was 48 % before morning substitution, the inhibitor titer was 0 BU. We continued the FVIII substi- tution with Beriate (3000-0-2000 IU/d) and saw no progression of hematoma and no suspect laboratory findings. After three days of treatment we found a low FVIII:C level (5%) before morning substitution, hemoglobin was 8.4 g/dl even though the patient had received 4 red blood cell concentrates. A massive hematoma in the soft tissue of right thorax and back muscles had developed. FVIII inhibitor testing:12.8

I. Scharrer/W. Schramm (Ed.)

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BU. FVIII substitution was stopped, treatment with FEIBA (2 x 6000 IU/d) initia- ted. During the next two days FEIBA dose rate was reduced (1 x 4000 IU/d) due to rising d-dimers (677µg/l). The FVIII inhibitor titer rose up to 16000 IU.

Our patient developed high body temperature up to 39°C, antibiotic treatment was started with Zienam (Imipenem, Cilastatin), Vancomycin (Vancomycin) and Sobelin (Clindamycin).

Due to recurrent fever (39°C) the hematoma was surgically removed under NovoSeven substitution. There was no bleeding complication during the peri- and postoperative period and NovoSeven was changed to FEIBA (2 x 4000 IU/d). The patient was discharged with prophylaxis 3 x 4000 IU FEIBA /week. One month later the hematoma was totally absorbed and FEIBA prophylaxis was changed to on demand therapy. Inhibitor titer was 4424 IU. ITT, plasmapheresis or Immun- adsorption was refused by the patient, a Rituximab (Mabthera) therapy is planned.

Discussion

Our patient has an uncommon history concerning a hemophilia A treatment in Germany. Possible treatment options were refused by the patient, therefore he had very few ED compared with other severe hemophilia A patients at his age.

Immobilisation due to hemophilic arthropathy and disablement could have been avoided with optimal treatment.

Our patient is not the typical PTP of a western country but rather like a patient in developing countries with less than optimum factor concentrate and blood com- ponent usage. Therefore the development of an inhibitor to FVIII is not uncommon in our patient, especially with the mutation type with high risk for inhibitor deve- lopment.

Nevertheless this case and a literature search caused us to ask for the situation of inhibitor development in PTPs in Germany today.

262 Ch. von Auer et al.

1 10 100 1000 10000 100000

21. 07. 03 26. 07. 03

31. 07. 03 05. 08. 03

10. 08. 03 15. 08. 03

20. 08. 03 25. 08. 03

30. 08. 03 04. 09. 03

09. 09. 03 14. 09. 03

19. 09. 03 24. 09. 03

29. 09. 03 0 2 4 6 8 10 12 14 16 18 20

In h . ( B U )

H b (g /d l)

C R P (m g /d l)

Surgery

Introduction of a multicenter PTP-inhibitor study

In September 2003 we started a retrospective study to record data about inhibitor development in PTPs in Germany. A questionnaire with the following questions was sent to 83 hemophilia treating facilities.

Table 1.

Diagnosis (Hemophilia A/B, Severity) Way of application

Gene mutatiton Concomitant medication

Exposure days Concomitant diseases

Factor VIII concentrate Concomitant blood transfusion

Reason for FVIII substitution at inhibitor development Concomitant vaccination Amount of given FVIII concentrate Inhibitor characteristic Before inhibitor development

Former change of product Immune Tolerance Theapy

So far 43 centres answered the questionnaire, 30 reported that no inhibitors in PTPs were detected during the last five years. 13 centres registered altogether 34 FVIII inhibitor developments in PTPs in the mentioned time period. Their data showed that there exist differing definitions for a PTP in Germany, referring to age of pati- ent, number of ED and former change of product. Further data will be collected and published.

In conclusion it can be said that inhibitor development in PTPs is still a serious and underestimated problem in hemophilia treatment today. A definition for »PTP«

from the SSC of the ISTH would be helpful.

Secondly a prospective, not product related study on inhibitor development in PTPs should be conducted.

58-Year-Old Hemophilia A Patient with High-Titer Inhibitor Development 263