Dykes

Gordon D. O. Lowe

Grunewald

Isobel D. Walker

Lian

Mark D. McColl

Morrison

Peter S. Maclean

Pfliegler

R. Campbell Tait

English

Crossref

Successful elimination of factor VIII inhibitor using Cyclosporin A

Maclean, P.S.

Tait, R.C.

Lowe, G.D.O.

Walker, I.D.

McColl, M.D.

Enlighten

CorrespondenceSUCCESSFUL ELIMINATION OF FACTOR VIII INHIBITOR USING CYCLOSPORIN AAcquired Factor VIII (FVIII) deficiency is an uncommon butsometimes catastrophic autoimmune condition for whichstandard immune suppression, such as steroid or immuno-globulin infusion, is often insufficient to induce long-termremission (Dykes et al, 2001). A number of second-linetherapies, such as cyclophosphamide, azathioprine andvincristine, have been used with varying success (Morrison& Ludlam, 1995). Here, we describe the use of cyclosporin Ain a patient in whom conventional treatments failed toeradicate the inhibitor. At present, only limited experienceexists of its use in this setting (Pfliegler et al, 1989).A 68-year-old woman with a 4-month history of easybruising presented with life-threatening retropharyngealhaemorrhage. She had no significant past medical history,and medication consisted of aspirin and naproxen. Coagu-lation studies at presentation demonstrated a normalprothrombin time and fibrinogen activity but a prolongedactivated partial thromboplastin time of 65 s (normal range32–48 s). Factor assays confirmed a reduced FVIII coagu-lant activity (FVIII:C) at 1 il ⁄ dl. An inhibitor was detectedand quantified at 54 Bethesda units (BU). von Willebrandfactor activity and antigen were both within the normalrange excluding acquired von Willebrand’s disease.Her initial treatment was with high-purity plasma-derived FVIII (Liberate, Scottish National Blood TransfusionService), commencing at 20 000 units twice daily, withprednisolone 60 mg and high-dose intravenous immuno-globulin (2 g ⁄ kg). Clinical response to treatment wasexcellent with no further haemorrhage. The patient’sinhibitor titre remained detectable at 10–20 BU withFVIII:C remaining below 20 il ⁄ dl over the succeedingmonths. The introduction of cyclophosphamide 50 mgdaily, 9 months after presentation, initially in conjunctionwith further prednisolone (1 mg ⁄ kg), rendered the inhibitortransiently undetectable, with FVIII:C peaking at 40 il ⁄ dl.However, with reduction of the prednisolone dose, theinhibitor returned, and the FVIII:C fell. After 9 months oftreatment with cyclophosphamide, it was discontinuedbecause of lack of a sustained response.Approximately 28 months after presentation, cyclosporinA (CyA) was introduced at 100 mg twice daily(3 mg ⁄ kg ⁄ d), initially with prednisolone (1 mg ⁄ kg). Atarget trough plasma CyA concentration of 200–250 mg ⁄ lwas achieved over 3 months with a dose of 175 mg twicedaily ( 5 mg ⁄ kg ⁄ d), during which time the prednisolonewas discontinued. The inhibitor titre fell and was undetect-able 3 months after the commencement of CyA. The FVIII:Crose to within the normal range following disappearance ofthe inhibitor (Fig 1). After 14 months of therapy with CyA,and with FVIII:C levels remaining in the normal range,cyclosporine was reduced and stopped over a 4-monthperiod. Ten months after cessation of all immunosuppres-sive therapy, the FVIII:C remains in the normal range withno detectable inhibitor.Permanent eradication of inhibitor without the need forcontinued therapy is the ultimate aim of immunosuppres-sive treatment for acquired haemophilia. Initial reduction ininhibitor titre may be achieved with high-dose intravenousimmunoglobulin and steroids; however, long-term clear-ance may not be achieved with this approach alone (Hayet al, 1996). Further options include cytotoxic regimens orimmunosuppressant agents such as cyclosporine. As noFig 1. Factor VIII and inhibitor levels.British Journal of Haematology, 2003, 122, 1024–10261024  2003 Blackwell Publishing Ltdregime has been universally successful, and there have beenno large immunomodulatory studies, no gold standardtreatment has been established (Grunewald et al, 2001).Cytotoxic therapy may be associated with neutropenicsepsis; such cases have been reported in the treatment ofacquired haemophilia (Lian et al, 1989). On the other handCyA is well recognized as a precipitant of hypertension andrenal impairment in addition to its anticipated immuno-suppressive effects. The choice of treatment must then reston the perceived risk of the options available.This case demonstrates a lasting response attributed toCyA that was not achieved either by first-line therapy withsteroid and intravenous immunoglobulin or by second-linetherapy with cyclophosphamide. Although we cannotexclude spontaneous remission of the patient’s FVIII inhib-itor, the reduction in inhibitor titre commensurate with theintroduction of CyA makes this unlikely. We conclude thatCyA warrants consideration in patients refractory to first-line therapy for this rare but serious autoimmune disorder.Peter S. Maclean1R. Campbell Tait1Gordon D. O. Lowe1Isobel D. Walker1Mark D. McColl21Haemophilia Centre, GlasgowRoyal Infirmary, Glasgow, and2Department of Haematology,Crosshouse Hospital,Kilmarnock, UK. E-mail:petermaclean@btopenworld.comREFERENCESDykes, A.C., Walker, I.D., Lowe, G.D.O. & Tait, R.C. (2001) Com-bined prednisolone and intravenous immunoglobulin treatmentfor acquired factor VIII inhibitors: a 2-year review. Haemophilia,7, 160–163.Grunewald, M., Beneke, H., Guthner, C., Germowitz, A., Brom-mer, A. & Griesshammer, M. (2001) Acquired haemophilia:experiences with a standardized approach. Haemophilia, 7,164–169.Hay, C.R.M., Colvin, B.T., Ludlam, C.A., Hill, F.G.H. & Preston,F.E. (1996) Recommendations for the treatment of factor VIIIinhibitors: from the UK Haemophilia Centre Directors’ Organi-sation Working Party. Blood Coagulation and Fibrinolysis, 7,134–138.Lian, E.C.Y., Larecada, A.F. & Chiu, A.Y.Z. (1989) Combinationimmunosuppressive therapy after factor VIII infusion for ac-quired factor VIII inhibitor. Annals of Internal Medicine, 110,774–778.Morrison, A.E. & Ludlam, C.A. (1995) Acquired haemophilia and itsmanagement. British Journal of Haematology, 89, 231–236.Pfliegler, G., Boda, Z., Harsfalvi, J., Flora-Nagy, M., Sari, B., Pecze, K.& Rak, K. (1989) Cyclosporin treatment of a woman withacquired haemophilia due to factor VIIIC inhibitor. PostgraduateMedical Journal, 65, 400–402.Keywords: acquired Factor VIII deficiency, Factor VIIIinhibitor, cyclosporin A.MISCONCEPTIONS IN THALASSAEMIA DIAGNOSISA full blood count was requested on a 2-day-old Pakistaniboy. The child had mild anaemia with thalassaemic indices,blood film showed anisocytosis, poikilocytosis, target cellsand polychromasia (Table I). High-performance liquid chro-matography suggested a three alpha gene deletion withhaemoglobin Barts 27Æ7%, haemoglobin F 44Æ6% and hae-moglobin A 19%.The mother’s prenatal test results were normal (Table I).The father’s results suggested alpha-thalassaemia trait orsilent beta-thalassaemia trait (Table I). No other antenataltesting had been done as the fetus was not felt to be at risk ofserious haemoglobinopathy.Further questioning of the mother revealed she had hadin vitro fertilization (IVF) using donated ova in another UKcity. The donor, from Cyprus, had declared a family historyof thalassaemia at the IVF clinic and therefore underwentscreening. This was reported as showing possible irondeficiency, and a card was issued stating that she had nosignificant haemoglobinopathy. Antenatal haemoglobinop-athy screening for the biological mother during a previouspregnancy had also been reported as normal. Two furtherseparate screens over a period of years had failed tocomment on the significance of thalassaemic indices inthe presence of a normal haemoglobin and Hb A2.DNA analysis showed the natural mother to have aMediterranean a0 deletion (–MED ⁄aa), the father a 3Æ7-kba+-thalassaemia deletion (–a3Æ7 ⁄ aa) and the baby haemo-globin H disease (–a3Æ7 ⁄ –MED).The donated ova from the same woman had also beenused in other pregnancies, including a pregnancy using thedonated ova and a sperm donor of Asian origin. This spermdonor had not had a haemoglobinopathy screen and had tobe recalled.This case highlights common problems in thalassaemiadiagnosis, screening and reporting. Although guidelines forthe laboratory diagnosis of haemoglobinopathies exist(British Committee for Standards in Haematology, GeneralHaematology, 1998), there is currently no standardizedreporting of results. The British Committee for Standards inHaematology (BCSH) guidelines state that screening isequally important in cases where pregnancy is the result ofartificial insemination from a donor or in vitro fertilization,Table I. Haematology results of the patient and his parents.Hb(g ⁄ dl)MCV(fl)MCH(pg)RBC(· 1012 ⁄ l)HbA2(%)HbF(%)SickletestBaby 10Æ8 75 22Æ9 6Æ03Father 14Æ3 81Æ5 26Æ9 5Æ31 2Æ2 < 1Æ0 NegativeMother 13Æ1 82Æ5 28Æ3 4Æ64 2Æ5 < 1Æ0 NegativeDonor 13Æ2 66 20Æ5 6Æ44 2Æ9 < 1Æ0 NegativeCorrespondence 1025 2003 Blackwell Publishing Ltd, British Journal of Haematology 122: 1024–1026yet confidentiality issues mean that this information doesnot have to be passed on. Screening of both egg and semendonors is also recommended by the Human Fertilization andEmbryology Authority, 2001), the British Andrology Soci-ety, 199) and the British Fertility Society (2000).Although the majority of populations at risk of a-thalas-saemia have a+ deletions, it is recommended that thea0-thalassaemia trait should be detected in prospectiveparents to predict the occurrence of haemoglobin Bartshydrops fetalis.Mutations causing the a0-thalassaemia trait are foundpredominantly in south-east Asia, southern China (–SEA ⁄aa,–FIL ⁄aa and –THAI ⁄ aa) and the Mediterranean, particularlyCyprus, Turkey and Greece (–MED ⁄ aa).DNA analysis should be done in patients from theseethnic groups with a MCH < 25 pg and where b- anddb-thalassaemia and haemoglobin Lepore have beenexcluded.In this case, the ethnic origin of the natural mother wasnot taken into account and the a0-thalassaemia traittherefore not considered. In such cases, it is necessary toadd a statement that the ‘a-thalassaemia trait cannot beexcluded’ whether iron deficiency is present or not.The National Health Service (NHS) plan is committed to anational, linked antenatal and neonatal screening pro-gramme for the haemoglobinopathies (NHS Plan, 2000).We anticipate that this will give clear guidance as to whichpopulation groups are to be screened to achieve standard-ized reporting. These guidelines should include adviceregarding the screening of semen and egg donors.Joost J. van VeenRichard KellyClaire WalkerJosh WrightDepartment of Haematology,Royal Hallamshire Hospital,Sheffield, UK. E-mail:Josh.Wright@sth.nhs.ukREFERENCESBritish Andrology Society (1999) British Andrology Society guide-lines for the screening of semen donors for donor insemination.Human Reproduction, 14, 1823–1826.British Committee for Standards in Haematology, General Haema-tology (1998) The laboratory diagnosis of haemoglobinopathies.British Journal of Haematology, 101, 783–792.British Fertility Society (2000) Recommendations for good practiceon the screening of egg and embryo donors. Human Fertility, 3,162–165.Human Fertilisation and Embryology Authority (2001) Code ofPractice, 5th edn. HFEA, London.NHS Plan (2000) HMSO, London.Keywords: haemoglobinopathy, antenatal screening,alpha-thalassaemia, in vitro fertilization.1026 Correspondence 2003 Blackwell Publishing Ltd, British Journal of Haematology 122: 1024–1026

British Andrology Society guidelines for the screening of semen donors for donor insemination.

British Committee for Standards in Haematology, General Haematology

HMSO, London. Keywords: haemoglobinopathy, antenatal screening, alpha-thalassaemia, in vitro fertilization. 1026 Correspondence

Human Fertilisation and Embryology Authority

Recommendations for good practice on the screening of egg and embryo donors.

Successful elimination of factor VIII inhibitor using cyclosporin A

http://eprints.gla.ac.uk/556/1/Br_Jo_Maem_122%2C_1024.pdf

Successful elimination of factor VIII inhibitor using cyclosporin A

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