j.1365-2141.2001.02873-4.x

British Journal of Haematology, 2001, 114, 241±246

Correspondence

TESTING SOKAL'S AND THE NEW PROGNOSTIC SCORE FOR CHRONIC MYELOID LEUKAEMIA

TREATED WITH a-INTERFERON: COMMENTS

We read with great interest the article by the ItalianCooperative Study Group on Chronic Myeloid Leukaemia(CML) (2000) who applied the new CML score (Table I) ofHasford et al (1998) to a data set of 272 patients treatedwith interferon alpha (IFN-a).

The credibility of a prognostic model is increased whenconfirmation comes from outside the institution at whichthe prognostic model was evaluated. The Italian CooperativeStudy Group on CML (2000) was the first to publish suchexternal validation for the new CML score. Among theirpatients, the classification of the new CML score led to threerisk groups with statistically significantly different survivaltimes. Their results substantially support the new CMLscore's validity.

Because of the particular inclusion criterion `age , 56years', the Italian sample consisted of 78% of patients withthe same age group (, 50 years). Taking this restriction ofvariability into account, the performance of the new CMLscore in the Italian sample is even more remarkable.

However, the gist of the paper by the Italian CooperativeStudy Group on CML (2000) was a detailed comparisonbetween the new CML score and the Sokal score (Sokal et al,1984). The reason why Hasford et al (1998) aimed at theidentification of a new prognostic model was because theSokal score could not provide a satisfactory risk groupdiscrimination for survival of IFN-treated patients in acouple of samples; a result which is also displayed by thepaper of the Italian Cooperative Study Group on CML(2000) who noticed a statistically significantly differentsurvival between the low-risk group and the intermediate-risk group of the new CML score, but not between thecorresponding groups of the Sokal score. Their data suggestwhy test results were different: compared with the Sokalscore, the new CML score placed 28 (21%) more patientsbut only six more observed deaths in the low-risk group.This and basically identical low-risk survival curves withthe same median survival time (105 months) for either

score indicate that the new CML score's allocation of 160patients to the low-risk group was justified. They alsoshowed that 23 of these 28 additional patients hadintermediate risk according to the Sokal score. Leaving asubstantial number of actual low-risk patients in anintermediate-risk group does, of course, increase its mediansurvival time and decreases the statistical differencebetween the survival curves of both risk groups. On theother hand, an intermediate-risk group including low-riskpatients increases the difference in survival when comparedwith the high-risk group. The high-risk groups of bothscores had a median survival of 45 months, but 15 of 62high-risk patients according to the Sokal score (24%) had asurvival time of more than 60 months, three of them withcensored survival times . 96 months. With regard to thenew CML score, only 4 out of 25 patients (16%) hadsurvival times . 60 months, all of whom died before month96.

The Sokal score was developed within a sample ofchemotherapy-treated patients. This is generally acceptedas a reason why it does not work satisfactorily withpatients treated otherwise. However, there was also adifferent methodical approach in defining boundaries.Regarding the new CML score, the minimal P-valueapproach was applied, a statistical procedure which isable to identify boundaries maximizing the difference ofthe resulting groups with respect to the investigatedoutcome variable. Thus, boundaries were suggested byreal data and the three risk groups with the most differentsurvival curves were selected. In contrast, Sokal et al(1984) `divided into three subgroups of roughly similarsize, using hazard ratios of 0´8 and 1´2 as boundaries.'This indicates that the decision for the boundaries wasdriven by the idea of establishing risk groups of similarsize and, maybe, by choosing boundaries that wereequidistant from the hazard ratio 1´0. Their three riskgroups were also different with regard to survival, but

q 2001 Blackwell Science Ltd 241

Table I. Correction of the coefficients given for age and basophils in Table I of the article of the ItalianCooperative Group on CML (2000): the New CML score's value is evaluated by Table I.

New CML score � 1000 � [0´6666 � (0, when age , 50 completed years; 1, otherwise)0´0420 � (spleen size in cm under left costal margin)

0´0584 � (% blasts in peripheral blood)

0´0413 � (% eosinophils in peripheral blood)0´2039 � (0, when basophils , 3% in peripheral blood; 1, otherwise)

1´0956 � (0, when platelet count , 1500±109/l; 1, otherwise)]

boundaries were rather suggested by Sokal et al (1984)than by real data. It is improbable that their suspectednon-statistical proceeding of defining risk groups depictsthe `real' percentages of patients who should belong tothe low-risk or high-risk groups as well as the new CMLscore does. Moreover, Sokal et al (1984) assigned meanvalues for missing items that `may have introduced aslight bias against prognostic variation'.

Hence, we cannot agree with the conclusions of theItalian Cooperative Group on CML (2000). We do not thinkthat the Sokal score remains useful for these kind of patientsand are concerned by the authors' implicative recommen-dation to use the Sokal score instead of the new CML scorefor the identification of high-risk patients.

The patients to whom the two scores attribute differentrisk groups are the patients to whom the prognostic modelpreferred by the clinicians really matters. If any clinicianrelies on the wrong high-risk group allocation of the Sokalscore, he or she might turn down a therapy including IFN-afor his or her patient. This could be harmful to the patient:patients with intermediate risk or low risk according to thenew CML score have the potential to become a haemato-logical or cytogenetic responder when treated with IFN-aand, within either risk group, both kind of responses lead toa statistically significantly better survival compared withnon-responders.

A sample of `younger' patients with a high-risk group ofless than 10% should be taken as good news. It does notmake sense to try to artificially enlarge this risk group at thecost of patients who are in fact intermediate-risk patientsand could respond to IFN-a.

1Research Group CML,c/o GIS, and 2Institutefor Medical Informatics,Biometry andEpidemiology (IBE),University of Munich,Munich, Germany.E-mail: [email protected]

Markus Pfirrmann1

Professor Dr Joerg Hasford2

REFERENCES

Italian Cooperative Study Group on Chronic Myeloid LeukaemiaWriting Committee: Bonifazi, F., De Vivo, A., Rosti, G., Tiribelli,

M., Russo, D., Trabacchi, E., Fiachini, M., Montefusco, E. &

Baccarani, M. (2000) Testing Sokal's and the new prognostic

score for chronic myeloid leukaemia treated with a-interferon.British Journal of Haematology, 111, 587±595.

Hasford, J., Pfirrmann, M., Hehlmann, R., Allan, N.C., Baccarani,

M., Kluin-Nelemans, J.C., Alimena, G., Steegmann, J.L. & Ansari,

H., Writing Committee for the Collaborative CML PrognosticFactors Project Group (1998) A new prognostic score for survival

of patients with chronic myeloid leukemia treated with interferon

alfa. Journal of the National Cancer Institute, 90, 850±858.Sokal, J.E., Cox, E.B., Baccarani, M., Tura, S., Gomez, G.A.,

Robertson, J.E., Tso, C.Y., Braun, T.J., Clarkson, B.D., Cervantes,

F. & Rozman, C., the Italian Cooperative CML Study Group (1984)

Prognostic discrimination in `good-risk' chronic granulocyticleukemia. Blood, 63, 789±799.

Keywords: prognostic scores, chronic myeloid leukaemia,interferon-a, Sokal score.

REPLY TO PFIRRMANN AND HASFORD

We share the satisfaction of Joerg Hasford and MarkusPfirrmann in the good performance of the new Euro score inan independent series of a-interferon-treated chronic myeloidleukaemia (CML) patients; a satisfaction which is increasedbecause one of us (M.B.) was a co-author of the paper reportingon the new score (Hasford et al, 1998) and the Italian StudyGroup gave a substantial contribution to the generation of thenew score. We think and confirm that the new score marks animprovement but discussing this may further improve it. Wehave a couple of comments on the letter. One commentconcerns the survival of high-risk patients. The mediansurvival of these patients was identical with either score, andthe median is what really matters when many patients die,and die quickly. A small number of long-term survivors mayalso be found in a high-risk group. As an example, it is clearthat patients with advanced-stage Hodgkin's disease do worsethan patients with early-stage disease, yet some advanced-stage patients may also be cured. Selecting only very few caseswith a dreadful prognosis may be statistically rewarding but itdoes not help the doctor much. Another comment concernsthe relationship between the risk groups and the response toa-interferon. This relationship was well established for theSokal's score, but not yet established for the new Euro score.

We have looked at this relationship in our study (ItalianCooperative Study Group on CML, 2000) and have found thatthe relationship between cytogenetic response and risk scorewas better with Sokal's than with the Euro score. Althoughawaiting other studies, we confirm our conclusion that theEuro score is probably better but has some limitations, andthat Sokal's score is still valid for interferon-treated patientstoo. Currently, we use both systems.

1Institute of Haematology andClinical Oncology `L. and A.SeraÁgnoli', Bologna University,2Division of Haematology Udine,University Hospital, and3Department of CellularBiotechnologies and Haematology,Roma University `La Sapienza',Rome, Italy. E-mail:[email protected]

Francesca Bonifazi1

Antonio de Vivo1

Gianantonio Rosti1

Mario Tiribelli2

Domenico Russo2

Elena Trabacchi1

Mauro Fiacchini1

Enrico Montefusco3

Michele Baccarani1

on behalf of theItalian CooperativeStudy Group onChronic MyeloidLeukaemia

242 Correspondence

q 2001 Blackwell Science Ltd, British Journal of Haematology 114: 241±246

REFERENCES

Hasford, J., Pfirrmann, M., Hehlmann, R., Allan, N.C., Baccarani,

M., Kluin-Nelemans, J.C., Alimena, G., Steegmann, J.L. & Ansari,

H., Writing Committee for the Collaborative CML Prognostic

Factors Project Group (1998) A new prognostic score forsurvival of patients with chronic myeloid leukemia treated with

interferon alfa. Journal of the National Cancer Institute, 90, 850±

858.

Italian Cooperative Study Group on Chronic Myeloid Leukaemia

Writing Committee: Bonifazi, F., De Vivo, A., Rosti, G., Tiribelli,

M., Russo, D., Trabacchi, E., Fiachini, M., Montefusco, E. &Baccarani, M. (2000) Testing Sokal's and the new prognostic

score for chronic myeloid leukaemia treated with a-interferon.

British Journal of Haematology, 111, 587±595.

Keywords: CML, prognosis, interferon.

TFR2 Y250X MUTATION IN ITALY

Hereditary haemochromatosis is an autosomal recessive disorderof iron metabolism, associated with mutations in the HFE gene.In Northern Europe, the majority of patients are homozygousfor a C282Y mutation. A second mutation (H63D) has beendescribed but its role in iron overload is controversial (Federet al, 1996). Other mutations in HFE are extremely rare andare usually private mutations. Haemochromatosis in Italy isheterogeneous and the frequency of C282Y homozygosityamong patients is approximately 64% (Piperno et al, 1998). Afew patients with an early onset form of haemochromatosis havebeen described and the respective locus (HFE2) mapped on 1q(Roetto et al, 1999). Moreover, recently a new type ofhaemochromatosis (HFE3) has been characterized in six patientsfrom two Italian families of Sicilian origin. These patients arehomozygous for a nonsense mutation (Y250X) in the transferrinreceptor 2 (TFR2) on 7q22 (Camaschella et al, 2000).

We tested DNA samples to determine the frequency of theTFR2 Y250X mutation in Italy in order to evaluate theusefulness of including this mutation in our diagnosticpanel for haemochromatosis.

We studied 68 samples from a cohort of Italian newborns ofSouth-Central origin, previously tested to define the C282Yfrequency in Italy (Restagno et al, 1999), and 41 unrelatedhealthy blood donors (37 men and 4 women) of Sicilian origin,who showed mildly elevated serum ferritin (399 ^ 84 mg/l);transferrin saturation levels of this group were not available. In

addition, we studied 30 patients (25 men and 5 women) withserum parameters of iron overload (serum ferritin1691 ^ 1267 mg/l, range 565±5525; transferrin saturation80´3 ^ 22´3%, range 32±100) referred to our service forgenetic diagnosis of haemochromatosis but found negative forthe C282Y mutation. Three patients were H63D homozygous.

The Y250X mutation was detected using polymerase chainreaction (PCR) of TFR2 exon 6 followed by restriction analysis.PCR was performed in a final volume of 50 ml containing100 ng of DNA, 1 U of Taq polymerase, 25 pmol of eachprimer and 1 mmol/l MgCl2 with a protocol of 30 cycles (30 sat 978C for denaturation, 30 s at 568C for annealing and 30 sat 728C for extension). The primers used for the analysis wereas follows: forward 5 0-TGC ACT GGG TCG ATG AG-3 0, reverse5 0-CTC AAG CCC TCC CTC T-3 0. The amplified product wasdigested with MaeI (Boehringer Mannheim) according to themanufacturer's recommendations and digestion productswere analysed by agarose 2% gel electrophoresis (Fig 1). TheC282Y and H63D mutations in the HFE gene were detectedusing PCR, followed by digestion with RsaI and MboI,respectively, as previously described (Jouanolle et al, 1997).

We analysed a total of 280 chromosomes. The Y250Xmutation was not found among iron-loaded patients. In thegroup of newborns and blood donors (218 chromosomes), oneindividual was found to be heterozygous for the Y250Xmutation, which translates into a carrier frequency of 0´9%(allelic frequency � 0´45%) for individuals of selected geogra-phical origin. This suggests that Y250X is a rare mutation, andthat Y250X testing in non-HFE haemochromatosis patients willnot be cost-effective, even in Italy where haemochromatosis isheterogeneous.

1Dipartimento Scienze Cliniche eBiologiche, UniversitaÁ di Torino,Azienda Ospedaliera S.Luigi,Orbassano, Torino, 2Servizio diImmunoematologia e MedicinaTransfusionale, AziendaOspedaliera `Civile-M.PaternoÁArezzo', Ragusa, and3Dipartimento di PatologiaClinica, Laboratorio di GeneticaMolecolare, Ospedale InfantileRegina Margherita, Torino,Italy. E-mail:[email protected]

Marco De Gobbi1

Maria Rosa Barilaro1

Giovanni Garozzo2

Luca Sbaiz3

Federica Alberti1

Clara Camaschella1

Fig 1. MaeI restriction enzyme digestion of amplified exon 6. In thenormal sequence (lane 2±3), two fragments are obtained (238 bp

and 117 bp). In the mutated sequence, the 238 bp is cleaved into

134 bp and 104 bp fragments (lane 1). The Y250X heterozygote

shows four fragments: 238, 134, 117 and 104 bp (lane 4). U,undigested fragment; MWM, molecular-weight marker.


Correspondence 243

ACKNOWLEDGMENTS

This work was partly supported by MURST 40% and IRCCS-Pavia 1998.

REFERENCES

Camaschella, C., Roetto, A., CalõÁ, A., De Gobbi, M., Garozzo, G.,

Carella, M., Majorano, N., Totaro, A. & Gasparini, P. (2000) Thegene TFR2 is mutated in a new type of haemochromatosis

mapping to 7q22. Nature Genetics, 25, 14±15.

Feder, J.N., Gnirke, A., Thomas, W., Tsuchihashi, Z., Ruddy, D.A.,

Basava, A., Dormishian, F., Domingo, R., Ellis, M.C., Fullan, A.,Hinton, L.M., Jones, N.L., Kimmel, B.E., Kronmal, G.S., Lauer, P.,

Lee, V.K., Loeb, D.B., Mapa, F.A., McClelland, E., Meyer, N.C.,

Mintier, G.A., Moeller, N., Moore, T., Morikang, E., Prass, C.E.,Quintana, L., Starnes, S.M., Schatzman, R.C., Brunke, K.J.,

Drayana, D.T., Rish, N.J., Bacon, B.R. & Wolff, R.K. (1996) A

novel MHC class I-like gene is mutated in patients with hereditary

hemochromatosis. Nature Genetics, 13, 399±408.Jouanolle, A.M., Fergelot, P., Gandon, G., Yaouanq, J., Le Gall, J.Y. &

David, V. (1997) A candidate gene for hemochromatosis:

frequency of the C282Y and H63D mutations. Human Genetics,

100, 544±547.

Piperno, A., Sampietro, M., Pietrangelo, A., Arosio, C., Lupica, L.,

Montosi, G., Vergani, A., Fraquelli, M., Girelli, D., Pasquero, P.,Roetto, A., Gasparini, P., Fargion, S., Conte, D. & Camaschella, C.

(1998) Heterogeneity of hemochromatosis in Italy. Gastro-

enterology, 114, 996±1002.

Restagno, G., Gomez, A.M., Sbaiz, L., De Gobbi, M., Roetto, A.,

Bertino, E., Fabris, C., Fiorucci, G.C., Fortina, P. & Camaschella, C.

(1999) A pilot C282Y hemochromatosis screening in Italian

newborns by TaqmanTM technology. Genetic Testing, 4, 177±181.

Roetto, A., Totaro, A., Cazzola, M., Cicilano, M., Bosio, S., D'Ascola,

G., Carella, M., Zelante, L., Kelly, A., Cox, M.T., Gasparini, P. &Camaschella, C. (1999) The juvenile hemochromatosis locus

maps to chromosome 1q. American Journal of Human Genetics,

64, 1388±1393.

Keywords: haemochromatosis, HFE, TFR2, mutationanalysis, prevalence.

TREATMENT OF REFRACTORY AUTOIMMUNE HAEMOLYTIC ANAEMIA WITH ANTI-CD20

(RITUXIMAB)

Autoimmune haemolytic anaemia (AIHA) of the warm typeresults from the production of autoantibodies that bind tored blood cells and lead to their destruction. The establishedtreatment consists of corticosteroids alone or in combina-tion with azathioprine or cyclophosphamide (Schwartz et al,2000). Refractoriness to these drugs is seen in only a smallportion of the patients. Rituximab is an anti-CD20chimaeric monoclonal antibody that recognizes the CD20antigen on B-lymphocytes and leads to their lysis. The drugis used to treat patients with indolent non-Hodgkinlymphoma (Onrust et al, 1999), and it has been shown to

be helpful in the treatment of some patients with refractoryautoimmune disorders including secondary immune throm-bocytopenia (Ratanatharathorn et al, 2000), cold agglutinindisease (Lee & Kueck, 1998) and polyneuropathy related toIgM antibodies (Levine & Pestronk, 1999).

We report the 8-year course of a 68-year-old male patientwith AIHA. Treatment with prednisolone, azathioprine,cyclophosphamide, mycophenolate-mofetil and pulsed high-dose dexamethasone led to either transient or no responses.Clinical and laboratory examination before treatment withrituximab revealed decompensated haemolytic anaemia.Full blood count before treatment showed haemoglobin (Hb)8´4 g/dl, white blood count 12´0 � 109/l, platelets141 � 109/l, neutrophils 10´8 � 109/l, lymphocytes0´49 � 109/l, CD19-positive cells 4% of lymphocytes,reticulocytes 14´9%, haptoglobin 10 mg/l, total bilirubin90´63 mmol/l, lactate dehydrogenase (LDH) 759 U/l. Bonemarrow biopsy showed hyperplastic erythropoiesis.

After obtaining informed consent, rituximab at 375 mg/m2 was given once a week for 4 weeks to baseline therapyconsisting of 15 mg/d prednisolone (Fig 1). Apart fromminor chills during the first infusion, there were no side-effects. After the first rituximab infusion, CD19-positive cellsin the peripheral blood decreased from 4% to undetectablelevels and remained below 0´05% of the lymphocytes duringthe observation period. Although the direct antiglobulin testremained positive, haemolysis decreased during the6 months of observation after treatment (Hb 12´3 g/dlversus 8´4 g/dl, LDH 759 U/l vs. 483 U/l, total bilirubin71´82 mmol/l vs. 90´63 mmol/l). Reticulocyte count andhaptoglobin value did not change. The patient is now welland largely asymptomatic. This shows that rituximab may bea tolerable alternative in the treatment of refractory AIHA.

Fig 1. Haemoglobin concentration after rituximab application(4 � 375 mg/m2) in a patient with refractory autoimmune

haemolytic anaemia. Pred, prednisolone; Azt, azathioprine 2 mg/

kg/d; Cyc, cyclophosphamide 1´3 mg/kg/d; MMF, mycophenolate-mofetil 2 g/d; Dexa, dexamethasone 40 mg (once).

244 Correspondence


1Bloodbank and 2Haematologicaland Oncological Department,ChariteÂ Campus Virchow-Klinikum, Berlin, GermanyE-mail: [email protected]

Norbert Ahrens1

Dorothea Kingreen2

Axel Seltsam1

Abdulgabar Salama1

REFERENCES

Lee, E.J. & Kueck, B. (1998) Rituxan in the treatment of cold

agglutinin disease. Blood, 92, 3490±3491.Levine, T.D. & Pestronk, A. (1999) IgM antibody-related poly-

neuropathies: B-cell depletion chemotherapy using rituximab.

Neurology, 52, 1701±1704.

Onrust, S.V., Lamb, H.M. & Balfour, J.A. (1999) Rituximab. Drugs,

58, 79±88; Discussion 89±90.

Ratanatharathorn, V., Carson, E., Reynolds, C., Ayash, L.J., Levine, J.,Yanik, G., Silver, S.M., Ferrara, J.L. & Uberti, J.P. (2000) Anti-CD20

chimeric monoclonal antibody treatment of refractory immune-

mediated thrombocytopenia in a patient with chronic graft-versus-host disease. Annals of Internal Medicine, 133, 275±279.

Schwartz, R.S., Berkman, E.M. & Silberstein, L.E. (2000) Auto-

immune hemolytic anemias. In: Hematology: Basic Principles and

Practice (ed. by R. Hoffmann, E.J. Benz, Jr, S.J. Shattil, B. Furie, H.J.Cohen, L.E. Silberstein & P. McGlave), pp. 611±630. Philadelphia.

Keywords: refractory autoimmune haemolytic anaemia,AIHA, anti-CD20, rituximab.

THALIDOMIDE AND LOW-DOSE DEXAMETHASONE IN MYELOMA TREATMENT

We recently reported our experience of treating ninepatients who had advanced myeloma with thalidomide(Myers et al, 2000). We have now accrued data on 26patients, with an overall response rate of 77% (with areduction of at least 25% in paraprotein/light-chainexcretion), 53% having a reduction of 50% or more. Wenote with interest the letter by Tiplady & Summerfield(2000) reporting the use of continuous, low-dose dexa-methasone (4 mg) and showing a response rate of 6 out of15 patients (40%) with at least a 50% reduction inparaprotein in patients with advanced myeloma.

Seven of our patients had low-dose dexamethasoneadded, in five cases because of a lack of a continuingresponse to thalidomide alone and in two cases because of asevere rash with thalidomide, which was abolished by theaddition of dexamethasone. The latter was used in a similarway to that described by Tiplady & Summerfield (2000),commencing at 4 mg and reducing slowly over a fewmonths. Five of the seven patients showed further reduc-tions in paraprotein/light-chain excretion of 80%, 68%,61%, 34% and 21% (the latter reduction was just 1 weekafter commencing dexamethasone). Two patients did notrespond. The two patients with a rash had reductions of68% and 34%. Of the other patients, most had previouslybeen treated with pulsed dexamethasone with either noresponse or unacceptable side-effects.

Other authors report synergistic effects of dexamethasoneand thalidomide, possibly via their effects on interleukin 6(IL-6), other cytokines in the marrow milieu and a directeffect on myeloma cells. A recent study by Rajkumar et al(2000) reported a 77% response to the combination of

200 mg of thalidomide plus pulsed dexamethasone innewly diagnosed cases of myeloma. Side-effects were notinsignificant in this study, with skin rash in 50%, sedationin 42%, constipation in 59% and neuropathy in 35%. Theuse of continuous low-dose dexamethasone with or withoutthalidomide was associated with relatively fewer side-effectsin both Tiplady's study and ours (Myers et al, 2000; Tiplady& Summerfield, 2000) and should be considered as analternative to pulsed dexamethasone plus thalidomide incases in which the response to thalidomide alone is poor.

Department of Haematology,Queens Medical Centre,University Hospital,Nottingham, UK.E-mail: [email protected]

B. MyersC. GrimleyG. Dolan

REFERENCES

Myers, B., Crouch, D. & Dolan, G. (2000) Thalidomide treatment in

advanced refractory myeloma. British Journal of Haematology,111, 986.

Rajkumar, S.V., Hayman, S., Fonseca, R., Dispenzieri, A., Lacy, M.,

Geyer, S., Wellik. L., Lust, J., Kyle, R., Greipp, P., Gertz, M. &

Witzig, T. (2000) Thalidomide plus dexamethasone andthalidomide alone as first line therapy for newly diagnosed

myeloma. Blood, 96, 11168a.

Tiplady, C.W. & Summerfield, G.P. (2000) Continuous low-dosedexamethasone in relapsed or refractory multiple myeloma.

British Journal of Haematology, 111, 381.

Keywords: myeloma, thalidomide, dexamethasone.

USE OF RECOMBINANT FACTOR VIIA FOR POST-OPERATIVE HAEMORRHAGE IN A PATIENT WITH

GLANZMANN'S THROMBASTHENIA AND HUMAN LEUCOCYTE ANTIGEN ANTIBODIES

Recombinant factor VIIa is licensed for the treatment ofpatients with inherited or acquired haemophilia withinhibitors to coagulation, but has also been used to treatbleeding conditions without inhibitors to coagulation

proteins, such as hereditary factor VII (FVII) deficiency,factor XI (FXI) deficiency, inherited platelet disorders andvon Willebrand disease (Hedner, 1998). The haemostaticeffect of the agent may be by activating coagulation on the


Correspondence 245

surface of platelets. Even when only a small number ofactivated platelets are present, activation of factor X (FX) byFVIIa may produce enough thrombin for local fibrinproduction at bleeding sites (Monroe et al, 1997).

Glanzmann's thrombasthenia is a rare inherited plateletfunction disorder with abnormalities of the membraneglycoprotein (GP) IIb/IIIa receptor. Clinical manifestationsinclude mucosal and post-operative bleeding (d'Oiron et al,2000). Transfusion of platelets may promote haemostasis,but repeated transfusions may stimulate anti-humanleucocyte antigen (HLA) and anti-GP IIb/IIIa immunizationand cause platelet refractoriness. Factor VIIa may be auseful haemostatic option in such cases.

Three cases have recently been reported of Glanzmann'sthrombasthenia with anti-GPIIb/IIIa antibodies treatedpreoperatively with factor VIIa (d'Oiron et al, 2000). Therewas no surgical bleeding in any of the patients, althoughone had a thromboembolic complication. There has alsobeen a case of Glanzmann's thrombasthenia with anti-HLAantibodies in which HLA-matched platelets and FVIIa weresuccessfully used during major surgery (Wielenga et al,1998). In this case, HLA-matched platelets alone had notbeen sufficient to prevent bleeding complications duringprevious dental treatment. In both these reports, all patientsalso received tranexamic acid.

We have treated a patient with Glanzmann's throm-basthenia and anti-HLA alloantibodies with FVIIa for post-operative haemorrhage. The 33-year-old woman with type IGlanzmann's thrombasthenia underwent elective lumbardiscectomy. She had documented anti-HLA antibodies butno anti-GPIIb/IIIa antibodies. Previous epistaxes and trau-matic bleeding had responded well to HLA-matchedplatelets with tranexamic acid. Immediately prior to andfollowing surgery she received HLA-matched plateletswithout tranexamic acid. Twenty minutes after surgeryshe had a brisk 250 ml haemorrhage from the surgicalwound which persisted despite application of a pressuredressing. A single bolus of 4´8 mg (60 mg/kg) of recombi-nant factor VIIa was given while awaiting further HLA-matched platelets. Bleeding stopped 15 min following this

without further platelet transfusions. No further factor VIIawas administered.

This and other recent cases suggest that emergencyhaemostasis can be achieved with FVIIa (d'Oiron et al,2000) for a platelet refractory state secondary to anti-HLA oranti-GP IIb/IIIa alloantibodies in patients with Glanzmann'sthrombasthenia. This occurred in our case without additionaltreatment with tranexamic acid. The level of risk ofthromboembolism associated with FVIIa is unknown. Thethrombosis reported in the patient with Glanzmann'sthrombasthenia by d'Oiron et al (2000) may have beenrelated to a higher VIIa dose, prolonged treatment durationand concurrent anti-fibrinolytic therapy.

Reference Centre for Haemostatic andThrombotic Disorders, St. Thomas'Hospital, London, UK. E-mail:[email protected]

R. K. PatelG. F. SavidgeS. Rangarajan

REFERENCES

Hedner, U. (1998) Recombinant activated factor VII as a universal

haemostatic agent. Blood Coagulation and Fibrinolysis, Suppl.1,S147±52.

Monroe, D.M., Hoffman, M., Oliver, J.A. & Robert, H.R. (1997)

Platelet activity of high-dose factor VIIa is independent of tissue

factor. British Journal of Haematology, 99, 542±547.d'Oiron, R., Menart, C., Trzeciak, M.C., Nurden, P., Fressinaud, E.,

Dreyfus, M., Laurian, Y. & Negrier, C. (2000) Use of recombinant

factor VIIa in 3 patients with inherited type I Glanzmann'sthrombasthenia undergoing invasive procedures. Thrombosis and

Haemostasis, 84, 644±7.

Wielenga, J.J., Siebel, Y., van Buuren, H.R., Berends, F.J., Schipperus,

M.R., van Vliet, H.D.D.M. & Kappers, M.C. (1998) Use ofrecombinant factor VIIa and HLA matched platelets to prevent

bleeding during and after major surgery in a patient with

Glanzmann's thrombasthenia. Haemophilia, 4, 299 (abstract).

Keywords: Glanzmann's thrombasthenia, HLA-antibodies,factor VIIa, platelet disorders, anti-Gp IIb/IIIa receptorantibodies.

246 Correspondence


j.1365-2141.2001.02873-4.x

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