2003; baxter - Supplements - Haematologica

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94F. Baudo et al.Prolongation of the activated partial thromboplastintime (aPTT) with a normal prothrombintime (PT) is the hallmark of the laboratory diagnosis.The objectives of therapy are to control thebleeding and suppress the autoantibodies. In 1999the Italian Hemophilia Centers carried out a surveyof the cases of acquired factor VIII inhibitorsregistered in the previous 15 years. The data collectedby this survey are presented in this report.Design and MethodsA questionnaire was mailed to 42 ItalianHemophilia Centers. The following informationconcerning each patient was requested: the primarycondition (if present); the initiating causeof bleeding (e.g. trauma, surgery, other events) orits spontaneous occurrence; the site of bleeding;its severity evaluated by hemoglobin level and bytransfusion requirement; the type (anti FVIII oranti FIX) and the titer of the inhibitor; theanamnestic response if present; the therapyadministered to control the bleeding; agentsused, modality of administration and results; theimmunosuppressive therapy; drugs and modalityof their administration, side effects and results;for the pregnancy-related cases, temporal correlationwith bleeding. Complete remission (CR)was defined as a normal level of FVIII or FIX andno detectable inhibitor; partial remission (PR)was defined as an inhibitor titer < 10 Bethesdaunit (BU) or a decrease of 50% if the baselineinhibitor titer was 10BU or a decrease less than 50% of the baselinevalue.Mild bleeding was defined as self-limited ecchymosesand cutaneous hematomata. Severe bleedingwas defined as retroperitoneal, intracranial, orocular; a fatal hemorrhages; requirement of ≥ 2red blood cell packs; or a decrease of ≥ 2 g ofhemoglobin.Statistical analysisStatistical analyses were performed using theStudent’s t test (Program MEDCALC, release1999). p values < 0.05 were considered statisticallysignificant.Table 1. Characteristics of the patients and clinical conditionsassociated with acquired inhibitor development; wholepopulation.Patients 96Inhibitor FVIII/IX 95/1Sex: male/female 38/58Age (median-range) 65 (2-88)male 69 (5-85)female 40 (2-88)Clinical conditions* n (%)Idiopathic 45 (46.8)Concomitant conditions 51 (53.2)autoimmune 16(16.6)malignant tumor 9 (9.4)post-partum 20 (21)HCV hepatitis 3 (3.1)HBV hepatitis 1 (1)pemphigo 1 (1)sarcoidosis 1 (1)*Children: idiopathic 2 years old, (FIX inhibitor), nephrotic syndrome 5 years old(FVIII inhibitor).Table 2. Site of bleeding. The majority of the patients bledfrom more than one site.Sites of bleeding First episode Relapse96 patients % 31 patients %Muscle 59 61.4 16 51.6Central nervous system 0 -- 2 6.5Gastro-intestinal tract 5 5.2 4 13.0Urogenital system 13 13.5 2 6.5Mucosa 13 13.5 3 9.7Skin 36 37.5 5 16.1Abdomen 8 8.3 2 6.5Joint* 7 7.3 5 16.1*Incidence higher than previously reported.ResultsTwenty centers contributed information on atotal of 96 patients. The requested informationwas not available for all the patients, thereforethe data presented do not always refer to allpatients. Anti FVIII antibodies were identified in95 patients and anti FIX antibody in one; 38 ofthe patients were male and 58 were female. Themedian age was 65 years (range 2-88), 69 formales (range 5-85) and 40 for females (range 2-88). No underlying disease was shown in 45 cases(46.8%). Twenty cases (20.8%) were related topregnancy and 9 (9.4%) to malignant tumors: (2cases of lung tumor, one each of pancreas, seminoma,astrocytoma, tonsil, urinary bladder, idiopathicmyelofibrosis, multiple myeloma [Table1]). Muscles, skin, mucosae and the urogenitaltract were the most frequent sites of bleeding(Table 2), and the majority of patients had bleedingfrom more than one site. The incidence ofhemarthroses was 7%, higher than that previouslyreported. The overall median follow-up is 7years (range 1-20); in the post-partum cases 8years (range 0.5-15), in the idiopathic and theautoimmune cases 4 (range 1-13) and 6 (range1-11) years, respectively. In a few patients a previousmild bleeding was overlooked. In 65patients (67.7%) the bleeding occurred spontaneously,in 31 (32.3%) cases, 15 of which idiopathicand 16 secondary, the index bleedoccurred during or after an intervention (Table3). In 4 cases a hysterectomy was carried outbecause of uncontrollable metrorrhagia (3 caseshaematologica vol. 88(supplement n. 12):september <strong>2003</strong>
IV International Workshop on Immune Tolerance in Hemophilia 95Table 3. In 31/96 (15 idiopathic, 16 with concomitant disease)the inhibitor was identified because of bleeding aftera procedure.Clinical conditionNumber of patientsElective surgery 12Dental extraction 3Post-partum hysterectomy 4Trauma 8Intramuscular injection (primary disease not reported) 3Bone marrow biopsy 1Total number 31Elective surgery: hiatus hernia; pace maker insertion; cholecystectomy;herniotomy; nephrectomy; appendectomy; hysterectomy for fibroma (2 cases);1 case of psoas hematoma and 1 case of corpus luteum-related bleeding weremisdiagnosed before surgery; the diagnosis was unknown in two cases.Table 4. Characteristics of the patients in relation to treatment.Table 5. Type of therapy and control of bleeding at the firstepisode.Single modalityMultiple modalities*Number of treated patients 26 32Type of therapyhigh dose immunoglobulins 2−−−DDAVP 4 1human FVIII 6 9porcine FVIII 5 6APCC 4 6rFVIIa 5 8immuno-adsorption−−−2Mean inhibitor titer BU (+ SD) 30.7 (8.1) 85.4 (363)^Mean Hb g/dl (+ SD) 7.7 (2.1) 7.4 (1.7)^^p = n.s.; APCC = activated prothrombin complex concentrate;DDAVP = vasopressin; *Last treatment that controlled the bleeding;patients treated previously with a variety of agents.Clinical condition Treated Not treatedIdiopathic 35 5Autoimmune 7 8Post-partum 13 7HBV/HCV hepatitis 3 1Malignant tumors 6 3Miscellaneous 2 0total number 66 24 §not evaluable for response 5* N.A.evaluable 61 N.A.Bleedingspontaneous 35 19induced 26 5mild 15 11severe 34 4not defined 12 9Mean Hb g/dL (SD) 8.2 (2.4) 10.9 (3.1)°Mean inhibitor titer BU (SD) 61.7 (262.4) 25.1 (38.4)^Exitus for bleeding 3 1N.A. = not applicable; °p
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