Intensive exposure to factor VIII is a risk factor for inhibitor development in mild hemophilia A
2003; Elsevier BV; Volume: 1; Issue: 6 Linguagem: Inglês
10.1046/j.1538-7836.2003.00230.x
ISSN1538-7933
AutoresAnjali Sharathkumar, David Lillicrap, V. Blanchette, Melissa Kern, Jayne Leggo, A. M. Stain, L. Brooker, Manuel Carção,
Tópico(s)Cancer-related gene regulation
ResumoSummaryBackground: Inhibitors are rare in boys with mild hemophilia A (MHA; factor (F)VIII:C > 5%) but may arise following intense FVIII exposure, e.g. continuous infusion (CI). Objectives: To determine the impact of intense FVIII exposure in inhibitor formation in MHA at our institution and to compare this with previous reports. Patients and methods: We reviewed FVIII exposure and inhibitor development in boys (ages 0–18 years) with MHA followed at our institution from 1996 to 2001 and conducted a Medline search (1966–2002) on the experience of inhibitor development following intensive/CI exposure to FVIII. Results: We identified 54 boys with MHA. Twenty-nine (54%) had been exposed to FVIII. Seven had received FVIII by CI. Four developed inhibitors; three high titer (at ages 10 years, 16 years and 17 years) and one low titer (at 1 month old). All four had received a CI of recombinant (r) FVIII of at least 6 days within 6 weeks of developing inhibitors. Baseline FVIII levels fell to < 1% in all cases and the three with high-titer inhibitors developed severe bleeding. Immune tolerance therapy (ITT) was attempted in two boys and was successful in one. Our literature search identified 35 cases (only four children) with MHA developing inhibitors following intense FVIII exposure often in the context of surgery. Conclusions: The incidence of inhibitors in our MHA population was 7.4%. If expressed according to exposure the incidence was significantly higher: 14% (4/29) for any exposure to FVIII and 57% (4/7) for exposure by CI. A prospective study to address whether CI is associated with an increased incidence of inhibitor development in MHA is warranted. Background: Inhibitors are rare in boys with mild hemophilia A (MHA; factor (F)VIII:C > 5%) but may arise following intense FVIII exposure, e.g. continuous infusion (CI). Objectives: To determine the impact of intense FVIII exposure in inhibitor formation in MHA at our institution and to compare this with previous reports. Patients and methods: We reviewed FVIII exposure and inhibitor development in boys (ages 0–18 years) with MHA followed at our institution from 1996 to 2001 and conducted a Medline search (1966–2002) on the experience of inhibitor development following intensive/CI exposure to FVIII. Results: We identified 54 boys with MHA. Twenty-nine (54%) had been exposed to FVIII. Seven had received FVIII by CI. Four developed inhibitors; three high titer (at ages 10 years, 16 years and 17 years) and one low titer (at 1 month old). All four had received a CI of recombinant (r) FVIII of at least 6 days within 6 weeks of developing inhibitors. Baseline FVIII levels fell to < 1% in all cases and the three with high-titer inhibitors developed severe bleeding. Immune tolerance therapy (ITT) was attempted in two boys and was successful in one. Our literature search identified 35 cases (only four children) with MHA developing inhibitors following intense FVIII exposure often in the context of surgery. Conclusions: The incidence of inhibitors in our MHA population was 7.4%. If expressed according to exposure the incidence was significantly higher: 14% (4/29) for any exposure to FVIII and 57% (4/7) for exposure by CI. A prospective study to address whether CI is associated with an increased incidence of inhibitor development in MHA is warranted. Bleeding in hemophiliacs may be prevented or arrested by the augmentation of endogenous factor (F)VIII or administration of exogenous FVIII. The development of allo-antibodies against exogenous 'wild' type FVIII, known as 'inhibitors', is currently the most serious complication in the management of hemophilia patients [1Scandella D.H. Properties of anti-factor VIII inhibitor antibodies in hemophilia A patients.Semin Thromb Hemost. 2000; 26: 137-42Crossref PubMed Scopus (34) Google Scholar]. Inhibitors neutralize FVIII leading to treatment failure and are therefore usually detected when bleeding episodes fail to respond to appropriate FVIII replacement [2Strauss H.S. Merler E. Characterization and properties of an inhibitor of factor 8 in the plasma of patients with hemophilia A following repeated transfusions.Blood. 1967; 30: 137-50Crossref PubMed Google Scholar, 3Capel P. Toppet M. Van Remoortel E. Fondu P. Factor VIII inhibitor in mild haemophilia.Br J Haematol. 1986; 62: 786-7Crossref PubMed Scopus (11) Google Scholar]. Inhibitor formation is reflective of an immune response against a 'foreign' FVIII molecule. The pathogenesis of inhibitor development is better understood in severe hemophilia A (SHA), where hemophilia is associated with mutations (large deletions, inversion mutations and premature stop codon mutations) in the FVIII gene resulting in a complete absence ( 5% for mild hemophilia A (MHA). Current opinion is that in many such cases this FVIII is conformationally altered with subtle changes rendering it antigenically distinct from exogenous 'wild' type FVIII [1Scandella D.H. Properties of anti-factor VIII inhibitor antibodies in hemophilia A patients.Semin Thromb Hemost. 2000; 26: 137-42Crossref PubMed Scopus (34) Google Scholar, 4Hoyer L.W. Why do so many haemophilia A patients develop an inhibitor?.Br J Haematol. 1995; 90: 498-501Crossref PubMed Scopus (34) Google Scholar, 5Hay C.R. Ludlam C.A. Colvin B.T. Hill F.G. Preston F.E. Wasseem N. Bagnall R. Peake I.R. Berntorp E. Mauser Bunschoten E.P. Fijnvandraat K. Kasper C.K. White G. Santagostino E. Factor VIII inhibitors in mild and moderate-severity haemophilia A. UK Haemophilia Centre Directors Organisation.Thromb Haemost. 1998; 79: 762-6Crossref PubMed Scopus (201) Google Scholar, 6Kesteven P.J. Holland L.J. Lawrie A.S. Savidge G.F. Inhibitor to factor VIII in mild haemophilia.Thromb Haemost. 1984; 52: 50-2Crossref PubMed Scopus (22) Google Scholar, 7Peerlinck K. Jacquemin M.G. Arnout J. Hoylaerts M.F. Gilles J.G. Lavend'homme R. Johnson K.M. Freson K. Scandella D. Saint-Remy J.M. Vermylen J. Antifactor VIII antibody inhibiting allogeneic but not autologous factor VIII in patients with mild hemophilia A.Blood. 1999; 93: 2267-73Crossref PubMed Google Scholar, 8White B. Cotter M. Byrne M. O'Shea E. Smith O.P. High responding factor VIII inhibitors in mild haemophilia—is there a link with recent changes in clinical practice?.Haemophilia. 2000; 6: 113-5Crossref PubMed Scopus (36) Google Scholar, 9Oldenburg J. Brackmann H.H. Schwaab R. Risk factors for inhibitor development in hemophilia A.Haematologica. 2000; 85: 7-13PubMed Google Scholar]. Consequently, in this setting, wild type FVIII may still be potentially immunogenic. In MHA the development of inhibitors is a serious but infrequently reported complication (3–13%), occurring more commonly later in life, often following intensive FVIII replacement for surgery or trauma [1Scandella D.H. Properties of anti-factor VIII inhibitor antibodies in hemophilia A patients.Semin Thromb Hemost. 2000; 26: 137-42Crossref PubMed Scopus (34) Google Scholar, 5Hay C.R. Ludlam C.A. Colvin B.T. Hill F.G. Preston F.E. Wasseem N. Bagnall R. Peake I.R. Berntorp E. Mauser Bunschoten E.P. Fijnvandraat K. Kasper C.K. White G. Santagostino E. Factor VIII inhibitors in mild and moderate-severity haemophilia A. UK Haemophilia Centre Directors Organisation.Thromb Haemost. 1998; 79: 762-6Crossref PubMed Scopus (201) Google Scholar, 10Beck P. Giddings J.C. Bloom A.L. Inhibitor of factor VIII in mild haemophilia.Br J Haematol. 1969; 17: 283-8Crossref PubMed Scopus (28) Google Scholar, 11Ehrenforth S. Kreuz W. Scharrer I. Linde R. Funk M. Gungor T. Krackhardt B. Kornhuber B. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs.Lancet. 1992; 339: 594-8Abstract PubMed Scopus (516) Google Scholar, 12Sultan Y. Prevalence of inhibitors in a population of 3435 hemophilia patients in France. French Hemophilia Study Group.Thromb Haemost. 1992; 67: 600-2Crossref PubMed Scopus (123) Google Scholar, 13Strauss H.S. Acquired circulating anticoagulants in hemophilia A.N Engl J Med. 1969; 281: 866-73Crossref PubMed Scopus (85) Google Scholar, 14McMillan C.W. Shapiro S.S. Whitehurst D. Hoyer L.W. Rao A.V. Lazerson J. The natural history of factor VIII:C inhibitors in patients with hemophilia A: a national cooperative study. II. Observations on the initial development of factor VIII:C inhibitors.Blood. 1988; 71: 344-8Crossref PubMed Google Scholar]. Due to cross-reactivity with endogenous FVIII, the development of inhibitors in most patients with MHA results in a fall in the endogenous level of FVIII:C, converting patients to a severe phenotype (FVIII:C <1%) [5Hay C.R. Ludlam C.A. Colvin B.T. Hill F.G. Preston F.E. Wasseem N. Bagnall R. Peake I.R. Berntorp E. Mauser Bunschoten E.P. Fijnvandraat K. Kasper C.K. White G. Santagostino E. Factor VIII inhibitors in mild and moderate-severity haemophilia A. UK Haemophilia Centre Directors Organisation.Thromb Haemost. 1998; 79: 762-6Crossref PubMed Scopus (201) Google Scholar, 6Kesteven P.J. Holland L.J. Lawrie A.S. Savidge G.F. Inhibitor to factor VIII in mild haemophilia.Thromb Haemost. 1984; 52: 50-2Crossref PubMed Scopus (22) Google Scholar, 7Peerlinck K. Jacquemin M.G. Arnout J. Hoylaerts M.F. Gilles J.G. Lavend'homme R. Johnson K.M. Freson K. Scandella D. Saint-Remy J.M. Vermylen J. Antifactor VIII antibody inhibiting allogeneic but not autologous factor VIII in patients with mild hemophilia A.Blood. 1999; 93: 2267-73Crossref PubMed Google Scholar, 8White B. Cotter M. Byrne M. O'Shea E. Smith O.P. High responding factor VIII inhibitors in mild haemophilia—is there a link with recent changes in clinical practice?.Haemophilia. 2000; 6: 113-5Crossref PubMed Scopus (36) Google Scholar, 15Lechner K. Ludwig E. Niessner H. Thaler E. Factor VIII inhibitor in a patient with mild hemophilia A.Haemostasis. 1972; 1: 261-70PubMed Google Scholar, 16Bovill E.G. Burns S.L. Golden E.A. Factor VIII antibody in a patient with mild haemophilia.Br J Haematol. 1985; 61: 323-8Crossref PubMed Scopus (17) Google Scholar]. In contrast to SHA [4Hoyer L.W. Why do so many haemophilia A patients develop an inhibitor?.Br J Haematol. 1995; 90: 498-501Crossref PubMed Scopus (34) Google Scholar, 8White B. Cotter M. Byrne M. O'Shea E. Smith O.P. High responding factor VIII inhibitors in mild haemophilia—is there a link with recent changes in clinical practice?.Haemophilia. 2000; 6: 113-5Crossref PubMed Scopus (36) Google Scholar, 9Oldenburg J. Brackmann H.H. Schwaab R. Risk factors for inhibitor development in hemophilia A.Haematologica. 2000; 85: 7-13PubMed Google Scholar, 17European Study Group of Factor VIII Antibody.Development of factor VIII antibody in haemophilic monozygotic twins.Scand J Haematol. 1979; 23: 64-8PubMed Google Scholar, 18Peerlinck K. Arnout J. Gilles J.G. Saint-Remy J.M. Vermylen J. A higher than expected incidence of factor VIII inhibitors in multitransfused haemophilia A patients treated with an intermediate purity pasteurized factor VIII concentrate.Thromb Haemost. 1993; 69: 115-8Crossref PubMed Scopus (175) Google Scholar, 19Fijnvandraat K. Turenhout E.A. Van Den Brink E.N. Ten Cate J.W. Van Mourik J.A. Peters M. Voorberg J. The missense mutation Arg593→Cys is related to antibody formation in a patient with mild hemophilia A.Blood. 1997; 89: 4371-7Crossref PubMed Google Scholar, 20Hay C.R. Lozier J.N. Lee C.A. Laffan M. Tradati F. Santagostino E. Ciavarella N. Schiavoni M. Fukui H. Yoshioka A. Teitel J. Mannucci P.M. Kasper C.K. Safety profile of porcine factor VIII and its use as hospital and home-therapy for patients with haemophilia-A and inhibitors: the results of an international survey.Thromb Haemost. 1996; 75: 25-9Crossref PubMed Scopus (88) Google Scholar, 21Schwaab R. Brackmann H.H. Meyer C. Seehafer J. Kirchgesser M. Haack A. Olek K. Tuddenham E.G. Oldenburg J. Haemophilia A: mutation type determines risk of inhibitor formation.Thromb Haemost. 1995; 74: 1402-6Crossref PubMed Scopus (301) Google Scholar, 22Hay C.R. Ollier W. Pepper L. Cumming A. Keeney S. Goodeve A.C. Colvin B.T. Hill F.G. Preston F.E. Peake I.R. HLA class II profile: a weak determinant of factor VIII inhibitor development in severe haemophilia A. UKHCDO Inhibitor Working Party.Thromb Haemost. 1997; 77: 234-7Crossref PubMed Scopus (175) Google Scholar], little is known regarding risk factors for inhibitor development in MHA and specifically regarding factor exposure (amount and intensity of FVIII exposure, type of FVIII used, and context in which exposure occurs). In 1970 Crowell commented that the less frequent need for transfusions in mild hemophiliacs might be partly responsible for their low incidence of inhibitors [23Crowell Jr, E.B. A factor VIII inhibitor in a mild hemophiliac.Am J Med Sci. 1970; 260: 261-3Crossref PubMed Scopus (11) Google Scholar]. In contrast, Strauss did not find a higher cumulative factor exposure in severe hemophiliacs who developed inhibitors than in those who did not [13Strauss H.S. Acquired circulating anticoagulants in hemophilia A.N Engl J Med. 1969; 281: 866-73Crossref PubMed Scopus (85) Google Scholar]. Neither paper examined the relationship between inhibitor development and intensity of exposure. Traditionally, FVIII has been administered by episodic bolus injections (BI). Disadvantages of BIs are the concentration peaks and troughs that occur resulting in a risk of bleeding during troughs and inefficient and costly usage associated with peaks. Continuous infusion (CI) of FVIII eliminates peaks and troughs and, since it has been shown to be a safe and effective method of administering FVIII, has become extensively advocated [24Varon D. Martinowitz U. Continuous infusion therapy in haemophilia.Haemophilia. 1998; 4: 431-5Crossref PubMed Scopus (33) Google Scholar, 25Tagariello G. Davoli P.G. Gajo G.B. De Biasi E. Risato R. Baggio R. Traldi A. Safety and efficacy of high-purity concentrates in haemophiliac patients undergoing surgery by continuous infusion.Haemophilia. 1999; 5: 426-30Crossref PubMed Scopus (23) Google Scholar]. Recent reports associating inhibitor development in MHA following exposure to FVIII by CI [8White B. Cotter M. Byrne M. O'Shea E. Smith O.P. High responding factor VIII inhibitors in mild haemophilia—is there a link with recent changes in clinical practice?.Haemophilia. 2000; 6: 113-5Crossref PubMed Scopus (36) Google Scholar] prompted our group to review our institutional experience in MHA (54 boys) to determine the impact of FVIII exposure in the pathogenesis of inhibitor formation. These 54 boys were prospectively followed with yearly inhibitor screening. For boys developing inhibitors we present detailed information regarding their clinical courses and management. Additionally, we conducted a search of all available literature (1966–2002) on the experience of inhibitor development in MHA cases following intensive or continuous exposure to FVIII. Boys with MHA (defined as a FVIII:C level between 5% and 40% with normal von Willebrand antigen and ristocetin cofactor levels) up to the age of 18 years followed at The Hospital for Sick Children in Toronto, Canada between the years 1996 and 2001 were eligible for study. An upper level of 40% was chosen as blood type O individuals may have FVIII levels as low as 40% without having hemophilia. Retrospective chart reviews were conducted to evaluate demographic data relating to hemophilia (FVIII:C level, desmopressin; 1-deamino-8-d-arginine vasopressin (DDAVP) responsiveness, and family history of hemophilia), lifetime FVIII usage (type, amount and intensity of factor used, and age at first exposure) and inhibitor development. Total amount of exposure was expressed as cumulative exposure days (CED), an exposure day (ED) being defined as a day in which a patient receives at least one dose of FVIII regardless of source [plasma derived (pd) or recombinant (r)], amount or method of administration (BI vs. CI). Intensity of exposure was expressed as the maximum number of consecutive ED at any one time regardless of method of administration. For patients who developed inhibitors, chart reviews were conducted to evaluate the context of inhibitor development, management of bleeds postinhibitor development, specific management of the inhibitor and patients' clinical course. For all patients, determination of FVIII:C levels was performed using a one-stage clotting assay. Inhibitor testing was performed using the Bethesda assay. For patients developing inhibitors FVIII gene mutation analysis was performed in the Canadian National Hemophilia Genotyping Laboratory at Queen's University, Kingston, Ontario. In each case, genomic DNA was obtained by a salt extraction method. Initial mutation screening was performed on polymerase chain reaction-amplified FVIII exons by conformation-sensitive gel electrophoresis. Fragments demonstrating heteroduplex formation were subjected to automated DNA sequencing [26Williams I.J. Abuzenadah A. Winship P.R. Preston F.E. Dolan G. Wright J. Peake I.R. Goodeve A.C. Precise carrier diagnosis in families with haemophilia A: use of conformation sensitive gel electrophoresis for mutation screening and polymorphism analysis.Thromb Haemost. 1998; 79: 723-6Crossref PubMed Scopus (90) Google Scholar]. A Medline search (1966–2002) was conducted using combinations of key words: mild hemophilia A, inhibitor, continuous infusion, and supplemented by additional references located in the bibliographies of listed articles. Cases were accepted only if it was clearly stated that the patient had received a CI or daily exposure to FVIII for at least 4 days. Four days was chosen as bleeds may be treated for 2 or 3 days but not usually for 4 days or more. Articles that used qualitative terms describing intense exposure were also included. The 54 boys were diagnosed with MHA at a mean age of 2.5 years (median 1.5 years; range 4 days to 16 years). Patients' mean baseline FVIII:C level was 17.5% (median 15.0%; range 6–38%). Forty-five of 51 boys in whom DDAVP response testing was performed had either a complete (n = 35; 69%) or partial response (n = 10; 20%) to DDAVP. Complete response was defined as a response satisfying the following two criteria: at least a doubling of FVIII:C level over baseline and a rise in FVIII:C level to at least 30% 1 h post-DDAVP. Partial response was defined as a response satisfying only one of the above two criteria. Twenty-nine (54%) of the 54 boys have been exposed to FVIII some time during their childhood: four to pdFVIII, 15 to rFVIII, and 10 to both (Table 1). Mean age at initial exposure to any FVIII was 5.4 years (range 5 days to 16.3 years); 2.3 years (range 21 days to 6.6 years) for pdFVIII and 8.0 years (range 5 days to 16.3 years) for rFVIII. Boys were much more likely to be exposed if they were non-responders (n = 6; 86% exposed) vs. partial/complete responders (n = 45; 48% exposed) to DDAVP (P < 0.01). Boys exposed to factor had lower endogenous baseline FVIII:C levels (mean 14.9%; range 6–29%) than non-exposed boys (mean 20.5%; range 6–38%), but among exposed boys cumulative exposure (CED) or intensity of exposure (consecutive ED) was not correlated with baseline FVIII:C levels.Table 1Characteristics of factor (F)VIII exposure in boys with mild hemophilia A (MHA) pre-inhibitor development (ranked according to intensity of exposure)PatientBaseline FVIII %pdFVIIIrFVIIIInfusion strategy BI/CIInhibitor, yes/noAge (years) at first exposureCED (days)Max. intensity of exposure (days)Age (years) at first exposureCED (days)Max. intensity of exposure (days)11662116.32727CIY210–––0.012727CIY329†Sibling pairs (Patients 3 and 26, 10 and 22).–––16.21612CIY4270.82111–––BIN512–––2.24610CIN670.631812.373BIN7125.2749.6278BIN8121.7114.0248BIN91014212.6148BIN1013*Sibling pairs (Patients 3 and 26, 10 and 22).–––10.1138CIY11186.611810.521BIN1215–––0.188CIN13110.12112.197BIN1416–––7.1136BIN15261.8126–––BIN1623–––7.766CIN177–––14.594BIN18100.8549.633BIN198–––1.8163BIN2093.910212.851BIN21150.962–––BIN2221*Sibling pairs (Patients 3 and 26, 10 and 22).–––4.122BIN2326–––16.221BIN24201.4111.311BIN2510–––2.411BIN2619†Sibling pairs (Patients 3 and 26, 10 and 22).–––6.211BIN2712–––5.911BIN2813–––4.911BIN2961.511–––BINCED, Cumulative exposure days, Max. intensity of exposure, maximum number of consecutive days that patient exposed to FVIII either by continuous infusion (CI) or bolus infusions alone (BI)—the number is in bold. –, Not exposed; Y, yes; N, no.* Sibling pairs (Patients 3 and 26, 10 and 22).† Sibling pairs (Patients 3 and 26, 10 and 22). Open table in a new tab CED, Cumulative exposure days, Max. intensity of exposure, maximum number of consecutive days that patient exposed to FVIII either by continuous infusion (CI) or bolus infusions alone (BI)—the number is in bold. –, Not exposed; Y, yes; N, no. For the 29 boys exposed to any FVIII, the mean number of CEDs was 16.3 days (1–46 days). Sixteen boys received FVIII daily for at least 6 consecutive days, seven by CI and nine by BI. Four of the seven exposed to CI developed inhibitors (high-titre in three); all within 6 weeks of exposure. In contrast, none of the nine boys exposed to daily BI (minimum of 6 consecutive ED) alone developed inhibitors (P = 0.02 by Fisher's exact test). Details of the boys developing inhibitors following CI are presented below and in Table 2. Three boys (patients 5, 12 and 16 of Table 1) also exposed to a CI of rFVIII (10 days, 8 days and 6 days) did not develop inhibitors. These three boys were exposed to CI at the ages of 2.2 years, 2 months and 7.7 years for a depressed skull fracture, an incarcerated hernia and a tonsillectomy, respectively.Table 2Characteristics of patients with inhibitorsCase 1Case 2Case 3Case 4Baseline FVIII (%)1613294–10Post-DDAVP FVIII (%)365512914Age at INH detection16.3 years10.1 years16.2 years33 daysEvent leading to INHHemarthrosisAnkle fractureKnee hemarthrosis with arthrocentesisNeonatal ICHExposure detailsCI × 14 days, then BI q 12 h × 13 daysCI × 6 days, then BI q 2 days × 2 weeksCI × 11 days, then 4 BI over 10 daysCI × 27 daysFVIII ED (pre INH)27131627Presentation of INHFailure to respond to FVIIIFailure to respond to FVIIIFailure to respond to FVIIIRoutine surveillanceTime: exposure to INH detection (weeks)6664FVIII (%) at INH detection< 1< 1< 1< 1Max. INH to H and P FVIII (BU)12 and 16 BU51 and 122 BU166 and 56 BU2 and 0 BUBleeds post-INH(Over 3 months)(Over 1 year)(Over 2 years)None Joint bleeds229 ST/muscle3413 Hematuria135 OtherEpistaxis-1Treatment of bleeds post-INHPFVIII, FEIBA, rFVIIarFVIII, PFVIII, FEIBA, rFVIIarFVIII, FEIBA, rFVIIarFVIIIManagement of INHAt 3 months: plasmapheresis + corticosteroids and ITT × 1 monthTherapy refusedAt 19 months: plasmapheresis + ITT × 1 yearProphylaxis (3×/ week) for 1 yearCourse of INHDisappeared 3.5 monthsDisappeared 14 monthsPersistentDisappeared 12 monthsFollow-up (years)3434.5Gene mutation analysisMissense mutation: Val2016Ala (exon 19: A3 domain): documented 10 times in HAMSTeRS. No prior report of inhibitorsMissense mutation: Pro1854Leu (exon 17: A3 domain): not previously documented in HAMSTeRSMutation not identified: CSGE and MDE screens negative Exons 12, 15, 18 and 26 normal by sequencing HAMSTeRSMissense mutation: Asn2286Lys (exon 26; C2 domain): not previously documented inFVIII, Factor VIII; INH, inhibitor; ED, exposure days; CI, continuous infusion; BI, bolus infusion; rFVIII, recombinant factor VIII; ICH, intracranial hemorrhage; H, human; P, porcine; BU, Bethesda units; ST, soft tissue; ITT, immune tolerance therapy; CSGE, Conformation-Sensitive Gel Electrophoresis; MDE, Mutation Detection Enhancing Gel Electrophoresis; HAMSTeRS, Hemophilia A Mutation Registry. Open table in a new tab FVIII, Factor VIII; INH, inhibitor; ED, exposure days; CI, continuous infusion; BI, bolus infusion; rFVIII, recombinant factor VIII; ICH, intracranial hemorrhage; H, human; P, porcine; BU, Bethesda units; ST, soft tissue; ITT, immune tolerance therapy; CSGE, Conformation-Sensitive Gel Electrophoresis; MDE, Mutation Detection Enhancing Gel Electrophoresis; HAMSTeRS, Hemophilia A Mutation Registry. The incidence of inhibitors in our patients, expressed according to overall number of patients with MHA, is 7.4%. However, the incidence is 14% (4/29) if expressed according to MHA patients exposed to any exogenous FVIII. The incidence is 25% if expressed as a percentage of patients exposed to at least 6 consecutive ED (reflecting intensity of exposure). The incidence is 57% (4/7) if expressed as a percentage of patients exposed to FVIII by CI. Case 1 is a boy with MHA (partial responder to DDAVP) diagnosed at the age of 6 years. Prior to diagnosis he had experienced only mild mucosal bleeds for which he had not received medical intervention. At the age of 6 years and 8 years he received pdFVIII (single BIs each time) followed by DDAVP for left knee hemarthroses. At 16.3 years of age he sustained a severe trauma-related right knee hemarthrosis. He was managed with a CI of 3–5 IU kg−1 h−1 of rFVIII for 2 weeks followed by daily BI of 50 IU kg−1 for a further 13 days (total 27 CED). Six weeks later, he presented with another right knee hemarthrosis, which this time failed to respond to treatment. An inhibitor screen was positive and his baseline FVIII:C level was now < 1%. Over the next 2 months, he experienced multiple joint and soft tissue bleeds for which he was initially managed with porcine (P)FVIII (PFVIII; Hyate:C®; Ipsen Biopharm, Wrexham, UK). This was discontinued following an episode of wheezing, headache and back pain and an anamnestic rise in the inhibitor titer to PFVIII. He was subsequently treated with either recombinant factor VIIa (rFVIIa; Novoseven®; NovoNordisk, Bagsvaerd, Denmark) or Factor Eight Inhibitor Bypassing Activity (FEIBA®; Baxter, Glendale, CA, USA). He developed multiple, simultaneous severe bleeds (hemarthroses, forearm bleed with compartment syndrome and hematuria) and given his persistent high-titer inhibitor [12 BU to human (H) and 16 to (P) FVIII] he underwent plasmapharesis. Concurrently he was placed on methylprednisolone (1 g kg−1 day−1) for 3 days and a CI of rFVIII (20 IU kg−1 h−1) for 1 week. His inhibitor disappeared on day 11 post-plasmapharesis. Upon cessation of rFVIII replacement his baseline FVIII:C level was 28%. He has remained free of inhibitors and without bleeds 2 years since inhibitor disappearance. Gene mutation analysis studies revealed that the patient had a missense mutation with a T→C transition at nucleotide 6104 resulting in a change in the encoded amino acid at codon 2016 (exon 19: A3 domain) from valine to alanine. Case 2 was diagnosed at 7 years of age after presenting with a large post-traumatic hematoma. He was a DDAVP responder with his FVIII:C level increasing from 13% to 55%. At diagnosis he was treated with DDAVP. At age 10.1 years, he had an ankle fracture necessitating surgery. Hemostasis was obtained by a BI of 100 IU kg−1 of rFVIII (patient's first exposure) followed by a CI of 2–3 IU kg−1 h−1 for 6 days followed by alternate day BI for a further 2 weeks (13 CED; 8 consecutive ED). Six weeks later, he presented with hematuria and a left thigh bleed. Inhibitor screen was positive and his endogenous FVIII:C level was now < 1%. Over the next year he experienced numerous bleeds and was hospitalized on 10 occasions for management of bleeds. His highest inhibitor titer was 51 BU to HFVIII and 122 BU to PFVIII. His family refused immune tolerance therapy (ITT). His inhibitor disappeared spontaneously 14 months after appearance. He is currently well and free of inhibitors (3 years' follow-up) and his endogenous FVIII:C level is 21%. He has not required any treatment since inhibitor disappearance. Gene mutation analysis revealed a C→T missense mutation at codon 1854 (nucleotide 5618) in exon 17 (A3 domain), resulting in the substitution of a leucine residue for proline. This patient's younger brother (patient 22 of Table 1; 4 years younger) also has MHA (baseline FVIII:C: 21%) and has had one hemarthrosis requiring exposure to rFVIII (2 CED) without developing an inhibitor. Case 3 was diagnosed with MHA at the age of 12 years by family studies following a diagnosis of MHA in his younger half-brother (patient 26 of Table 1). A second, also younger, half-brother was diagnosed with MHA (never exposed to FVIII). All three are DDAVP responders. At the age of 16.2 years, the patient sustained a severe (sports-related) right knee hemarthrosis. Arthrocentesis was performed before referral to our institution, to rule out septic arthritis and, despite the known diagnosis of MHA, prophylactic DDAVP or FVIII was not given. The hemarthrosis worsened post-procedure and the boy was then referred to our institution. He was treated with rFVIII; 100 IU kg−1 BI followed by a 4–5 IU kg−1 h−1 CI for a period of 11 days (12 CED). This was his first exposure to FVIII. He received 4 BIs of rFVIII over the next 10 days (16 CED). Six weeks later he presented with a right iliopsoas bleed. His FVIII:C level was now < 1% and an inhibitor was detected. Over the next 2 years he experienced a total of 19 hemorrhages requiring multiple hospitalizations of 4–28 days in duration an
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