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Keywords:

  • continuous infusion;
  • factor VIII exposure;
  • inhibitors;
  • mild hemophilia A

Abstract

  1. Top of page
  2. Abstract
  3. Background
  4. Patients
  5. Methods
  6. Results
  7. Case reports
  8. Discussion
  9. Acknowledgements
  10. References

Summary. 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.


Background

  1. Top of page
  2. Abstract
  3. Background
  4. Patients
  5. Methods
  6. Results
  7. Case reports
  8. Discussion
  9. Acknowledgements
  10. References

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 [1]. Inhibitors neutralize FVIII leading to treatment failure and are therefore usually detected when bleeding episodes fail to respond to appropriate FVIII replacement [2,3].

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 (<1%) of circulating FVIII:C [4,5]. In contrast, other patients with hemophilia have measurable levels of endogenous FVIII; 1–5% for moderate hemophilia and >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 [1,4–9]. 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 [1,5,10–14]. 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%) [5–8,15,16].

In contrast to SHA [4,8,9,17–22], 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 [23]. In contrast, Strauss did not find a higher cumulative factor exposure in severe hemophiliacs who developed inhibitors than in those who did not [13]. 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 [24,25].

Recent reports associating inhibitor development in MHA following exposure to FVIII by CI [8] 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.

Patients

  1. Top of page
  2. Abstract
  3. Background
  4. Patients
  5. Methods
  6. Results
  7. Case reports
  8. Discussion
  9. Acknowledgements
  10. References

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.

Methods

  1. Top of page
  2. Abstract
  3. Background
  4. Patients
  5. Methods
  6. Results
  7. Case reports
  8. Discussion
  9. Acknowledgements
  10. References

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 [26].

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.

Results

  1. Top of page
  2. Abstract
  3. Background
  4. Patients
  5. Methods
  6. Results
  7. Case reports
  8. Discussion
  9. Acknowledgements
  10. References

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 1.  Characteristics 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/no
Age (years) at first exposureCED (days)Max. intensity of exposure (days)Age (years) at first exposureCED (days)Max. intensity of exposure (days)
  1. 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. *,†, Sibling pairs (Patients 3 and 26, 10 and 22).

11662116.32727CIY
2100.012727CIY
32916.21612CIY
4270.82111BIN
5122.24610CIN
670.631812.373BIN
7125.2749.6278BIN
8121.7114.0248BIN
91014212.6148BIN
1013*10.1138CIY
11186.611810.521BIN
12150.188CIN
13110.12112.197BIN
14167.1136BIN
15261.8126BIN
16237.766CIN
17714.594BIN
18100.8549.633BIN
1981.8163BIN
2093.910212.851BIN
21150.962BIN
2221*4.122BIN
232616.221BIN
24201.4111.311BIN
25102.411BIN
26196.211BIN
27125.911BIN
28134.911BIN
2961.511BIN

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 2.  Characteristics of patients with inhibitors
 Case 1Case 2Case 3Case 4
  1. 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.

Baseline FVIII (%)1613294–10
Post-DDAVP FVIII (%)365512914
Age at INH detection16.3 years10.1 years16.2 years33 days
Event leading to INHHemarthrosisAnkle fractureKnee hemarthrosis with arthrocentesisNeonatal ICH
Exposure 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 days
FVIII ED (pre INH)27131627
Presentation of INHFailure to respond to FVIIIFailure to respond to FVIIIFailure to respond to FVIIIRoutine surveillance
Time: exposure to INH detection (weeks)6664
FVIII (%) at INH detection< 1< 1< 1< 1
Max. INH to H and P FVIII (BU)12 and 16 BU51 and 122 BU166 and 56 BU2 and 0 BU
Bleeds post-INH(Over 3 months)(Over 1 year)(Over 2 years)None
 Joint bleeds229 
 ST/muscle3413 
 Hematuria135 
 Other  Epistaxis-1 
Treatment of bleeds post-INHPFVIII, FEIBA, rFVIIarFVIII, PFVIII, FEIBA, rFVIIarFVIII, FEIBA, rFVIIarFVIII
Management of INHAt 3 months: plasmapheresis + corticosteroids and ITT × 1 monthTherapy refusedAt 19 months: plasmapheresis + ITT × 1 yearProphylaxis (3×/ week) for 1 year
Course of INHDisappeared 3.5 monthsDisappeared 14 monthsPersistentDisappeared 12 months
Follow-up (years)3434.5
Gene 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 in

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 reports

  1. Top of page
  2. Abstract
  3. Background
  4. Patients
  5. Methods
  6. Results
  7. Case reports
  8. Discussion
  9. Acknowledgements
  10. References

Case 1 (patient 1 of Table 1)

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[RIGHTWARDS ARROW]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 (patient 10 of Table 1)

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[RIGHTWARDS ARROW]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 (patient 3 of Table 1)

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 and was treated with a variety of agents including rFVIIa, FEIBA and PFVIII. Eighteen months after inhibitor detection he underwent 4 days of plasmapheresis and was commenced on ITT (100 IU kg−1 day−1 of rFVIII), which he remained on for 1 year. This proved ineffective and was discontinued. He continues to have a high-titer inhibitor (currently 96 BU to H- and 0 BU to PFVIII).

Gene mutation analysis has, to date, failed to reveal any deletion, insertion or point mutation involving the FVIII gene. Direct sequencing of the FVIII gene is in progress.

Case 4 (patient 2 of Table 1)

Case 4 was born at term by forceps-assisted vaginal delivery after a failed vacuum extraction. It was not appreciated that there was a family history of hemophilia. He presented on day 5 of life with drowsiness and poor feeding. An intracranial hemorrhage and MHA were diagnosed. Surgical evacuation of the intracranial hemorrhage was performed with rFVIII; 100 IU kg−1 BI followed by a CI of 3 IU kg−1 h−1 (total 27 CED). Four weeks later he was found to have a baseline FVIII:C level of < 1% and a low-titer inhibitor (2 BU to H-, 0 to PFVIII). He was commenced on prophylaxis with rFVIII 100 IU kg−1 thrice weekly. On this regimen he did not experience any spontaneous bleeds. At 1 year of age, no inhibitor was detectable and his endogenous FVIII:C level was now 4–10%. Since inhibitor disappearance, he has undergone two surgical procedures, each time receiving a CI of rFVIII without inhibitor reappearance. At 4 years of age DDAVP testing showed only a partial response.

Gene mutation analysis revealed a T[RIGHTWARDS ARROW]G transversion (asparagine to lysine) at nucleotide 6915 (codon 2286) in exon 26 (C2 domain).

Discussion

  1. Top of page
  2. Abstract
  3. Background
  4. Patients
  5. Methods
  6. Results
  7. Case reports
  8. Discussion
  9. Acknowledgements
  10. References

MHA is genotypically heterogeneous and mutations have been reported throughout all domains, other than the B domain, of the FVIII gene. In MHA only particular missense mutations appear to be associated with inhibitor formation [4,5,9,27]. These tend to be clustered in or around certain immunogenic ‘hot spots’; amino acids 482–501 of the A2 domain and 2248–2312 of the C2 domain near the C1–C2 junction [1,5,19,28,29]. Various investigators have suggested that the risk of developing an inhibitor in MHA may be largely confined to a few kindreds possessing high-risk genotypes. Hay et al. reported a 41% inhibitor incidence among siblings of boys with MHA and inhibitors [5], and Knobe et al. described two families with MHA each with multiple members with inhibitors [30].

Our four patients were unrelated and had different mutations. Two of the three mutations in our patients were missense mutations in the A3 domain; one (case 1) Val2016Ala (exon 19) substitution represents a relatively minor change to a small hydrophobic amino acid. A high prevalence of this mutation has been found in a small region in the Canadian province of Newfoundland where 44 affected males have been identified with this mutation [31]. None of these 44 males has developed inhibitors. There are a number of other reports of this mutation but as yet no reports of inhibitors associated with this mutation. The second mutation (case 2), Pro1854Leu (exon 17), is a novel missense mutation and probably involves the interruption of an α helix which may induce a conformational change in the mutant protein. Case 4 had a missense mutation (Asn2286Lys) in the C2 domain which alters the charge of the molecule and probably its protein conformation. These boys emphasize the mutational heterogeneity associated with inhibitor development in MHA. Two of our four boys with inhibitors had younger hemophilic brothers—three in total. None of these brothers has developed inhibitors despite two of them having been exposed to FVIII, albeit receiving considerably less total, and less intense exposure. A lingering concern is what is the risk of inhibitor development in these younger siblings should they experience a similar intense exposure to FVIII as their older siblings, and should this concern influence management of bleeds in these younger siblings.

Our observations as well as studies involving monozygotic hemophilic twins discordant for inhibitors suggest that factors other than FVIII genotype predispose patients with MHA to the development of inhibitors [17]. Some of these factors may be genetic and might include mutations and polymorphisms of proteins involved in immune response and cytokine production [32]. Other factors may be related to the intensity of factor exposure [9,22,32,33].

Although the overall incidence of inhibitors in our MHA population (7.4%) was low and consistent with literature reports (3–13%) [34], all of our patients who developed inhibitors did so after CI. This suggests that the actual CI method of administering FVIII may be associated with an increased risk of inhibitor development. There are no prospective studies reporting the incidence of inhibitors in MHA patients exposed to a CI. Available literature reports primarily consist of single case reports or small case series, and these papers often omit details necessary to link intense exposure to inhibitor development, e.g. duration and type of exposure and time to inhibitor development post-exposure. Furthermore, many publications fail to describe adequately the exposure but instead use qualitative terms (‘extensive perioperative’, ‘frequent high doses’, ‘several times’ and ‘intense use’) to suggest intense exposure.

Our literature search identified 21 reports describing 35 patients with MHA developing an inhibitor following intensive exposure to FVIII (Table 3). Most reports involved one to five cases and FVIII exposure occurred usually in the context of surgery. In 12 patients CI was specifically described as the method of exposure. Most patients developing inhibitors were exposed to at least 7–10 days of either daily BI or CI. All types of factor concentrate were involved in these cases and no association could be made between inhibitor development and type of factor used. Most reports involved adults and only four children (ages 6 months, 7 years, 8 years, and 11 years) with MHA have been previously reported to have developed inhibitors following intensive FVIII exposure. In keeping with the observation that MHA patients developing inhibitors tend to be older, we found that our three patients developing inhibitors following CI were all 10 years of age or older. In contrast, the three boys in our population who did not develop an inhibitor following CI were all under 10 years of age.

Table 3.  Medline search of inhibitor development in mild hemophilia A patients receiving intensive factor VIII exposure (minimum, daily BI × 4 days or CI)
ReportsNo. of patientsBaseline FVIII (%)Age at INH (years)Type of FVIIIExposureDays (post exp) to INH developmentMax. INH titer (BU)Reason for treatment
  1. F, Factor; INH, inhibitor; post exp, post-exposure; BI, bolus infusion; CI, continuous infusion; BU, Bethesda Units; NR, not reported; C, cryoprecipitate; pd, plasma-derived; r, recombinant. Note: Hay 1998 includes patients from previous reports.

Beck 1969 [10]2821CBI × 12 days91Surgery
552CBI × 13 days1515Surgery
Crowell 1970 [23]14–721CBI × 20 days2312.5Surgery
Lechner 1972 [15]1620CBI × 36 days340.75Trauma
Shapiro 1975 [45]11050CBI > 7 days≈ 3040Surgery
Kesteven 1984 [6]17–1426pdBI × 16 days90173 Oxford UTrauma
Bovill 1985 [16]11468pd + CBI × 10 days114.0Surgery
Suzuki 1995 [46]11760rCI × 15 days10630Surgery
Fijnvandraat 1997 [19]12019pd + C‘Extensive perioperative’NR22Surgery
Thompson 1997 [28]18–1141rBI × 35 days28128Surgery
Baglin 1998 [40]21149pdCI (NR)<2067Surgery
1565pdCI (NR)<201.5Surgery
Hay 1998 [5]≈ 2/3 of 26>5 (in 22 of 26 patients)Median = 33 (7–71)NR‘Intensive replacement therapy’Immediately preceding INH developmentMean: 22.5NR
Van den Brink 1999 [27]12963pdCI × 5 days42250Surgery
Peerlinck 1999 [7]12339pdNR‘Shortly thereafter’305Surgery
Tagariello, 1999 [25]1NR41pdCI × 12 days12NRSurgery
Koestenberger 2000 [47]1NR0.5rCI × 9 days9170Surgery
White 2000 [8]2519rCI × 5 days + BI × 5 days3070Surgery
740rCI × 5 days + BI × 5 days2187Surgery
Robbins 2001 [44]11616rCI × 2 days + BI × 5 days2850Surgery
Puetz 2001 [43]1107rCI × 4 days13421Trauma
Knobe 2001 [30]5108r‘Frequent high doses’1208.4Burn
1045rNRNR9Surgery
1411r‘Several times’3012Trauma
2071rNRNR10.6Surgery
2067NR‘Short period’NR11GI bleed
Vlot 2002 [48]13068pdBI × 24 days15036.1Surgery
Liu 2002 [49]3NRNRNR‘Intense use’NR91Surgery
5NRNRCI (NR)NRNRSurgery
18NRNRCI (NR)NRNRSurgery

The incidence of inhibitor development in MHA following intense FVIII exposure is not known. Certainly not all MHA patients exposed to a CI develop an inhibitor; in our series, three of seven boys exposed to a CI of FVIII did not develop an inhibitor. Nonetheless, some hemophilia treatment centers have recommended against the use of CI in MHA patients [35]. In the absence of adequate data to support an evidence-based recommendation, we believe that the role of intensive FVIII exposure as a risk factor for inhibitor formation, both in the form of bolus and CI, merits further study. Such a study will need to be both prospective and multicenter.

The mechanism(s) by which CI of FVIII might result in a higher incidence of inhibitor formation are unknown. One possibility is that FVIII given as a CI is modified into a more antigenic form during storage ex vivo by dilution (if performed) or by prolonged contact with plastic infusion materials or with inflamed veins. We speculate that perhaps when FVIII is given as a CI into peripheral veins of patients with MHA some leakage subcutaneously could result in a more immunogenic type of exposure. Intensive FVIII exposure in patients with MHA always occurs in the context of significant bleeds or major surgery, as in all four of our patients. In these situations, it is possible that extensive tissue damage and associated inflammation facilitates an antibody response against exogenous FVIII due to the presence of immunological ‘danger signals’[36]. In keeping with this is the observation of Kaufman et al. that animals exposed to FIX during periods of inflammation can develop inhibitors to FIX [37].

All four of our patients who developed inhibitors did so after exposure to rFVIII. This includes one patient who had previously been exposed to pdFVIII (two non-consecutive BI) without inhibitor formation. At this time there is no definitive evidence to indicate a higher risk of inhibitor development with recombinant vs. plasma-derived FVIII products [11,28,38,39]. Although a higher incidence of inhibitors has been documented with the increased use of rFVIII, confounding variables (increased inhibitor surveillance, increasing use of prophylaxis, and greater use of CI) may explain the apparent increase in inhibitor development [40].

The clinical impact of the inhibitors in our four patients varied from minimal (case 4; low titer) to severe bleeding (cases 1, 2, and 3; all high titer). Consistent with literature reports, our three cases with high-titer inhibitors developed a severe and unusual bleeding pattern reminiscent of that seen in acquired hemophilia [5,19,29,41,42]. The morbidity and mortality for such patients is high [5]. Reports suggest that these MHA patients with inhibitors respond differently to management. Unlike in cases of SHA, spontaneous disappearance of inhibitors in MHA occurs (as in case 2), and is thought to result from auto-tolerance from ongoing production of endogenous FVIII [5,43]. ITT appears to be less effective in patients with MHA [5,44]. Immune suppression (corticosteroids, cyclophosphamide, etc.) is perceived to be more important than immune tolerance in patients with MHA [10]. In our series of four patients, ITT was attempted in two cases, and was successful in one (with plasmapharesis and corticosteroids). Presently, there are insufficient data to recommend any specific ITT regimen for MHA patients with inhibitors. Prospective studies are needed to determine the subset of MHA patients with high-titer inhibitors who would merit this demanding and expensive treatment strategy.

Based on our observations and previous reports of inhibitor development in MHA patients following intensive exposure to FVIII, we recommend that physicians who care for such patients closely monitor them for inhibitor development in the event that they are intensely exposed to FVIII.

In conclusion, inhibitor formation is an increasingly recognized problem in patients with MHA and prospective studies are needed to determine which patients are at risk for the development of inhibitors. Our observations suggest that intense exposure to FVIII, possibly in the form of CI, may be associated with an incidence of inhibitor formation similar to that observed in SHA cases. Boys with MHA who are intensely exposed to FVIII by CI should be carefully monitored for inhibitor development. A prospective multicenter study to address the issue of inhibitors in MHA post-CI and following other intense exposures to FVIII is warranted.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Background
  4. Patients
  5. Methods
  6. Results
  7. Case reports
  8. Discussion
  9. Acknowledgements
  10. References

Presented in part at the 44th Annual Meeting of the American Society of Hematology, Philadelphia, 2002. We thank Dr M. Rand for her critical review of this manuscript.

References

  1. Top of page
  2. Abstract
  3. Background
  4. Patients
  5. Methods
  6. Results
  7. Case reports
  8. Discussion
  9. Acknowledgements
  10. References
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