Congenital fibrinogen disorders: a retrospective clinical and genetic analysis of the Prospective Rare Bleeding Disorders Database.

ABSTRACT: Congenital fibrinogen deficiency (CFD) is a rare bleeding disorder caused by mutations in FGA, FGB, and FGG. We sought to comprehensively characterize patients with CFD using PRO-RBDD (Prospective Rare Bleeding Disorders Database). Clinical phenotypes, laboratory, and genetic features were investigated using retrospective data from the PRO-RBDD. Patients were classified from asymptomatic to grade 3 based on their bleeding severity. In addition, FGA, FGB, and FGG were sequenced to find causative variants. A total of 166 CFD cases from 16 countries were included, of whom 123 (30 afibrinogenemia, 33 hypofibrinogenemia, 55 dysfibrinogenemia, and 5 hypodysfibrinogenemia) were well characterized. Considering the previously established factor activity and antigen level thresholds, bleeding severity was correctly identified in 58% of the cases. The rates of thrombotic events among afibrinogenemic and hypofibrinogenemic patients were relatively similar (11% and 10%, respectively) and surprisingly higher than in dysfibrinogenemic cases. The rate of spontaneous abortions among 68 pregnancies was 31%, including 86% in dysfibrinogenemic women and 14% with hypofibrinogenemia. Eighty-six patients received treatment (69 on-demand and/or 17 on prophylaxis), with fibrinogen concentrates being the most frequently used product. Genetic analysis was available for 91 cases and 41 distinct variants were identified. Hotspot variants (FGG, p.Arg301Cys/His and FGA, p.Arg35Cys/His) were present in 51% of dysfibrinogenemia. Obstetric complications were commonly observed in dysfibrinogenemia. This large multicenter study provided a comprehensive insight into the clinical, laboratory, and genetic history of patients with CFDs. We conclude that bleeding severity grades were in agreement with the established factor activity threshold in nearly half of the cases with quantitative defects.

Efficacy and safety of von Willebrand factor concentrate almost devoid of factor VIII (Wilfactin®) in paediatric patients under 6 years of age with severe von Willebrand disease.

BACKGROUND: Plasma-derived von Willebrand factor (VWF) (Wilfactin®, LFB, France) was developed for prophylaxis and treatment of haemorrhages in both adults and adolescents with von Willebrand disease (VWD). Replacement therapy in paediatric patients is a key element of the clinical trial programme. MATERIAL AND METHODS: Patients aged <6 years with severe VWD were enrolled in a multinational, open-label study to evaluate the in vivo recovery for Wilfactin®, and its efficacy in preventing and treating bleeding episodes and during surgery. Overall haemostatic efficacy based on a 4-point scale was assessed by investigators. The treatment period ≥18 months investigated the long-term safety. RESULTS: Nine patients, including 7 with type 3 VWD were exposed to treatment with Wilfactin® for up to 4.2 years. Recovery of VWF in 7 patients (n=5 type 3, n=1 type 2, n=1 type 1) was 1.8±0.4 IU/dL per IU/kg. Of the 62 bleeds, 89% were controlled with one (73%) or two (16%) infusions of Wilfactin®. The median dose per infusion was 54 IU/kg. A factor VIII dose was co-administered in 1.6% of bleeds. "Excellent"/"Good" haemostatic efficacy was achieved in 90.3% of episodes. Six patients underwent 11 minor surgical interventions. Treatment duration was 1 day (range: 1-6 days) with a dose administered 30-60 minutes before procedure of 56 IU/kg (range: 41-106 IU/kg). Haemostasis was rated as "Excellent" in all surgeries. During 4-year prophylactic treatment in one patient, breakthrough bleeds were reported in 2.2% of infusions. No VWF inhibitors, thromboembolic events or allergic/anaphylactic-type reactions were observed following a total exposure of 770 days. DISCUSSION: The results show that Wilfactin® provides a safe and effective treatment in patients <6 years of age with severe VWD.

Inhibitor incidence in an unselected cohort of previously untreated patients with severe haemophilia B: a PedNet study.

The incidence of FIX inhibitors in severe hemophilia B (SHB) is not well defined. Frequencies of 3-5% have been reported but most studies to date were small, including patients with different severities, and without prospective follow-up for inhibitor incidence. Study objective was to investigate inhibitor incidence in patients with SHB followed up to 500 exposure days (ED), the frequency of allergic reactions, and the relationship with genotypes. Consecutive previously untreated patients (PUPs) with SHB enrolled into the PedNet cohort were included. Detailed data was collected for the first 50 ED, followed by annual collection of inhibitor status and allergic reactions. Presence of inhibitors was defined by at least two consecutive positive samples. Additionally, data on factor IX gene mutation was collected. 154 PUPs with SHB were included; 75% were followed until 75 ED, and 43% until 500 ED. Inhibitors developed in 14 patients (7 high-titre). Median number of ED at inhibitor manifestation was 11 (IQR 6.5-36.5). Cumulative inhibitor incidence was 9.3% (95%CI 4.4-14.1) at 75 ED, and 10.2% (5.1-15.3) at 500 ED. Allergic reactions occurred in 4 (28.6%) inhibitor patients. Missense mutations were most frequent (46.8%) overall but not associated with inhibitors. Nonsense mutations and deletions with large structural changes comprised all mutations among inhibitor patients and were associated with an inhibitor risk of 26.9% and 33.3%, respectively. In an unselected, well-defined cohort of PUPs with SHB, cumulative inhibitor incidence was 10.2% at 500 ED. Nonsense mutations and large deletions were strongly associated with the risk of inhibitor development. The PedNet Registry is registered at clinicaltrials.gov; identifier: NCT02979119.

The factor VIII treatment history of non-severe hemophilia A.

BACKGROUND: In patients with non-severe hemophilia A, we lack detailed knowledge on the timing of treatment with factor VIII (FVIII) concentrates. This knowledge could provide information about the expected treatment timing in patients with severe hemophilia A treated with non-replacement therapies. OBJECTIVE: To assess the FVIII treatment history in patients with non-severe hemophilia A. METHODS: Patients with non-severe hemophilia (baseline FVIII activity [FVIII:C] 2-40 IU/dL) were included from the INSIGHT study. The primary outcome was median age at first FVIII exposure (ED1). In a subgroup of patients for whom more detailed information was available, we analyzed the secondary outcomes: median age at first 20 EDs, annualized bleeding rate for all bleeds (ABR), joint bleeds (AJBR), and major spontaneous bleeds (ASmBR). RESULTS: In the total cohort (n = 1013), median baseline FVIII activity was 8 IU/dL (interquartile range [IQR] 4-15) and the median age at ED1 was 3.7 years (IQR 1.4-7.7). Median age at ED1 rose from 2.5 years (IQR 1.2-5.7) in patients with FVIII:C 2-5 IU/dL to 9.7 years (IQR 4.8-16.0) in patients with FVIII:C 25-40 IU/dL. In the subgroup (n = 104), median age at ED1, ED5, ED10, and ED20 was 4.0 years (IQR 1.4-7.6), 5.6 years (IQR 2.9-9.3), 7.5 years (IQR 4.4-11.3), and 10.2 years (IQR 6.5-14.2), respectively. Median ABR, AJBR, and ASmBR were 1.1 (IQR 0.5-2.6), 0.3 (IQR 0.1-0.7), and 0 (IQR 0-0), respectively. CONCLUSION: This study demonstrates that in non-severe hemophilia A, the age at first FVIII exposure increases with baseline FVIII:C and that major spontaneous bleeds rarely occur.

ITI Treatment is not First-Choice Treatment in Children with Hemophilia A and Low-Responding Inhibitors: Evidence from a PedNet Study.

BACKGROUND: Limited data exist on the clinical impact of low-responding inhibitors and the requirement for immune tolerance induction (ITI) treatment to establish tolerance, reduce bleeding, and improve outcome. The aim of this article is to describe the therapeutic management of children with severe hemophilia A and low-responding inhibitors and its effect on bleeding phenotype. METHODS: The REMAIN (Real-life Management of Inhibitors) study is a satellite study of the PedNet registry. It included unselected children with severe hemophilia A (factor VIII [FVIII] < 0.01 IU/mL) born between January 1, 1990 and December 31, 2009 who developed clinically relevant inhibitors and were followed-up for at least 3 years after the first positive inhibitor test. RESULTS: A total of 260 patients with inhibitors were identified and 68 of them (26%) had low-responding inhibitors (peak < 5 BU/mL). Five patients were lost to follow-up and 63 were included in this study. The median follow-up was 3.7 years (interquartile range: 3.0-7.5). ITI was started in 51/63 (81%) patients. The median time from ITI start to first negative inhibitor titer was similar with low-dose and high-dose ITI regimens (2.5 and 3.1 months, respectively). Ten of the 12 patients who did not receive ITI were treated with regular prophylaxis and reached a negative titer after a median of 6.5 months. Bleeding rate was low in all patients with no difference between treatment regimens. CONCLUSION: In children with low-responding inhibitors negative titers were reached with regular FVIII treatment irrespective of the regimen (i.e., prophylaxis or ITI).

Impact of target joint and FVIII inhibitor οn bone properties in children with haemophilia A: A peripheral quantitative computed tomography study.

BACKGROUND: Haemophilic children are prone to low bone mass accrual. OBJECTIVE: To assess bone properties in haemophilic children, using peripheral quantitative computed tomography (pQCT) and to correlate findings with clinical data. SUBJECTS/METHODS: Peripheral quantitative computed tomography scan of both radii and tibiae were performed in 31 haemophilic A children (severe 24, mean age 11.2 years). Seven subjects had a history of inhibitors. Five children had an upper extremity target-joint and 12 had at least one lower extremity target-joint. The following parameters were measured: trabecular, total and cortical bone density and content (TBD, ToBD, CBD, TbC, CC), strength-stress index (SSI), and tibial cross-sectional area (CA), outer and inner bone contour length (PERI, ENDO) and cortical thickness (CTHC). RESULTS: Mean right radius TBD was significantly higher than the left one (P = 0.015). In subjects with arm target-joint, radius TBD was significantly lower in the target than in non-target arm (186.6 ± 60.4 vs 218.6 ± 39.8, P = 0.032). Left arm target-joint subjects had significantly lower left radius TBD in comparison to subjects without arm target-joint (155.4 ± 50.3 vs 215.7 ± 37.9, P = 0.019). There were no similar differences in leg target-joint. Bone quality and geometry parameters in cortical compartment were significantly lesser in inhibitor group, with statistically significant side-to-side differences for legs and arms and left side predominance. CONCLUSION: In children with haemophilia A and a history of target-joint and/or FVIII inhibitor, abnormalities may occur in the long bones as were revealed by pQCT, where low trabecular density and weak cortical bone quality in upper and lower extremities, respectively, were confirmed.

Desmopressin in moderate hemophilia A patients: a treatment worth considering.

Desmopressin increases endogenous factor VIII levels in hemophilia A. Large inter-individual variation in the response to desmopressin is observed. Patients with a lower baseline factor VIII activity tend to show a reduced response, therefore, desmopressin is less frequently used in moderate hemophilia A patients (baseline factor VIII activity 1-5 international units/deciliter), even though factor VIII levels may rise substantially in some of them. We aim to describe the response to desmopressin in moderate hemophilia A patients and to identify predictors. We selected data on 169 patients with moderate hemophilia from the multicenter Response to DDAVP In non-severe hemophilia A patients: in Search for dEterminants (RISE) cohort study. Adequate response to desmopressin was defined as a peak factor VIII level ≥ 30, and excellent response as ≥ 50 international units/deciliter after desmopressin administration. We used univariate and multiple linear regression techniques to analyze predictors of the peak factor VIII level. Response was considered adequate in 68 patients (40%), of whom 25 showed excellent response (15%). Intravenous administration, age, pre-desmopressin factor VIII activity and von Willebrand factor antigen, peak von Willebrand factor activity and desmopressin-induced rise in von Willebrand factor antigen were significant predictors of peak factor VIII level and explained 65% of the inter-individual variation. In 40% of moderate hemophilia A patients, desmopressin response was adequate, thus it is important not to with-hold this group of patients from desmopressin responsiveness. Among the six predictors that we identified for desmopressin-induced factor VIII rise, factor VIII activity and desmopressin-induced rise in von Willebrand factor antigen had the strongest effect.

Risk Factors for the Progression from Low to High Titres in 260 Children with Severe Haemophilia A and Newly Developed Inhibitors.

In children with severe haemophilia A, inhibitors to factor VIII (FVIII) usually develop during the first 50 treatment exposure days and are classified as low or high titre depending on the peak inhibitor titre being greater or less than 5 Bethesda units/mL (BU/mL). Classification of the inhibitor may change with time, as some low-titre inhibitors progress to high titre following re-exposure to FVIII concentrate. The aim of this study was to investigate potential risk factors for such a progression in children with severe haemophilia A and newly diagnosed inhibitors. This study was a follow-up study of the PedNet Registry and included 260 children with severe haemophilia A and inhibitors born between 1990 and 2009 and recruited consecutively from 31 haemophilia centres. Clinical and laboratory data were collected from the date of each child's first positive inhibitor test for at least 3 years. At the time of first positive inhibitor test, 49% (n = 127) had low-titre inhibitors, with 50% of them progressing to high titre and only 25% maintaining low titres. The FVIII gene (F8) mutation type was known in 247 patients (95%), and included 202 (82%) null mutations. The progression to high-titre inhibitors was associated with null F8 mutations (odds ratio [OR]: 2.6; 95% confidence interval [CI]: 1.0­6.5), family history of inhibitors (OR: 7.2; 95% CI: 1.8­28.4) and the use of high-dose immune tolerance induction, defined as ≥100 IU FVIII concentrate/kg/d (OR: 3.9; 95% CI: 1.5­10.0). These results suggest that high-dose immune tolerance induction should be avoided as the initial strategy in patients who develop low-titre FVIII inhibitors.

Intracranial haemorrhage in children and adolescents with severe haemophilia A or B - the impact of prophylactic treatment.

The discussion of prophylactic therapy in haemophilia is largely focused on joint outcomes. The impact of prophylactic therapy on intracranial haemorrhage (ICH) is less known. This study aimed to analyse ICH in children with haemophilia, with a focus on different prophylaxis regimens and sequelae of ICH. We conducted a multicentre retrospective and prospective study that included 33 haemophilia centres from 20 countries. Inclusion criteria were children and adolescents born between 1993 and 2014, with severe haemophilia A or B without inhibitors. Participants were categorized by prophylaxis regimen: full, partial or none, based on dose and dose frequency of regular infusions. The cohort study included 1515 children: 29 cases of ICH over 8038 patient years were reported. The incidence of ICH in the prophylaxis group, 0·00033 cases of ICH/patient year, was significantly lower compared to the no prophylaxis group, 0·017 cases of ICH/patient year (RR 50·06; P < 0·001) and the partial prophylaxis group, 0·0050 cases of ICH/patient year (RR 14·92; P = 0·007). In the on-demand-group, 8% (2/24) children with ICH died and 33% had long-term sequelae, including intellectual and behavioural problems, paresis and epilepsy. Children on regular, frequent prophylaxis have a low risk of ICH compared to those using non-frequent or no prophylaxis.

Cochlear implantation is safe and effective in patients with MYH9-related disease.

BACKGROUND: MYH9-related disease (MYH9-RD) is a rare syndromic disorder deriving from mutations in MYH9, the gene for the heavy chain of non-muscle myosin IIA. Patients present with congenital thrombocytopenia and giant platelets and have a variable risk of developing sensorineural deafness, kidney damage, presenile cataract, and liver abnormalities. Almost all MYH9-RD patients develop the hearing defect, which, in many individuals, progresses to severe to profound deafness with high impact on quality of life. These patients are potential candidates for cochlear implantation (CI), however, no consistent data are available about the risk to benefit ratio of CI in MYH9-RD. The only reported patient who received CI experienced perisurgery complications that have been attributed to concurrent platelet defects and/or MYH9 protein dysfunction. METHODS: By international co-operative study, we report the clinical outcome of 10 patients with MYH9-RD and severe to profound deafness who received a CI at 8 institutions. RESULTS: Nine patients benefited from CI: in particular, eight of them obtained excellent performances with restoration of a practically normal hearing function and verbal communication abilities. One patient had a slightly worse performance that could be explained by the very long duration of severe deafness before CI. Finally, one patient did not significantly benefit from CI. No adverse events attributable to MYH9-RD syndrome were observed, in particular no perisurgery bleeding complications due to the platelet defects were seen. Patients' perioperative management is described and discussed. CONCLUSIONS: CI is safe and effective in most patients with MYH9-RD and severe to profound deafness and should be offered to these subjects, possibly as soon as they develop the criteria for candidacy.

Spectrum of the mutations in Bernard-Soulier syndrome.

Bernard-Soulier syndrome (BSS) is a rare autosomal recessive bleeding disorder characterized by defects of the GPIb-IX-V complex, a platelet receptor for von Willebrand factor (VWF). Most of the mutations identified in the genes encoding for the GP1BA (GPIbα), GP1BB (GPIbß), and GP9 (GPIX) subunits prevent expression of the complex at the platelet membrane or more rarely its interaction with VWF. As a consequence, platelets are unable to adhere to the vascular subendothelium and agglutinate in response to ristocetin. In order to collect information on BSS patients, we established an International Consortium for the study of BSS, allowing us to enrol and genotype 132 families (56 previously unreported). With 79 additional families for which molecular data were gleaned from the literature, the 211 families characterized so far have mutations in the GP1BA (28%), GP1BB (28%), or GP9 (44%) genes. There is a wide spectrum of mutations with 112 different variants, including 22 novel alterations. Consistent with the rarity of the disease, 85% of the probands carry homozygous mutations with evidence of founder effects in some geographical areas. This overview provides the first global picture of the molecular basis of BSS and will lead to improve patient diagnosis and management.

Venous thromboembolism at uncommon sites in neonates and children.

We retrospectively analyzed the data of 24 children (whereof 11 neonates), with non-central venous line-related and nonmalignancy-related venous thromboembolism (VTE) at uncommon sites, referred to our Unit from January 1999 to January 2012. Thirty patients who also suffered deep vein thrombosis, but in upper/low extremities, were not included in the analysis. The location of rare site VTE was: portal (n=7), mesenteric (n=2) and left facial vein (n=1), spleen (n=3), lung (n=3), whereas 10 neonates developed renal venous thrombosis. The majority of patients (91.7%) had at least 1 risk factor for thrombosis. Identified thrombophilic factors were: antiphospholipid antibodies (n=2), FV Leiden heterozygosity (n=6), MTHFR C677T homozygosity (n=4), protein S deficiency (n=2), whereas all neonates had age-related low levels of protein C and protein S. All but 6 patients received low-molecular-weight heparin, followed by warfarin in 55% of cases, for 3 to 6 months. Prolonged anticoagulation was applied in selected cases. During a median follow-up period of 6 years, the clinical outcome was: full recovery in 15 patients, evolution to both chronic portal hypertension and esophageal varices in 2 children, and progression to renal failure in 7 of 10 neonates. Neonates are greatly vulnerable to complications after VTE at uncommon sites, particularly renal. Future multicentre long-term studies on neonatal and pediatric VTE at unusual sites are considered worthwhile.

MYH9-related disease: a novel prognostic model to predict the clinical evolution of the disease based on genotype-phenotype correlations.

MYH9-related disease (MYH9-RD) is a rare autosomal-dominant disorder caused by mutations in the gene for nonmuscle myosin heavy chain IIA (NMMHC-IIA). MYH9-RD is characterized by a considerable variability in clinical evolution: patients present at birth with only thrombocytopenia, but some of them subsequently develop sensorineural deafness, cataract, and/or nephropathy often leading to end-stage renal disease (ESRD). We searched for genotype-phenotype correlations in the largest series of consecutive MYH9-RD patients collected so far (255 cases from 121 families). Association of genotypes with noncongenital features was assessed by a generalized linear regression model. The analysis defined disease evolution associated to seven different MYH9 genotypes that are responsible for 85% of MYH9-RD cases. Mutations hitting residue R702 demonstrated a complete penetrance for early-onset ESRD and deafness. The p.D1424H substitution associated with high risk of developing all the noncongenital manifestations of disease. Mutations hitting a distinct hydrophobic seam in the NMMHC-IIA head domain or substitutions at R1165 associated with high risk of deafness but low risk of nephropathy or cataract. Patients with p.E1841K, p.D1424N, and C-terminal deletions had low risk of noncongenital defects. These findings are essential to patients' clinical management and genetic counseling and are discussed in view of molecular pathogenesis of MYH9-RD.

Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study.

The objective of this study was to examine the association of the intensity of treatment, ranging from high-dose intensive factor VIII (FVIII) treatment to prophylactic treatment, with the inhibitor incidence among previously untreated patients with severe hemophilia A. This cohort study aimed to include consecutive patients with a FVIII activity < 0.01 IU/mL, born between 2000 and 2010, and observed during their first 75 FVIII exposure days. Intensive FVIII treatment of hemorrhages or surgery at the start of treatment was associated with an increased inhibitor risk (adjusted hazard ratio [aHR], 2.0; 95% confidence interval [CI], 1.3-3.0). High-dose FVIII treatment was associated with a higher inhibitor risk than low-dose FVIII treatment (aHR, 2.3; 95% CI, 1.0-4.8). Prophylaxis was only associated with a decreased overall inhibitor incidence after 20 exposure days of FVIII. The association with prophylaxis was more pronounced in patients with low-risk F8 genotypes than in patients with high-risk F8 genotypes (aHR, 0.61, 95% CI, 0.19-2.0 and aHR, 0.85, 95% CI, 0.51-1.4, respectively). In conclusion, our findings suggest that in previously untreated patients with severe hemophilia A, high-dosed intensive FVIII treatment increases inhibitor risk and prophylactic FVIII treatment decreases inhibitor risk, especially in patients with low-risk F8 mutations.

Deep vein thrombosis and pulmonary embolism in a child with diabetic ketoacidosis and protein s deficiency: a case report.

INTRODUCTION: Diabetic ketoacidosis (DKA) is considered a hypercoagulable state, which may be exacerbated in patients with thrombophilia and lead to thrombosis. CASE REPORT: We report on a 5.5-year-old boy, who was admitted to the pediatric department with DKA due to newly diagnosed type 1 diabetes. Low-grade fever was reported for 6 days prior to admission and continued during DKA management, with negative septic screening. After DKA management, the child developed symptoms of iliofemoral deep vein thrombosis (DVT). A family history of protein S (PS) deficiency was revealed. He was initially treated intravenously with antibiotics and unfractionated heparin, which, after 2 days, was switched to low-molecular-weight heparin and vitamin K antagonist (VKA) due to poor anticoagulant response. On the 6th day of anticoagulant treatment, the patient presented with pulmonary embolism (PE); he continued with VKA and antibiotics, with significant clinical improvement. Prolonged fever was attributed to DVT and PE. The patient was discharged on oral anticoagulants and insulin. CONCLUSION: We report on a child with congenital PS deficiency and DKA who developed DVT and PE despite anticoagulant treatment. It is important in children presenting with DKA to seek thoroughly for a medical history of thrombophilia and to start early thromboprophylaxis in such cases in order to prevent a possible thrombosis.

MYH9-related disease: five novel mutations expanding the spectrum of causative mutations and confirming genotype/phenotype correlations.

MYH9-related disease (MYH9-RD) is a rare autosomal dominant syndromic disorder caused by mutations in MYH9, the gene encoding for the heavy chain of non-muscle myosin IIA (myosin-9). MYH9-RD is characterized by congenital macrothrombocytopenia and typical inclusion bodies in neutrophils associated with a variable risk of developing sensorineural deafness, presenile cataract, and/or progressive nephropathy. The spectrum of mutations responsible for MYH9-RD is limited. We report five families, each with a novel MYH9 mutation. Two mutations, p.Val34Gly and p.Arg702Ser, affect the motor domain of myosin-9, whereas the other three, p.Met847_Glu853dup, p.Lys1048_Glu1054del, and p.Asp1447Tyr, hit the coiled-coil tail domain of the protein. The motor domain mutations were associated with more severe clinical phenotypes than those in the tail domain.

Replacement therapy for bleeding episodes in factor VII deficiency. A prospective evaluation.

Patients with inherited factor VII (FVII) deficiency display different clinical phenotypes requiring ad hoc management. This study evaluated treatments for spontaneous and traumatic bleeding using data from the Seven Treatment Evaluation Registry (STER). One-hundred one bleeds were analysed in 75 patients (41 females; FVII coagulant activity <1-20%). Bleeds were grouped as haemarthroses (n=30), muscle/subcutaneous haematomas (n=16), epistaxis (n=12), gum bleeding (n=13), menorrhagia (n=16), central nervous system (CNS; n=9), gastrointestinal (GI; n=2) and other (n=3). Of 93 evaluable episodes, 76 were treated with recombinant, activated FVII (rFVIIa), eight with fresh frozen plasma (FFP), seven with plasma-derived FVII (pdFVII) and two with prothrombin-complex concentrates. One-day replacement therapy resulted in very favourable outcomes in haemarthroses, and was successful in muscle/subcutaneous haematomas, epistaxis and gum bleeding. For menorrhagia, single- or multiple-dose schedules led to favourable outcomes. No thrombosis occurred; two inhibitors were detected in two repeatedly treated patients (one post-rFVIIa, one post-pdFVII). In FVII deficiency, most bleeds were successfully treated with single 'intermediate' doses (median 60 µg/kg) of rFVIIa. For the most severe bleeds (CNS, GI) short- or long-term prophylaxis may be optimal.

Management of ligneous conjunctivitis in a child with plasminogen deficiency.

UNLABELLED: Plasminogen deficiency, a rare autosomal recessive disorder, is classified as type I (hypoplasminogenemia) or type II (dysplasminogenemia). Hypoplasminogenemia is characterized by impaired wound healing while ligneous conjunctivitis (LC) is its main manifestation presenting with redness of the conjunctivae and progression to pseudomembranes' formation on the palpebral surfaces. A 4-year-old girl with LC in her left eye and impaired vision was referred to our unit. The conjunctival membranes had been already excised twice, followed by recurrences. Soon after the third recurrence, a probable diagnosis of LC was suggested, confirmed by a reduced plasminogen activity at 20% (normal values 80-120%). Both of her parents have slightly reduced plasminogen levels (50-60%) without any relevant symptom. Fresh frozen plasma (FFP) was administered systemically and topically, initiating 2 days before surgical removal of pseudomembranes with electrocautery under general anaesthesia. Systemic FFP was administered for 12 days postoperatively, along with topical use; the later was continued thereafter for 3 months. No recurrence was noticed. The vision was improved. Two weeks after cessation of the topical treatment, pseudomembranes reappeared. Topical application of FFP was reinitiated soon thereafter, and the girl underwent a second operation to have the conjunctival pseudomembranes removed. The perioperative therapeutic management was as previously described. Systemic treatment was stopped at the end of the tenth day while topical application of FFP was being continued until now, 10 months postoperatively. No recurrence has been observed and the vision remains at 9/10. CONCLUSION: Since surgical excision of the conjunctival pseudomembranes alone in patients with LC does not protect from recurrences, the perioperative administration of FFP, both systemically and topically improves the outcome. Furthermore, the long-term application of topical FFP preparations seems to prevent recurrences and has a protective effect on the vision of these patients.