Is Hemophilia B Less Severe Than Hemophilia A? Results Of Global Coagulation Assays

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2352-2352 ◽  
Author(s):  
Maria Rosaria Fasulo ◽  
Maria Elisa Mancuso ◽  
Veena Chantarangkul ◽  
Antonino Cannavò ◽  
Marigrazia Clerici ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Phenotypic Variability ◽  
Gene Mutations ◽  
Factor Ix ◽  
Hemophilia B ◽  
Bleeding Tendency ◽  
Severe Hemophilia ◽  
Coagulation Assays ◽  
One Stage ◽  
Research Grant

Abstract Introduction Some observations suggest that severe hemophilia B (HB) may exhibit a milder bleeding tendency than severe hemophilia A (HA), however possible differences in the coagulation profile of severe HB and HA that may account for such phenotypic variability have not been extensively investigated. The aim of this study was to compare the clinical and laboratory phenotype of patients with severe HB (cases) with those with severe HA (controls) in order to ascertain potential determinants for a milder bleeding phenotype. Methods: patients with severe HB and HA (FIX and FVIII <1 IU/dL) of any age without inhibitor history followed up at a single center were asked to undergo blood sampling after a minimum wash-out period of 5 days from the last factor IX (FIX) or factor VIII (FVIII) infusion in order to perform coagulation assays including global testing by thrombin generation assay (TGA) and thromboelastography (TEG). Data on medical history, annual bleeding frequency, factor consumption, treatment regimen, orthopaedic status and FIX/FVIII gene mutations were collected from patients’ files. TGA was performed in platelet-rich plasma (PRP) with the addition of corn trypsin inhibitor (CTI) and TEG in whole citrated blood by means of the 4 channel ROTEM Gamma equipment. FIX and FVIII were measured by one-stage clotting and chromogenic assays. Results are available from the first 33 consecutive patients with severe hemophilia (16 HB and 17 HA) who agreed on and were able to maintain the required wash-out period. Age at enrolment (median: 40.8 and 41.2 years, interquartile range: 36-54 and 37-48, in HB and HA, respectively) and the proportion of patients with target joints (75% in HB and 82% in HA) were similar in the two groups. The proportion of patients on regular prophylaxis was higher in HA (41% vs 19% in HB) however not statistically different. HB patients had an older age at first bleed (median 2.8 vs 1.4 yrs in HA, p=0.05), lower prevalence of null gene mutations (13% vs 59% in HA, p<0.01) and lower rate of orthopaedic surgery (19% vs 71% in HA, p<0.01). Considering only patients treated on demand (10 HA and 13 HB), HB patients had less joint bleeds/year (median 1.4 vs 11 in HA, p=0.05), lower concentrate consumption (median 320 vs 1448 IU/kg/yr in HA, p=0.01) and a lower Hemophilia Joint Health Score (HJHS, median 5 vs 31 in HA, p<0.01). Baseline levels of FIX and FVIII were confirmed <1 IU/dL by both one-stage and chromogenic assays. The thrombin peak detected by TGA in HB was higher than in HA patients (median 30.4 vs 18.4 nM, p=0.05) but ETP values were similar. TEG testing showed that HB patients had a shorter Clotting Time (median 310 vs 598 sec in HA, p<0.01), a shorter Clotting Formation Time (median 93 vs 133 sec in HA, p<0.01) and a wider alfa-Angle (median 72 vs 65 degrees in HA, p<0.01) while Maximum Clot Firmness was similar in HA and HB patients. Conclusions: our results indicate that patients with severe HB may have a milder bleeding phenotype as compared with severe HA patients. Global coagulation assays such as TGA and TEG have the potential to reveal different coagulation profiles and to investigate correlations between clinical and laboratory phenotype in hemophilia. Further studies are warranted in order to explore the biological mechanisms that may enhance coagulation activation in hemophilia irrespective of FIX/FVIII activity in plasma. Disclosures: Fasulo: Pfizer: Unrestricted Research Grant Other. Santagostino:Pfizer: Unrestricted Research Grant Other.

scholarly journals Impact of Systematic Pharmacokinetic (PK) Profiles in a Cohort of 29 Patients Treated with Conventional and Extended-Half Life (EHL) Products

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1123-1123
Author(s):  
Teresa Ceglie ◽  
Berardino Pollio ◽  
Irene Ricca ◽  
Maria Messina ◽  
Claudia Linari ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Factor Ix ◽  
Hemophilia B ◽  
Null Mutation ◽  
Severe Hemophilia ◽  
Factor Level ◽  
On Demand ◽  
Active Life ◽  
Genetic Assessment

Introduction. Prophylaxis with factor concentrates reduces bleeding events and improves quality of life for adults and children with severe hemophilia. However, the optimal dosing and infusion frequency is not yet established. Integration of PK data into decision making is gaining support, in particular at the transition between conventional and EHL products. Here we report about 29 PK data of patients affected by hemophilia treated at our centre since childhood. Improved quality of life was our first aim, supposed that decreasing frequency of infusions or increasing the target through factor level allows a more active life without increased risk of bleeding. Patients' characteristics and methods. 18 patients (62%) were ≤ 18 years of age at PK time. 16 were affected by severe hemophilia A, 5 by moderate hemophilia A, 6 by severe hemophilia B and 2 by moderate hemophilia B. At PK time, 28 patients were on prophylaxis and 1 was on demand with recombinant factor IX. Median age at onset of prophylaxis was 9 years (range 3 months-38 years). Genetic assessment was available in 24 patients. Of these, 37.5% and 62.5% were carriers of null and not null mutations respectively. 4 patients were undergone to PK with standard products (1 Octocog alfa, 1 Simoctocog alfa, 1 Octocog alfa-Kovaltry®, 1 Turoctocog alfa) in order to define timing and dosage of successive infusions, while 25 patients switched to EHL factors (15 Efmoroctocog alfa, 2 Ionoctocog alfa, 7 Albutrepenonacog alfa, 1 Eftrenonacog alfa). In 15 patients a population-based PK (popPK) according to WAPPS-Hemo program was also performed. The annualized bleeding rate (ABR) was counted from patient's home bleeding records for one year before PK until now. Results. According to PK data, 21 patients (75%) decreased infusion frequency (100% hemophilia B and 67% hemophilia A patients). The remaining 7 hemophilia A patients maintained the same timing in order to increase the through factor level. Notably, 1 hemophilia B patient switched from on demand treatment to prophylaxis with EHL product due to the more acceptable schedule. 66% of null mutation patients and 73% of not null mutation patients decreased timing. Of 28 patients available at follow-up, 32%, 50% and 18% decreased, increased and maintained the same annual average factor consumption/kg, respectively. All patients had a good adherence after switch. In particular, the on demand patient started a regular prophylaxis with optimal compliance. ABR displayed a reduction with a median of 0 (range 0-5) after PK analysis compared to 1 (range 0-12) before the switch. Full PK vs popPK data obtained using at least two individual PK sampling points were almost similar. Conclusions. Our results remark the necessity of PK study especially in children due to the inter-individual variability independent of genetic assessment. Regarding factor IX, PK allowed us to propose timing even longer than that recommended by prescribing indications resulting in a better personalized prophylaxis. Moreover, our study demonstrates that a full PK analysis is feasible also in children. However, given similar results, popPK could be more feasible in most patients. Regarding consumption, the reduction of only 32% of patients reflects our aim to maintain a high safety profile in an active pediatric population. Nevertheless, the mean annualized consumption was just 0.6-fold increased in the remaining patients. This approach led us to further reduce ABR and in some cases to obtain a persistent no-bleeding status even with a full active life. Disclosures No relevant conflicts of interest to declare.

Prevalence of Discrepancy Between the Results of One-Stage and Chromogenic Factor VIII:C Assays in Iranian Patients with Mild / Moderate Hemophilia A

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4982-4982 ◽  
Author(s):  
Minoo Ahmadinejad ◽  
Fatemeh Vossough ◽  
Kataioon Karimi ◽  
Mohammad Reza Tabatabaei ◽  
Sanaz Homayoun ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Assessment Tools ◽  
Lower Activity ◽  
Bleeding Tendency ◽  
Severe Hemophilia ◽  
One Stage ◽  
Chromogenic Assay ◽  
Iranian Patients

Abstract Background: Factor VIII activity (FVIII:C) level is important in the diagnosis and classification of the severity of hemophilia A and can be measured by three methods (one- stage clotting based, two- stage clotting based and chromogenic). About one third of mild / moderate hemophilia A patients show considerable discrepancy in the results of FVIII:C assayed by the above mentioned methods. This group of patients are called "discrepant hemophilia A". Aims: To determine the prevalence of discrepancy in the results of FVIII:C assays by one- stage and chromogenic methods in Iranian patients with non-severe hemophilia A and the importance of this discrepancy in change of classification of disease severity. We also studied the relationship between the bleeding tendency of these patients with the level of FVIII:C for correct prediction of clinical behavior of the disease. Methods: FVIII:C level was measured using one- stage (FVIII:C1) and chromogenic (FVIII:CR) assays in 78 individuals with mild, moderate or carrier for hemophilia A. Exclusion criteria in our study was considered: receiving FVIII concentrate within 10 days before sampling or having normal results with both methods. Discrepancy was defined as a two- fold or greater difference between the results of two assays. aPTT and mixed-aPTT assays were also performed in all cases. The severity of bleeding symptoms was evaluated using three bleeding assessment tools (BATs): ISTH/SSC BAT, Condensed MCMDM-1VWD bleeding questionary and Vicenza bleeding questionary for the diagnosis of type 1 von willebrand disease. Results: In our study the FVIII:C level was normal with both one-stage and chromogenic methods in 5 patients so they were removed from the data. In the remaining 73 cases, assay discrepancy observed in 45 (62%) patients [43 cases with the lower activity in chromogenic assay (standard discrepancy) and two with the lower activity in the one- stage assay (reverse discrepancy)] ( see the Table and Flow-chart below). Classification of hemophilia A severity changed in 25 (34%) patients (20 patients changed from mild to moderate, 4 cases from mild to normal and 1 patient from normal to mild) based on the results of chromogenic assay. FVIII:C was normal in one patient with one- stage assay but chromogenic assay revealed mild deficiency. As a screening test aPTT did not prolong in 13 (17.8%) of our patients. The relation of ISTH bleeding phenotype with the results of FVIII:C assay by both methods were statistically meaningful; but not about "Vicenza bleeding questionary" and "Condensed MCMDM-1VWD" one. Conclusions: Regarding to the high prevalence of assay discrepancy in Iranian patients with non- severe hemophilia A (62%) and changing the classification of the severity of disease in 34% of cases by chromogenic assay, it is recommended that measurement of FVIII:C by both methods should be mandatory in reference coagulation labs in Iran for definitive exclusion of mild hemophilia A, however it is still not clear that which method is completely compatible with the clinical phenotype. Moreover, due to presence of a meaningful relation between ISTH BAT and FVIII:C levels, use of this BAT in hemophilia patients can help to improve the diagnosis accuracy. Figure Figure. Disclosures No relevant conflicts of interest to declare.

Aminoglycoside suppression of nonsense mutations in severe hemophilia

Blood ◽  
2005 ◽  
Vol 106 (9) ◽  
pp. 3043-3048 ◽  
Author(s):  
Paula D. James ◽  
Sanj Raut ◽  
Georges E. Rivard ◽  
Man-Chiu Poon ◽  
Margaret Warner ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Hemophilia A ◽  
Aminoglycoside Antibiotic ◽  
Bactericidal Effect ◽  
Factor Ix ◽  
Hemophilia B ◽  
Severe Hemophilia ◽  
Toxic Agent ◽  
Nonsense Mutations ◽  
Therapeutic Mechanism

AbstractAminoglycoside antibiotics exhibit their bactericidal effect by interfering with normal ribosomal activity. In this pilot study, we have evaluated the effect of the aminoglycoside antibiotic gentamicin on the factor VIII (FVIII) and IX levels of severe hemophiliacs with known nonsense mutations. Five patients were enrolled and each patient was given 3 consecutive days of gentamicin at a dose of 7 mg/kg intravenously every 24 hours. Two patients (patient no. 1: hemophilia A, Ser1395Stop; and patient no. 5: hemophilia B, Arg333Stop) showed a decrease in their activated partial thromboplastin time (aPTT), an increase in their FVIII (0.016 IU/mL, 1.6%) or FIX (0.02 IU/mL, 2%) levels, and an increase in thrombin generation. The remaining 3 patients (patient no. 2: hemophilia B, Arg252Stop; patient no. 3: hemophilia A, Arg2116Stop; and patient no. 4: hemophilia A, Arg427Stop) showed no response in the aPTTs or factor levels, but one (patient no. 2: hemophilia B, Arg252Stop) showed an increase in the factor IX antigen level (2%-5.5%) that persisted throughout the period of the study and was concordant with an increase in thrombin generation. Gentamicin is unlikely to be an effective treatment for severe hemophilia due to its potential toxicities and the minimal response documented in this report. This study, however, does provide a proof of principle, suggesting that ribosomal interference with a less toxic agent may be a potential therapeutic mechanism for severe hemophilia patients with nonsense mutations.

An immunological Method for Detection of the Carrier of Hemophilia B

1976 ◽  
Vol 36 (02) ◽  
pp. 441-450 ◽  
Author(s):  
Matsuzo Matsuoka ◽  
Masakazu Ito ◽  
Kaoru Takahashi ◽  
Nobuo Sakuragawa
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Neutralization Test ◽  
High Specificity ◽  
Factor Ix ◽  
Hemophilia B ◽  
Precipitation Reaction ◽  
Immunological Study ◽  
Severe Hemophilia ◽  
Heterologous Antibody

SummaryThis paper presents the results of an immunological study of hemophilia B and its carriers which used two kinds of antibodies, a heterologous antibody of high specificity and a homologous antibody developed in a patient with severe hemophilia B.1. The factor IX related antigen for hemophilia B could be determined by a neutralization test and not by a precipitation reaction.2. The activity of factor IX in a definite carrier of hemophilia B was significantly lower than that of factor VIII in a definite carrier of hemophilia A.3. In hemophilia B, there were no differences between the factor IX antigen determined by either the heterologous rabbit antibodies or the homologous antibodies. And there was no discrepancy between the factor IX antigen and the factor IX activity. Therefore, we cannot use this discrepancy for the detection of a carrier of hemophilia B.4. However, there was a discrepancy between the factor IX antigen determined by the neutralization test and the factor IX procoagulant activity in the patients of both hemophilia BM and hemophilia B+. The identical results were obtained in the cases of carriers of both hemophilia BM and hemophilia B+. These facts are very useful for the detection of carriers of hemophilia BM and hemophilia B+.

Low Prevalence of the Factor V Leiden Mutation Among “Severe” Hemophiliacs with a “Milder” Bleeding Diathesis

1995 ◽  
Vol 74 (05) ◽  
pp. 1255-1258 ◽  
Author(s):  
Arnaldo A Arbini ◽  
Pier Mannuccio Mannucci ◽  
Kenneth A Bauer
Keyword(s):  
Hemophilia A ◽  
Factor V Leiden ◽  
Protein S ◽  
Factor Ix ◽  
Hemophilia B ◽  
Factor V ◽  
Bleeding Diathesis ◽  
Mutation Site ◽  
Spontaneous Bleeding ◽  
Factor V Leiden Mutation

SummaryPatients with hemophilia A and B and factor levels less than 1 percent of normal bleed frequently with an average number of spontaneous bleeding episodes of 20–30 or more. However there are patients with equally low levels of factor VIII or factor IX who bleed once or twice per year or not at all. To examine whether the presence of a hereditary defect predisposing to hypercoagulability might play a role in amelio rating the hemorrhagic tendency in these so-called “mild severe” hemophiliacs, we determined the prevalence of prothrombotic defects in 17 patients with hemophilia A and four patients with hemophilia B selected from 295 and 76 individuals with these disorders, respectively, followed at a large Italian hemophilia center. We tested for the presence of the Factor V Leiden mutation by PCR-amplifying a fragment of the factor V gene which contains the mutation site and then digesting the product with the restriction enzyme Mnll. None of the patients with hemophilia A and only one patient with hemophilia B was heterozygous for Factor V Leiden. None of the 21 patients had hereditary deficiencies of antithrombin III, protein C, or protein S. Our results indicate that the milder bleeding diathesis that is occasionally seen among Italian hemophiliacs with factor levels that are less than 1 percent cannot be explained by the concomitant expression of a known prothrombotic defect.

F8 gene and phenotype: single player in a team?

Blood ◽  
2013 ◽  
Vol 121 (19) ◽  
pp. 3784-3785 ◽  
Author(s):  
Anna Pavlova
Keyword(s):  
Decision Making ◽  
Hemophilia A ◽  
Phenotypic Variability ◽  
Treatment Decision ◽  
Severe Hemophilia ◽  
Treatment Decision Making

In this issue of Blood, Carcao et al demonstrate that the phenotypic variability in patients with severe hemophilia A correlates with the F8 mutation, where patients with non-null mutations exhibit a milder bleeding phenotype compared with those with null mutations, although this difference is not likely to influence the treatment decision making.1

scholarly journals Factor IX New London: substitution of proline for glutamine at position 50 causes severe hemophilia B

Blood ◽  
1990 ◽  
Vol 75 (5) ◽  
pp. 1097-1104 ◽  
Author(s):  
JN Lozier ◽  
DM Monroe ◽  
S Stanfield-Oakley ◽  
SW Lin ◽  
KJ Smith ◽  
...  
Keyword(s):  
Translation Termination ◽  
Factor Ix ◽  
Hemophilia B ◽  
Molar Ratio ◽  
Carrier Status ◽  
Severe Hemophilia ◽  
Base Pairs ◽  
Human Factor Ix ◽  
Restriction Endonuclease Cleavage Site ◽  
Status Analysis

Abstract We describe a novel point mutation in the fourth exon of human factor IX (encoding the first EGF-like domain) in which cytosine is substituted for adenosine at position 10,401, resulting in the substitution of proline for glutamine at position 50 in the polypeptide chain. Sequence analysis of all eight exons, all exon-intron junctions, 160 base pairs (bp) of DNA 5′ to the proposed translation start site, and 60 bp 3′ to the translation termination site shows no other difference from the normal factor IX gene, with the exception of a previously described benign polymorphism at position 148 in the protein (Ala----Thr). The affected subject has severe hemophilia B with no detectable factor IX activity despite normal factor IX antigen levels. We purified the abnormal factor IX by immunoaffinity chromatography and demonstrated that its activation by factor Xla is markedly delayed compared with normal factor lX. Once activated, the abnormal factor lX binds antithrombin III in a 1:1 molar ratio, and the activated protein demonstrates catalytic activity, suggesting an intact active site. The mutation creates a new Bst Yl restriction endonuclease cleavage site. Restriction with Bst Yl shows the mutation in maternal DNA and offers the possibility of direct carrier status analysis and prenatal diagnosis in kindreds with this mutation. We designate this new mutation factor lXNew London. This is the only reported mutation in the first EGF-like domain that causes severe hemophilia B.

Mutation of Factor IX Cys178 is intolerant and may cause severe hemophilia B

2019 ◽  
Vol 183 ◽  
pp. 108-110 ◽  
Author(s):  
Xiong Wang ◽  
Linna Gao ◽  
Na Shen ◽  
Aiguo Liu ◽  
Yanjun Lu ◽  
...  
Keyword(s):  
Factor Ix ◽  
Hemophilia B ◽  
Severe Hemophilia
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