Dose Requirement for Replacement Therapy in Hemophilia A

1979 ◽  
Vol 42 (03) ◽  
pp. 825-831 ◽  
Author(s):  
Jean-Pierre Allain
Keyword(s):  
Clinical Effect ◽  
Hemophilia A ◽  
Clinical Results ◽  
Severe Hemophilia ◽  
Dose Requirement ◽  
Viii Level ◽  
The Relationship ◽  
In Vivo Recovery ◽  
Different Doses

SummaryIn order to determine the correlation between different doses of F. VIII and their clinical effect,. 70 children with severe hemophilia A were studied after treatment with single doses of cryoprecipitate. The relationship between plasma F. VIII levels or doses calculated in u/ kg of body weight and clinical results followed an exponential curve. Plasma F. VIII levels of 0.35 and 0.53 u/ml corresponded to 95 and 99% satisfactory treatment, respectively. Similar clinical results were obtained with 20 and 31 u/kg. When the in vivo recovery of F. VIII after lyophilized cryoprecipitate was 0.015 u/ml for each u/kg injected, plasma F. VIII levels of 0.30 and 0.47 u/ml respectively were achieved. Since home treatment is largely based on single infusions of F. VIII, it is suggested that moderate and severe hemorrhages be treated with a dose which will provide a plasma F. VIII level of 0.5 u/ml.

scholarly journals Dose Requirement for Substitution Therapy in Hemophilia A.

1977 ◽  
Author(s):  
J.P. Allain
Keyword(s):  
Factor Viii ◽  
Clinical Result ◽  
Hemophilia A ◽  
Factor Viii Activity ◽  
Dose Requirement ◽  
Plasma Factor ◽  
Post Infusion ◽  
The Relationship ◽  
Different Doses

In order to determine the relationship between different doses of factor VIII and their clinical effect,70 children with severe hemophilia A treated with single doses of cryoprecipitate were studied. Plasma factor VIII levels were tested by a one stage assay on samples taken before, and 30 and 60 min. post-infusion. Clinical failure was defined as an absence of clinical improvement or the occurrence of bleeding in another site within 24 hours post-treatment. The relationship between plasma factor VIII levels or doses injected in u/kg and clinical result followed an exponential curve. Calculated from 153 factor VIII recoveries, plasma factor VIII levels of 0.35 and 0.52 u/ml corresponded to 95 and 99% satisfactory treatment, respectively. The same clinical result was obtained with 20 and 31 u of factor VIII/kg when studied in 1043 infusions of lyophilized cryoprecipitate. The in vivo recovery being 0.015 u factor VIII activity/ml for 1 u/kg injected, these dosages provided plasma factor VIII levels of 0.30 and 0.47 u/ml respectively. Since home treatment is largely based on single infusions of factor VIII, it is suggested that most current bleedings can be adequately treated with a dose of factor VIII providing a plasma factor VIII activity of 0.30-0.35 u/ml.

Factor-VIII Inhibitor in Less Severely Affected Haemophilic Patients

1975 ◽  
Author(s):  
E. G. D. Tuddenham ◽  
A. L. Bloom ◽  
J. C. Giddings ◽  
C. A. Barrett
Keyword(s):  
Factor Viii ◽  
Factor Viii Inhibitor ◽  
Factor Viii Level ◽  
Replacement Treatment ◽  
Viii Level ◽  
Viii Inhibitor ◽  
In Vivo Recovery ◽  
Better Than

The occurrence of factor VIII inhibitor in five mild or moderately affected liaemophilic patients is described. In four patients the inhibitor inactivated endogenous factor VIII an dtemporarily converted them to severely affected haemophiliacs with factor VIII level of 0%. In the fifth patient, a brother of one of the others, the inhibitor although more potent did not inactivate the patient’s own factor VIII and did not completely inactivate normal factor VIII in vitro. This patient responded to treatment with factor-VIII concentrate but the in-vivo recovery was reduced. The patient’s plasma was tested against a panel of normal donors but it inactivated factor VIII in each to a similar extent and no evidence for normal factor-VIII groups was obtained. In the other patients the response to replacement treatment was also better than that usually seen in severely affected haemophilic patients with inhibitor. In the two related patients the inhibitors have so far persisted but in the unrelated patients the inhibitors eventually disappeared and did not always recur with subsequent therapy. The incidence of factor- VIII inhibitor in less severe haemophiliacs (factor VIII > 3% ) in this centre is 6% suggesting that the complication is more frequent in this type of patient than hitherto recognised.

scholarly journals Novel Severe Hemophilia a Mouse Model with Factor VIII Intron 22 Inversion

Biology ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 704
Author(s):  
Jeong Pil Han ◽  
Dong Woo Song ◽  
Jeong Hyeon Lee ◽  
Geon Seong Lee ◽  
Su Cheong Yeom
Keyword(s):  
Mouse Model ◽  
Hemophilia A ◽  
Clinical Symptoms ◽  
Structural Similarity ◽  
Coagulation Disorder ◽  
Severe Hemophilia ◽  
Spontaneous Bleeding ◽  
Intron 22 Inversion ◽  
Fviii Activity

Hemophilia A (HA) is an X-linked recessive blood coagulation disorder, and approximately 50% of severe HA patients are caused by F8 intron 22 inversion (F8I22I). However, the F8I22I mouse model has not been developed despite being a necessary model to challenge pre-clinical study. A mouse model similar to human F8I22I was developed through consequent inversion by CRISPR/Cas9-based dual double-stranded breakage (DSB) formation, and clinical symptoms of severe hemophilia were confirmed. The F8I22I mouse showed inversion of a 391 kb segment and truncation of mRNA transcription at the F8 gene. Furthermore, the F8I22I mouse showed a deficiency of FVIII activity (10.9 vs. 0 ng/mL in WT and F8I22I, p < 0.0001) and severe coagulation disorder phenotype in the activated partial thromboplastin time (38 vs. 480 s, p < 0.0001), in vivo bleeding test (blood loss/body weight; 0.4 vs. 2.1%, p < 0.0001), and calibrated automated thrombogram assays (Thrombin generation peak, 183 vs. 21.5 nM, p = 0.0012). Moreover, histological changes related to spontaneous bleeding were observed in the liver, spleen, and lungs. We present a novel HA mouse model mimicking human F8I22I. With a structural similarity with human F8I22I, the F8I22I mouse model will be applicable to the evaluation of general hemophilia drugs and the development of gene-editing-based therapy research.

scholarly journals Vitamin D in the Prevention and Treatment of Osteoarthritis: From Clinical Interventions to Cellular Evidence

Nutrients ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 243 ◽  
Author(s):  
Clara Yongjoo Park
Keyword(s):  
Vitamin D ◽  
Observational Studies ◽  
Pilot Trial ◽  
Clinical Results ◽  
Vitamin D Supplementation ◽  
Vitamin D Status ◽  
Randomized Controlled ◽  
The Relationship

Older adults are recommended vitamin D to prevent fractures. Though this population is also at risk of osteoarthritis (OA), the effect of vitamin D on OA is unclear and may differ by disease state. The relationship between vitamin D and OA during OA initiation and progression were considered in this narrative review of in vivo and in vitro studies. Regarding OA initiation in humans, the small number of published observational studies suggest a lack of association between induction of OA and vitamin D status. Most randomized controlled trials were performed in White OA patients with relatively high vitamin D status (>50 nmol/L). These studies found no benefit of vitamin D supplementation on OA progression. However, subset analyses and one randomized controlled pilot trial indicated that vitamin D supplementation may alleviate joint pain in OA patients with low vitamin D status (<50 nmol/L). As the etiology of OA is recently being more fully uncovered, better animal and cell models are needed. According to currently available clinical results, evidence is lacking to set a vitamin D level to prevent OA, and increasing vitamin D status above 50 nmol/L does not seem to benefit OA patients.

scholarly journals Thrombomodulin-modified thrombin generation after in vivo recombinant factor VIII treatment in severe hemophilia A

Haematologica ◽  
2008 ◽  
Vol 93 (9) ◽  
pp. 1351-1357 ◽  
Author(s):  
A. W.J.H. Dielis ◽  
W. M.R. Balliel ◽  
R. van Oerle ◽  
W. T. Hermens ◽  
H. M.H. Spronk ◽  
...  
Keyword(s):  
Factor Viii ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
Recombinant Factor Viii ◽  
Severe Hemophilia

scholarly journals Purification and characterization of factor VIII 372-Cys: a hypofunctional cofactor from a patient with moderately severe hemophilia A

Blood ◽  
1990 ◽  
Vol 75 (8) ◽  
pp. 1664-1672 ◽  
Author(s):  
DP O'Brien ◽  
JK Pattinson ◽  
EG Tuddenham
Keyword(s):  
Factor Viii ◽  
Heavy Chain ◽  
Time Course ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Thrombin Cleavage ◽  
Before And After ◽  
Functional Defect ◽  
Thrombin Activation

We have purified factor VIII from a patient with moderately severe hemophilia A (FVIII, 4 U/dL; FVIII:Ag, 110 U/dL) and subjected the protein to Western blot analysis after time course activation with thrombin. The cross reacting material-positive (CRM+) FVIII has the normal distribution of heavy and light chains before thrombin activation, and, after incubation with the enzyme, appropriate cleavages are made at positions 740 and 1689. However, the normal thrombin cleavage at position 372 in the heavy chain of this molecule does not occur. This result is consistent with the demonstration in the patient's leukocyte DNA of a C to T transition in codon 372, leading to the substitution of a cysteine for an arginine residue at the heavy chain internal cleavage site. The severely impaired functional activity of this molecule confirms that the heavy chain of FVIII must be proteolysed in order to effect full cofactor activation in vivo. However, a threefold activation was detected when this protein was incubated with thrombin. No evidence of thrombin-mediated cleavage at position 336 in the heavy chain was detected, in contrast to the variant recombinant B domainless-molecule, FVIII 372-Ile, described by Pittman and Kaufman (Proc Natl Acad Sci USA 85:2429, 1988). Using gel permeation studies of the FVIII/von Willebrand factor (vWF) complex before and after thrombin activation, we have demonstrated that the 40 Kd A2 domain of wild type FVIII dissociates from vWF after cleavage by the enzyme. In contrast, incomplete dissociation was detected in the case of FVIII 372-Cys. We conclude that the functional defect in FVIII 372-Cys is a consequence of the resistance to proteolysis of the internal scissile bond in the heavy chain.

Pharmacokinetic Properties of Recombinant Factor VIII Compared with a Monoclonally Purified Concentrate (Hemofil® M)

1992 ◽  
Vol 68 (04) ◽  
pp. 433-435 ◽  
Author(s):  
M Morfini ◽  
G Longo ◽  
A Messori ◽  
M Lee ◽  
G White ◽  
...  
Keyword(s):  
Factor Viii ◽  
Half Life ◽  
Hemophilia A ◽  
Recombinant Dna ◽  
Volume Of Distribution ◽  
Pharmacokinetic Properties ◽  
Recombinant Fviii ◽  
Reported Data ◽  
In Vivo Recovery

SummaryA recombinant FVIII preparation, Recombinate™, was compared with a high-purity plasma-derived concentrate, Hemofil® M, in 47 hemophilia A patients in a cross-over evaluation of pharmacokinetic properties. The recombinant material showed a significantly lower clearance, volume of distribution, and higher in vivo recovery, but a similar half-life to the plasma-based product.In a comparison with reported data from other standard concentrates, the recombinant preparation exhibited potentially better pharmacokinetic properties in that its clearance was slower and its half-life was longer.We conclude that the recombinant DNA method of preparation does not adversely affect the biological and pharmacological characteristics of the factor VIII molecule.

FVIII Recovery after a Single Infusion of Recalibrated ReFacto in 14 Severe Hemophilia A Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2143-2143
Author(s):  
Thierry Lambert ◽  
Claude Guérois ◽  
Valerie Gay ◽  
Natalie Stieltjes ◽  
Marie-Anne Bertrand ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Primary Objective ◽  
Activity Level ◽  
Chromogenic Substrate ◽  
Severe Hemophilia ◽  
K Value ◽  
Intention To Treat ◽  
Fviii Activity ◽  
Recombinant Fviii

Abstract Background: A field study among 6 reference laboratories in the EU using chromogenic substrate assays revealed in some laboratories a FVIII level lower than expected when measuring the potency of ReFacto, a B-domain deleted recombinant FVIII concentrate. In an attempt to resolve these discrepancies, the standard used for establishing the potency of ReFacto was recalibrated in 2003. Indeed after this recalibration, the amount of ReFacto protein in each International Unit (IU) has increased by approximately 20 percent without change in the labeled dosage strength. Objectives: The primary objective of this prospective study was to assess the FVIII recovery in severe hemophilia A patients receiving recalibrated ReFacto. Methods: The study was conducted in 10 French Hemophilia Treatment Centers in Previously Treated Patients (> 150 exposure days to any FVIII concentrate). A series of 4 blood samples per patient were collected in a non-bleeding state, respectively before, 15mn, 30mn and 60mn after intravenous bolus infusion of a single dose of 50 ±5 IU/kg of ReFacto. Plasma FVIII activity was determined in a central lab using a chromogenic substrate assay (Coamatic FVIIITM). Results: Fourteen severe hemophilia A patients (FVIII: C < 1%) were evaluable for intention to treat analysis. Median age was 25.5 years (range: 12–48). Median injected dose was 53.3 UI/kg (range 48.4–56.8). Maximal plasma FVIII activity level was obtained 15mn (n=10) or 30 mn (n=4) after the end of infusion. Mean incremental recovery (K value) was 2.20 ±0.27 UI/dL per UI/kg infused (range: 1.89–2.75) with a mean in vivo recovery of 105.2% (range: 87.6–133.8). Conclusions: In most cases the peak of FVIII activity was obtained 15 mn after the end of infusion. Recovery of recalibrated ReFacto was similar to the expected recovery with full-length FVIII concentrates.

scholarly journals Real-World Clinical and Laboratory Characteristics in Severe Hemophilia a Patients Commencing Emicizumab

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 9-9
Author(s):  
Gavin Ling ◽  
Aderonke Ajidahun ◽  
Steve K. Austin ◽  
Gerard Dolan ◽  
Aine McCormick
Keyword(s):  
United Kingdom ◽  
Clinical Efficacy ◽  
Real World ◽  
Hemophilia A ◽  
Pearson Correlation ◽  
Cross Reactivity ◽  
Severe Hemophilia ◽  
Real World Data ◽  
Low Level

Introduction Emicizumab (a bispecific antibody mimicking Factor VIIIa) has been authorised for use in the United Kingdom National Health Service (NHS) in severe hemophilia A patients with and without inhibitors since August 2019. The Summary of Product Characteristics estimates a steady state of emicizumab achieved after four loading doses for patients &gt;12 years of age at between 50-60ug/mL. Real world data outwith trial conditions are lacking to evaluate clinical efficacy, and which assays may be appropriate to determine emicizumab levels in vivo. Methods A prospective analysis of patients switching from FVIII concentrate to emicizumab was conducted at Guy's and St Thomas' Hospital Haemophilia Centre between September 2019 and July 2020 inclusive. Patients' age and weight were recorded and doses of emicizumab prescribed according to United Kingdom Haemophilia Centres' Doctors Organisation guidelines. Post emicizumab initiation, samples for coagulation testing were taken one week, four weeks and eight weeks after commencing emicizumab, with some pre-emicizumab initiation samples obtained. Three assays were used (human chromogenic FVIII assay (CSA) (Hyphen Biomed); bovine chromogenic FVIII assay (BCA) (Siemens); and a modified one-stage emicizumab assay (OSEA) with emicizumab calibrators to derive drug levels). Where possible with sufficient sample volume all three assays were run simultaneously. Results Within the cohort of all severe hemophilia A patients (n=118), 9 patients with inhibitors had already been previously switched from FVIII concentrate. 21 patients switched to emicizumab between September 2019 and July 2020, of which 2 patients had active FVIII inhibitors, with emicizumab prophylaxis patients comprising 25.4% (30/118) of the hospital cohort. Mean age of switchers was 39.3 years (standard deviation ± 13.9), with a mean dose of 116 ± 20.7mg on a weekly basis. 13/21 were on 1.5mg/kg weekly dosing and the remainder on fortnightly dosing at 3mg/kg. OSEA levels at 1 week (n=15), 4 weeks (n=15) and 8 weeks (n=7) were 19.7 ± 14.8ug/mL, 54.8 ± 11.7ug/mL and 61.3 ± 12.2ug/mL respectively. CSA results were 17 ± 9.0 IU/dL (n=9), 27.7 ± 6.7 IU/dL (n=10), and 26.7 ± 9.6 IU/dL (n=5) respectively. Simultaneous 1-stage based OSEA and CSA assays were performed on 20 samples, with high correlation between the two types of assay (Pearson correlation coefficient = 0.909 (CI 0.780-0.964, p &lt;0.0001)). Six pre-emicizumab initiation samples were tested for both OSEA and CSA, which suggested low-level cross-reactivity of OSEA with FVIII concentrate in vivo. 4/6 were non-washout samples, which showed apparent positive OSEA levels (range 2.3-7.9ug/mL) with corresponding CSA ranges from 17.6-86.6 IU/dL. BCA in 3 patients at 1 week showed a low level of residual FVIII (all &lt;8 IU/dL) consistent with prior FVIII infusions. All samples at 4 weeks and 8 weeks had undetectable FVIII concentrate levels consistent with the cessation of FVIII administration (bovine FVIII &lt;1 IU/dL) and correspondingly positive OSEA levels, confirming the lack of cross-reactivity between the two assays. No patients developed anti-emicizumab antibodies as determined by clinical efficacy or by APTT measurement. No patients required any surgical or interventional procedures during this period. One spontaneous bleed and one traumatic bleed were recorded in two separate patients. Conclusion Emicizumab in a real-world setting is confirmed in our experience to have excellent clinical efficacy with infrequent episodes of spontaneous bleeding. 18% of patients switched to emicizumab within a year of its availability on the NHS. It has been well-tolerated with no clinical or laboratory evidence of anti-drug antibodies as measured by APTT. The OSEA correlated well with levels predicted by the emicizumab SPC at each time point. At all concentrations an OSEA and CSA are highly correlated, which may suggest that only one of the two assays is routinely required in laboratory use to assay emicizumab. Caution is however advised in assessing OSEA on its own when FVIII concentrate has recently been administered as this may result in some low level, false positive results. Figure Disclosures Austin: Chugai: Honoraria. Dolan:Pfizer: Consultancy; Roche: Honoraria.

Sign in / Sign up

Export Citation Format

Share Document