Hemophilia A Mutations within the Factor VIII A2-A3 Subunit Interface Destabilize Factor VIIIa and Cause One-stage/ Two-stage Activity Discrepancy

2002 ◽  
Vol 88 (11) ◽  
pp. 781-787 ◽  
Author(s):  
William Hakeos ◽  
Hongzhi Miao ◽  
Nongnuch Sirachainan ◽  
Geoffrey Kemball-Cook ◽  
Evgueni Saenko ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Homology Model ◽  
Hydrophobic Core ◽  
Two Stage ◽  
Threefold Axis ◽  
Subunit Dissociation ◽  
One Stage ◽  
Fviii Activity ◽  
A Domains

SummaryThrombin-activated factor VIII (FVIIIa) is a heterotrimer with the A2 subunit in a weak ionic interaction with the A1 and A3-C1-C2 subunits. Dissociation of the A2 subunit correlates with inactivation of FVIIIa. A homology model (Blood 89:2413, 1997) of the triplicated A domains of factor VIII (FVIII) predicts a pseudo-threefold axis at the tightly packed hydrophobic core with several interdomain interactions. These lie at the interface of A1-A2, A2-A3 and A1-A3. We have previously demonstrated that hemophilia A mutations (R531H, A284E, S289L) within the predicted A1-A2 and A1-A3 interface disrupt potential intersubunit hydrogen bonds and have the molecular phenotype of increased rate of inactivation of FVIIIa due to increased rate of A2 subunit dissociation. Patients with these mutations exhibit a clinical phenotype where the FVIII activity by one-stage(1-st) assay is at least two-fold higher than by two-stage(2-st) assay. We have now also explored mutations within the predicted A2-A3 interface (N694I, R698W and R698L) that also have the phenotype of 1-st/2-st activity discrepancy. These mutations exhibit the same molecular mechanism of increased instability of FVIIIa as those mutations described along the A1-A2 and A1-A3 interfaces. This suggests that the entire tightly packed hydrophobic core within the predicted pseudo-threefold axis contributes to stabilization of FVIIIa.

Hemophilia A mutations associated with 1-stage/2-stage activity discrepancy disrupt protein-protein interactions within the triplicated A domains of thrombin-activated factor VIIIa

Blood ◽  
2001 ◽  
Vol 97 (3) ◽  
pp. 685-691 ◽  
Author(s):  
Steven W. Pipe ◽  
Evgueni L. Saenko ◽  
Angela N. Eickhorst ◽  
Geoffrey Kemball-Cook ◽  
Randal J. Kaufman
Keyword(s):  
Protein Interactions ◽  
Hemophilia A ◽  
Specific Activity ◽  
Homology Model ◽  
Optical Biosensor ◽  
Hydrophobic Core ◽  
Wild Type ◽  
Activity Assay ◽  
Subunit Dissociation ◽  
A Domains

Abstract Thrombin-activated factor VIII (FVIIIa) is a heterotrimer with the A2 subunit (amino acid residues 373-740) in a weak ionic interaction with the A1 and A3-C1-C2 subunits. Dissociation of the A2 subunit correlates with inactivation of FVIIIa. Patients with hemophilia A have been described whose plasmas display a discrepancy between their FVIII activities, where the 1-stage activity assay displays greater activity than the 2-stage activity assay. The molecular basis for one of these mutations, ARG531HIS, is an increased rate of A2 subunit dissociation. Examination of a homology model of the A domains of FVIII predicted ARG531 to lie at the interface of the A1 and A2 subunits and stabilize their interaction. Indeed, patients with mutations either directly contacting ARG531 (ALA284GLU, ALA284PRO) or closely adjacent to the A1-A2 interface in the tightly packed hydrophobic core (SER289LEU) have the same phenotype of 1-stage/2-stage discrepancy. TheALA284GLU andSER289LEU mutations in FVIII were produced by transfection of COS-1 monkey cells. Compared to FVIII wild-type both mutants had reduced specific activity by 1-stage clotting activity and at least a 2-fold lower activity by 2-stage analysis (COAMATIC), similar to the reported clinical data. Analysis of immunoaffinity purified ALA284GLU andSER289LEU proteins in an optical biosensor demonstrated that A2 dissociation was 3-fold faster for both FVIIIa mutants compared to FVIIIa wild-type. Therefore, these mutations within the A1 subunit of FVIIIa introduce a similar destabilization of the FVIIIa heterotrimer compared to the ARG531HISmutation within the A2 subunit and support that these residues stabilize the A domain interface of FVIIIa.

Genetics and Hemostatic Potential in Persons with Mild to Moderate Hemophilia A with a Discrepancy between One-Stage and Chromogenic FVIII Assays

2020 ◽  
Author(s):  
Annelie Strålfors ◽  
Danijela Mikovic ◽  
David Schmidt ◽  
Liselotte Onelöv ◽  
Nida Mahmoud Hourani Soutari ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Genetic Alterations ◽  
Plasma Samples ◽  
Background Factor ◽  
Novel Mutations ◽  
Endogenous Thrombin Potential ◽  
One Stage ◽  
Fviii Activity ◽  
A Domains

Abstract Background Factor VIII (FVIII) activity (FVIII:C) can be measured by different methods including one-stage clotting assays (OSAs) and chromogenic assays (CSAs). Discrepancy between FVIII:C assays is known and associated with genetic variations causing mild and moderate hemophilia A (HA). We aimed to study the discrepancy phenomenon and to identify associated genetic alterations. Further, we investigated if hemostatic global assays could discriminate the group with discrepant FVIII:C from them. Methods The study contained plasma samples from 45 patients with HA (PwHA) from Hemophilia Centers in Stockholm, Sweden, and Belgrade, Serbia. We measured FVIII:C with OSA and CSA, sequenced the F8 gene, and performed two global hemostatic assays; endogenous thrombin potential and overall hemostatic potential. Results Nineteen of 45 PwHA had a more than twofold higher FVIII:C using OSA compared to CSA and were considered discrepant. Thirty-four causal mutations were detected, where of five had not previously been associated with assay discrepancy. These novel mutations were p.Tyr25Cys, p.Phe698Leu, p.Met699Leu, p.Ile1698Thr, and Ala2070Val. We found no difference between discrepant and nondiscrepant cases with either of the global assays. Conclusion There was a discrepancy between FVIII:C assays in almost half of the PwHA, which for some could lead to missed HA diagnoses or misclassification of severity. Genotyping confirmed that mutations associated with FVIII:C discrepancy cluster in the A domains of F8, and five mutations not previously associated with FVIII:C discrepancy was identified. Global hemostatic assays did not contribute to distinguish assay discrepancy in PwHA.

Comparative Investigations on Factor VIII Assays

1975 ◽  
Author(s):  
R. Pflugshaupt ◽  
S. Moser ◽  
K. Züger ◽  
R. Bütler
Keyword(s):  
Factor Viii ◽  
High Activity ◽  
Hemophilia A ◽  
Statistical Evaluation ◽  
Two Stage ◽  
One Stage ◽  
Normal Plasma ◽  
Calibration Curves ◽  
Factor Viii Concentrates

Six one stage methods and one two stage method were tested for precision and reproducibility. With each method twenty calibration curves of normal plasma and two lots of Factor VIII concentrates were established. Statistical evaluation revealed only minor differences. Neither one of the methods was optimal for both the physiological-pathological region and the region of high activity preparations.Three selected methods were tested in vivo for accuracy: nine patients with hemophilia A were treated with equal amounts of Factor VIII concentrates or kryoprecipitates respectively. The methods showed different activities for preparations as well as for patient’s plasma. The discrepancy between measured and expected recovery differed for each method.

Mild Hemophilia A Caused by Increased Rate of Factor VIII A2 Subunit Dissociation: Evidence for Nonproteolytic Inactivation of Factor VIIIa In Vivo

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 176-183 ◽  
Author(s):  
S.W. Pipe ◽  
A.N. Eickhorst ◽  
S.H. McKinley ◽  
E.L. Saenko ◽  
R.J. Kaufman
Keyword(s):  
Factor Viii ◽  
Missense Mutation ◽  
Time Course ◽  
Hemophilia A ◽  
Specific Activity ◽  
Metabolic Labeling ◽  
Two Stage ◽  
One Stage ◽  
Thrombin Cleavage

Abstract Approximately 5% of hemophilia A patients have normal amounts of a dysfunctional factor VIII (FVIII) protein and are termed cross-reacting material (CRM)-positive. FVIII is a heterodimer (domain structure A1-A2-B/A3-C1-C2) that requires thrombin cleavage to elicit procoagulant activity. Thrombin-activated FVIII is a heterotrimer with the A2 subunit (amino acid residues 373 to 740) in a weak ionic interaction with the A1 and A3-C1-C2 subunits. Dissociation of the A2 subunit correlates with inactivation of FVIII. Recently, a phenotype of CRM-positive hemophilia A patients has been characterized whose plasma displays a discrepancy between their FVIII activities, where the one-stage clotting assay displays greater activity than the two-stage clotting assay. One example is a missense mutation whereARG531 has been substituted by HIS531. An FVIII cDNA construct was prepared containing theARG531HIS mutation and the protein was expressed in COS-1 monkey cells by transient DNA transfection. Metabolic labeling with [35S]-methionine demonstrated that ARG531HIS was synthesized at an equal rate compared with FVIII wild-type (WT) but had slightly reduced antigen in the conditioned medium, suggesting a modest secretion defect. A time course of structural cleavage of ARG531HISdemonstrated identical thrombin cleavage sites and rates of proteolysis as FVIII WT. Similar to the patient phenotypes,ARG531HIS had discrepant activity as measured by a one-stage activated partial thromboplastin time (aPTT) clotting assay (36% ± 9.6% of FVIII WT) and a variation of the two-stage assay using a chromogenic substrate (COAMATIC; 19% ± 6.9% of FVIII WT). Partially purified FVIII WT and ARG531HISproteins were subjected to functional activation by incubation with thrombin. ARG531HIS demonstrated significantly reduced peak activity and was completely inactivated after 30 seconds, whereas FVIII WT retained activity until 2.5 minutes after activation. Because the ARG531HIS missense mutation predicts a charge change to the A2 subunit, we hypothesized that theARG531HIS A2 subunit could be subject to more rapid dissociation from the heterotrimer. The rate of A2 dissociation, using an optical biosensor, was determined to be fourfold faster forARG531HIS compared with FVIII WT. Because the two-stage assay involves a preincubation phase before assay measurement, an increased rate of A2 dissociation would result in an increased rate of inactivation and reduced specific activity.

N1922S Mutation In the Factor VIII A3 Domain Produces a Rate-Limiting, Domain-Specific Folding Defect Leading to Hyposecretion of a Functional Protein

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2209-2209
Author(s):  
Ryan J. Summers ◽  
Shannon L. Meeks ◽  
John F. Healey ◽  
Harrison C. Brown ◽  
Ernest T Parker ◽  
...  
Keyword(s):  
Factor Viii ◽  
Intracellular Trafficking ◽  
Hemophilia A ◽  
Activity Level ◽  
Reactive Material ◽  
Domain Specific ◽  
One Stage ◽  
Fviii Activity ◽  
Coagulation Assay ◽  
Specific Activities

Abstract Abstract 2209 Factor VIII (fVIII) contains a domain sequence designated A1-A2-B-ap-A3-C1-C2. Mutation of Asn1922 to Ser (N1922S) in the A3 domain results in moderate to severe hemophilia A. However, it is unclear whether this mutation leads to secretion of cross-reactive material positive dysfunctional protein or decreased secretion of fVIII protein. We investigated the fVIII activity and antigen levels in a N1922S patient and found an activity level of 1.7% and an antigen of <4 ng/ml suggesting a secretion defect. To investigate this further, we constructed a B-domain deleted human fVIII cDNA encoding this mutation, designated N1922S fVIII, and compared its heterologous expression to non-mutated “wild-type” fVIII (wt-fVIII) in a baby hamster kidney-derived cell line. Levels of fVIII expression in cell culture media measured by antigen-capture ELISA were 0.011 and 0.73 mg/ml for N1922S fVIII and wt-fVIII, respectively. The corresponding media levels of fVIII activity measured by one-stage coagulation assay were 0.03 and 3.5 U/ml for N1922S fVIII and wt-fVIII, respectively. These values correspond to specific activities of 2800 and 4800 U/mg for N1922S fVIII and wt-fVIII, respectively. Consistent with this, both N1922S fVIII and wt-fVIII were over twenty-fold activatable by thrombin in the one-stage coagulation assay. These comparable coagulant activities of N1922S fVIII and wt-fVIII indicate that the N1922S mutation produces a kinetic block in the synthesis of a functionally normal fVIII protein. In contrast to media levels of fVIII, in-cell Western analysis revealed that intracellular levels of N1922S fVIII were similar to wt-fVIII. However, specific activities of N1922S fVIII and wt-fVIII in cell lysates were 290 and 6800 U/mg, respectively, indicating the presence of large amounts of a non-functional N1922S fVIII folding intermediate. Immunofluorescence microscopy demonstrated co-localization of wt-fVIII with both endoplasmic reticulum (ER)- and Golgi-resident proteins. In contrast, N1922S fVIII co-localized only with ER-resident proteins, indicating a kinetic block in intracellular trafficking between the ER and the Golgi. To investigate further whether the defect in N1922S fVIII trafficking was related to protein misfolding, we compared lysate-to-media antigenic ratios of N1922S fVIII and wt-fVIII using a panel of non-overlapping monoclonal antibodies (MAbs) consisting of one anti-A1, one anti-A2, three anti-A3, one anti-C1 and two anti-C2 MAbs. Lysate-to-media antigenic ratios for the anti-A1, anti-A2 and anti-C2 MAbs were similar between N1922S fVIII and wt-fVIII. In contrast, lysate-to-media ratios of the three anti-A3 MAbs and the anti-C1 MAb were markedly decreased for N1922S fVIII compared to wt-fVIII. This result indicates that the A1, A2 and C2 domains in N1922S fVIII fold independently into antigenically intact tertiary structures, but that folding is stalled in mutant A3 domain and its contiguous C1 domain. Because Asn1922 is buried in the interface of the two cupredoxin-like A3 subdomains in the two available X-ray structures of fVIII (Shen BW et al. Blood 2008;111:1240-1247; Ngo JC, et al. Structure 2008;16:597-606), the kinetic defect associated with this mutation may be due to slow association of intact A3 subdomains. This domain-specific defect in protein folding and intracellular trafficking is a novel mechanism for secretion defects leading to hemophilia A. Disclosures: No relevant conflicts of interest to declare.

Mild Hemophilia A Caused by Increased Rate of Factor VIII A2 Subunit Dissociation: Evidence for Nonproteolytic Inactivation of Factor VIIIa In Vivo

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 176-183 ◽  
Author(s):  
S.W. Pipe ◽  
A.N. Eickhorst ◽  
S.H. McKinley ◽  
E.L. Saenko ◽  
R.J. Kaufman
Keyword(s):  
Factor Viii ◽  
Missense Mutation ◽  
Time Course ◽  
Hemophilia A ◽  
Specific Activity ◽  
Metabolic Labeling ◽  
Two Stage ◽  
One Stage ◽  
Thrombin Cleavage

Approximately 5% of hemophilia A patients have normal amounts of a dysfunctional factor VIII (FVIII) protein and are termed cross-reacting material (CRM)-positive. FVIII is a heterodimer (domain structure A1-A2-B/A3-C1-C2) that requires thrombin cleavage to elicit procoagulant activity. Thrombin-activated FVIII is a heterotrimer with the A2 subunit (amino acid residues 373 to 740) in a weak ionic interaction with the A1 and A3-C1-C2 subunits. Dissociation of the A2 subunit correlates with inactivation of FVIII. Recently, a phenotype of CRM-positive hemophilia A patients has been characterized whose plasma displays a discrepancy between their FVIII activities, where the one-stage clotting assay displays greater activity than the two-stage clotting assay. One example is a missense mutation whereARG531 has been substituted by HIS531. An FVIII cDNA construct was prepared containing theARG531HIS mutation and the protein was expressed in COS-1 monkey cells by transient DNA transfection. Metabolic labeling with [35S]-methionine demonstrated that ARG531HIS was synthesized at an equal rate compared with FVIII wild-type (WT) but had slightly reduced antigen in the conditioned medium, suggesting a modest secretion defect. A time course of structural cleavage of ARG531HISdemonstrated identical thrombin cleavage sites and rates of proteolysis as FVIII WT. Similar to the patient phenotypes,ARG531HIS had discrepant activity as measured by a one-stage activated partial thromboplastin time (aPTT) clotting assay (36% ± 9.6% of FVIII WT) and a variation of the two-stage assay using a chromogenic substrate (COAMATIC; 19% ± 6.9% of FVIII WT). Partially purified FVIII WT and ARG531HISproteins were subjected to functional activation by incubation with thrombin. ARG531HIS demonstrated significantly reduced peak activity and was completely inactivated after 30 seconds, whereas FVIII WT retained activity until 2.5 minutes after activation. Because the ARG531HIS missense mutation predicts a charge change to the A2 subunit, we hypothesized that theARG531HIS A2 subunit could be subject to more rapid dissociation from the heterotrimer. The rate of A2 dissociation, using an optical biosensor, was determined to be fourfold faster forARG531HIS compared with FVIII WT. Because the two-stage assay involves a preincubation phase before assay measurement, an increased rate of A2 dissociation would result in an increased rate of inactivation and reduced specific activity.

Thrombin Potentiation of Factor VIII Procoagulant Activity: Assessment by the Two-Stage Assay

1982 ◽  
Vol 47 (02) ◽  
pp. 145-149 ◽  
Author(s):  
Robert G Kopitsky ◽  
Mary Ellen P Switzer ◽  
Patrick A McKee
Keyword(s):  
Factor Viii ◽  
Procoagulant Activity ◽  
Two Stage ◽  
Clotting System ◽  
One Stage ◽  
Fviii Activity ◽  
Thrombin Activation ◽  
The One ◽  
Dose Response Effect ◽  
Von Willebrand

SummaryFactor VIII (FVIII) procoagulant activity is the function of a plasma glycoprotein that is missing or inactive in patients with classic hemophilia. Numerous studies have shown that trace thrombin causes rapid enhancement followed by gradual inactivation of FVIII procoagulant activity. Recent evidence suggests that thrombin activation of the FVIII/von Willebrand factor (vWF) protein is required for inactivation to occur. All of these studies have used the one-stage partial thromboplastin time to assay FVIII activity. Other investigators have used the two-stage assay of FVIII activity and have been unable to demonstrate thrombin-induced enhancement of FVIII activity, although inactivation has consistently occurred. We performed experiments designed to help resolve this disagreement, using the two-stage assay specifically modified to detect thrombin potentiation of FVIII activity. The length of the first-stage incubation time was found to be critical in demonstrating the initial effect of thrombin on FVIII activity. Taking advantage of this finding we were able to show a 4.1 ± 0.5-fold enhancement of FVIII activity upon incubating purified FVin/vWF with 0.04 NIH unit thrombin per ml. The apparent enhancement of FVEQ activity declined with increasing thrombin concentration. Incubation with 0.08, 0.16, and 0.32 NIH unit thrombin per ml resulted in only 3.2 ± 0.5, 2.6 ± 0.5 and 1.5 ± 0.3-fold enhancement, respectively, of FVIII activity. As with results from the one-stage assay, activation was followed by slow inactivation of FVIH/vWF. Using the two-stage assay we also showed 100% inactivation and 100% inhibition of FVIII activity by plasmin and human anti-FVUI IgG, respectively. Plasmin inactivation of FVIII activity showed a dose-response effect. Thrombin was unable to activate plasmin-degraded FVin/vWF. Our results show that thrombin potentiation of FVni activity is easily demonstrable in the two-stage assay. These findings support the contention that activation of FVm activity by thrombin is prerequisite for inactivation and underscore the importance of thrombin activation of FVHI/vWF in the intrinsic clotting system.

Discrepancy between one-stage and chromogenic factor VIII activity assay results can lead to misdiagnosis of haemophilia A phenotype

2010 ◽  
Vol 30 (04) ◽  
pp. 207-211 ◽  
Author(s):  
A. Pavlova ◽  
J. Oldenburg
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Significant Proportion ◽  
Haemophilia A ◽  
Missense Mutations ◽  
One Stage ◽  
Chromogenic Assay ◽  
Fviii Activity ◽  
Mechanistic Basis

SummarySeverity of bleeding phenotype in hemophilia A (HA) depends on the underlying mutation in the F8 gene and, ultimately, on the concentration and functional integrity of the factor VIII (FVIII) protein in circulating plasma. Initial diagnosis for HA and monitoring of treatment is typically performed by measuring of FVIII activity by either one-stage assay or chromogenic assay.We review evidence for why both types of assay do not give comparable results in a significant proportion of patients with non-severe haemophilia A and why the discrepancy in results between both methods segregates with distinct subclasses of known missense mutations causing haemophilia A. The current understanding of the mechanistic basis for how FVIII:C assay discrepancies arise are discussed.We propose that both methods should be used in initial patient diagnosis along with follow-up genetic analysis to avoid potential misdiagnosis and to optimize treatment monitoring of patients with HA phenotypes.

scholarly journals Factor VIII Level Comparison in Patients with Severe Hemophilia a on Emicizumab with Inhibitors with One Stage, Bovine and Human Chromogenic Assays and the Factor VIII Equivalency of Emicizumab Using In Vivo Global Hemostasis Assays

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4234-4234
Author(s):  
Hande Kizilocak ◽  
Elizabeth Marquez-Casas ◽  
Joshua Brown ◽  
Jemily Malvar ◽  
Guy Young
Keyword(s):  
Factor Viii ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
Activated Partial Thromboplastin Time ◽  
Clotting Factor ◽  
Normal Range ◽  
One Stage ◽  
Chromogenic Assay ◽  
Coagulation Defect ◽  
Fviii Activity

Abstract Introduction Emicizumab is a recombinant, humanized bispecific monoclonal antibody that mimics the function of factor VIII (FVIII) which results in a significant reduction in the annualized bleeding rate in patients with hemophilia A (HA), however, the degree with which emicizumab corrects the coagulation defect remains unclear. The objective of this study was to compare the current available laboratory methods in clinical practice; one-stage clotting factor assays (OSCA), bovine and human chromogenic FVIII activity (bovCHR and humCHR, respectively) and FVIII Equivalency of Emicizumab by Thrombin Generation (F8EmT). Aims The aim of this study is to address the differences of FVIII activity with different techniques in patients with severe HA with inhibitors on emicizumab. Materials and Methods Factor VIII levels are determined with an activated partial thromboplastin time (aPTT), OSCA using SynthASil on the ACL TOP 500 (Instrumentation Laboratory, Bedford, MA). Factor VIII activity is also determined photometrically via the Chromogenix Coatest® SP4 FVIII chromogenic assay kit (bovCHR, Diapharma Group, West Chester, OH) and the Biophen FVIII:C chromogenic assay kit (humCHR, Aniara Diagnostica, West Chester, OH). For F8EmT, linear regression was utilized to model the FVIII levels as a function of the endogenous thrombin potential (ETP) and peak thrombin values for patients with mild/moderate hemophilia. Then, we used the ETP and peak thrombin results of the severe HA patients on emicizumab with the calibration curve to calculate their F8EmT. Association between patient weight and their F8EmT were also examined and evaluated by linear regression. Results Data is presented for eight patients with severe HA with inhibitors on emicizumab in the non-bleeding state (Table-1). All patients' FVIII levels measured with OSCA are in or above the normal range (94.0-289.1). Bovine chromogenic FVIII activity is in the severe hemophilia range for five out of eight patients, for the rest it is in the moderate hemophilia range. Human chromogenic FVIII activity ranged between 12.5-49.8%. Factor VIII Equivalency of Emicizumab by Thrombin Generation is either in the mild hemophilia or normal range in all participants of the study. Conclusion One-stage clotting factor assays demonstrated falsely high results as expected since it is activated partial thromboplastin time based. Bovine chromogenic FVIII activity results were consistent with the severe HA range of the patients though a few had results slightly above that level. Previous literature has stated that the humCHR in patients on emicizumab results in FVIII levels of ∼30% when emicizumab is at its therapeutic concentration (∼50 mcg/ml). This study also demonstrated similar results with 5/8 patients having levels 30-50%. F8EMT levels were mostly consistent with the humCHR. In conclusion, understanding the degree to which emicizumab corrects the coagulation defect of is an important goal as it has clinical implications.Certainly, additional studies with higher participant numbers are needed to confirm these findings. Figure 1 Figure 1. Disclosures Young: Apcintex, BioMarin, Genentech/Roche, Grifols, Novo Nordisk, Pfizer, Rani, Sanofi Genzyme, Spark, Takeda, and UniQure: Consultancy; Genentech/Roche, Grifols, and Takeda: Research Funding.

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