Coated-Platelet Levels May Explain Some Variability in Clinical Phenotype of Severe Hemophilia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1018-1018 ◽  
Author(s):  
Kapil Saxena ◽  
Kalpana Pethe ◽  
George L. Dale
Keyword(s):  
Factor Viii ◽  
Clinical Phenotype ◽  
Factor V ◽  
Healthy Controls ◽  
Severe Hemophilia ◽  
High Concentration ◽  
Co Activation ◽  
Bleeding Episodes ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Objective: To determine if variability in clinical phenotype of severe hemophilia patients is influenced by the percentage of coated-platelets. Background: Co-activation of platelets with thrombin and collagen results in a unique subset of platelets, with high levels of alpha granule proteins on their surface, such as Factor V, fibrinogen, von Willebrand factor, and thrombospondin. This subset of activated platelets is referred to as coated-platelets (J. Thromb. Haemostasis3:2185, 2005). The high concentration of adhesive and prohemostatic proteins observed on coated-platelets provides a unique procoagulant locus that may influence the number of bleeding episodes in patients with severe hemophilia. Methods: After informed consent, 3–5 ml of blood was drawn from patients with severe hemophilia (Factor VIII <1%) and healthy controls. The number of bleeding episodes reported in the last 6 months was taken as an indicator of clinical phenotype. Results: In 6 patients with more than 3 bleeds reported in the last 6 months (14 ± 4.9 bleeds; mean ± 1SD), the average coated-platelets percentage was 22.3 ± 11.2%. In 17 patients with 3 or less bleeds (1.6 ± 1.3) in the last 6 months, the average coated-platelets percentage was 37.6 ± 12.0%, a difference that was statistically significant (p=0.012). In healthy controls (n=12), the mean coated-platelets were 30.2 ± 9.5%. Conclusion: A higher percentage of coated-platelets may provide a better procoagulant locus for residual Factor VIII, thereby reducing the number of clinical bleeding episodes and partially explaining some variability observed in clinical phenotype of severe hemophilia.

scholarly journals BIVV001, a new class of factor VIII replacement for hemophilia A that is independent of von Willebrand factor in primates and mice

Blood ◽  
2020 ◽  
Vol 135 (17) ◽  
pp. 1484-1496 ◽  
Author(s):  
Ekta Seth Chhabra ◽  
Tongyao Liu ◽  
John Kulman ◽  
Susannah Patarroyo-White ◽  
Buyue Yang ◽  
...  
Keyword(s):  
Protein Engineering ◽  
Factor Viii ◽  
Von Willebrand Factor ◽  
Half Life ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
New Class ◽  
Pharmacokinetic Properties ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Factor VIII (FVIII) replacement products enable comprehensive care in hemophilia A. Treatment goals in severe hemophilia A are expanding beyond low annualized bleed rates to include long-term outcomes associated with high sustained FVIII levels. Endogenous von Willebrand factor (VWF) stabilizes and protects FVIII from degradation and clearance, but it also subjects FVIII to a half-life ceiling of ∼15 to 19 hours. Increasing recombinant FVIII (rFVIII) half-life further is ultimately dependent upon uncoupling rFVIII from endogenous VWF. We have developed a new class of FVIII replacement, rFVIIIFc-VWF-XTEN (BIVV001), that is physically decoupled from endogenous VWF and has enhanced pharmacokinetic properties compared with all previous FVIII products. BIVV001 was bioengineered as a unique fusion protein consisting of a VWF-DʹD3 domain fused to rFVIII via immunoglobulin-G1 Fc domains and 2 XTEN polypeptides (Amunix Pharmaceuticals, Inc, Mountain View, CA). Plasma FVIII half-life after BIVV001 administration in mice and monkeys was 25 to 31 hours and 33 to 34 hours, respectively, representing a three- to fourfold increase in FVIII half-life. Our results showed that multifaceted protein engineering, far beyond a few amino acid substitutions, could significantly improve rFVIII pharmacokinetic properties while maintaining hemostatic function. BIVV001 is the first rFVIII with the potential to significantly change the treatment paradigm for severe hemophilia A by providing optimal protection against all bleed types, with less frequent doses. The protein engineering methods described herein can also be applied to other complex proteins.

The Effect of Aquaporin 2 Gene Variations on Plasma Levels of von Willebrand Factor and Factor VIII and on the Risk of Venous Thrombosis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1749-1749
Author(s):  
Anne Yael Nossent ◽  
Johanne H. Ellenbroek ◽  
Marijke Frolich ◽  
Frits R. Rosendaal ◽  
Rogier M. Bertina ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Venous Thrombosis ◽  
Factor Viii ◽  
Von Willebrand Factor ◽  
Healthy Controls ◽  
Aquaporin 2 ◽  
Arterial Blood ◽  
Aqp2 Gene ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract High levels of von Willebrand factor (VWF) and factor VIII (FVIII) are a risk factor for thrombosis. Determinants of high VWF and FVIII levels are poorly understood. Secretion of VWF from endothelial storage pools is regulated by vasopressin type-2 receptor (V2R). Previously, we have shown that a V2R variant, which has increased binding affinity for its ligand vasopressin (AVP), is associated with increased levels of VWF and FVIII1. Nephrogenic Diabetes Insipidus (NDI) is a disorder characterized by renal insensitivity to AVP, caused by mutations in the genes encoding V2R or the aquaporin 2 water channel (AQP2). AQP2 expression is enhanced by stimulation of V2R. Patients with NDI are unable to concentrate their pre-urine. We hypothesized that carriers of AQP2 mutations compensate excess fluid loss by up-regulating AVP release and V2R expression, resulting in increased VWF and FVIII secretion. To test this hypothesis, we set up the Factor Eight in Nephrogenic Diabetus Insipidus study (FENDI), which includes 13 NDI families: 14 NDI patients (12 V2R- and 2 AQP2-linked), 14 carriers (9 V2R- and 5 AQP2-linked) and 25 unaffected family members, as well as 48 unrelated healthy individuals. In addition, we looked at effects of common AQP2 gene variations in a case-control study on venous thrombosis, the Leiden Thrombophilia Study (LETS), which consists of 474 patients with a first deep vein thrombosis and 474 healthy controls, sex and age matched to the patients. In the FENDI, no differences were observed between NDI patients, carriers and unaffected individuals in markers for fluid homeostasis such as hematocrite, serum osmolality and blood pressure. AVP reached detectable levels in all carriers of AQP2 mutations, compared to 27% and 56% in unrelated and related unaffected individuals, respectively. AVP levels, were, when detectable, elevated in all patients and carriers. VWF propeptide, a measure of the VWF secretion rate, VWF antigen and FVIII activity were also highest in carriers of AQP2 mutations. In the LETS, we sequenced a 6.6 kb long genomic region around the AQP2 gene in 25 selected individuals. We identified 18 single nucleotide polymorphisms (SNPs), of which 16 were genotyped in the entire LETS. Although reliable haplotypes could not be formed, due to recombination, the SNPs were linked within 5 clusters. In three of these clusters, up to 2.5-fold increases in thrombosis risk were observed. In these same clusters we observed associations of the AQP2 SNPs with arterial blood pressure. However, none of the AQP2 SNPs were associated with VWF or FVIII levels in healthy controls of the LETS. In conclusion, increased AVP levels in carriers of NDI-causing AQP2 mutations appear associated with increased VWF secretion. Furthermore, in the LETS, common AQP2 gene variations are associated with the risk of venous thrombosis.

The Role of Factor VIII C Domains in Sorting to Weibel-Palade Bodies

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2241-2241
Author(s):  
Eveline Bouwens ◽  
Maartje van den Biggelaar ◽  
Jan Voorberg ◽  
Koen Mertens
Keyword(s):  
Endothelial Cells ◽  
Factor Viii ◽  
Conflicts Of Interest ◽  
Factor V ◽  
C2 Domain ◽  
Structural Elements ◽  
Sorting Efficiency ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Abstract 2241 Recent studies have shown that factor VIII (FVIII) expressed in endothelial cells sorts with von Willebrand factor (VWF) to secretory Weibel-Palade bodies (WPBs). The sorting mechanism remains controversial although VWF is thought to be essential. However, mutations that lead to impaired FVIII-VWF complex assembly do not reduce the sorting efficiency of FVIII. As factor V (FV) and FVIII are highly homologous in structure, we addressed the possibility that FV sorts to WPBs as well. Our study was designed to identify domains in FVIII that are needed for sorting to WPBs by means of domain deletions and FVIII-FV domain exchange. As the C domains of FVIII contain membrane and VWF binding sites, we particularly focused on comparing the C domains of FVIII and FV. Blood outgrowth endothelial cells (BOECs) were transduced with lentiviral vectors encoding FV, FVIII deletion mutants, or FVIII-FV chimeras. We found by confocal microscopy and subcellular fractionations that FV displays a strong reduction in sorting efficiency (2% sorting efficiency) compared to FVIII (20% sorting efficiency). This indicates that sorting to WPBs is mediated by FVIII-specific structural elements. As the C domains of FVIII are implicated in membrane and VWF binding, these domains could drive sorting to WPBs. Therefore, we constructed FVIII variants lacking C domains to establish their role in WPB sorting. Quantitative determination of the sorting efficiencies demonstrates that the C1 domain is not of major importance for sorting to WPBs (10% sorting efficiency), whereas the C2 domain is (not detectable in WPB fractions). Moreover, exchanging the FVIII C domains for corresponding domains of FV also suggests that the C2 domain drives WPB sorting (3% sorting efficiency). This leads to the conclusion that FVIII sorting to WPBs is driven by FVIII-specific structural elements in both C domains, but in particular the C2 domain. Disclosures: No relevant conflicts of interest to declare.

Effect of the Factor V Leiden Mutation on the Clinical Expression of Severe Hemophilia A

2000 ◽  
Vol 83 (03) ◽  
pp. 387-391 ◽  
Author(s):  
I.R. Walker ◽  
J. Teitel ◽  
M.-C. Poon ◽  
B. Ritchie ◽  
J. Akabutu ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Geometric Mean ◽  
Factor V Leiden ◽  
Significant Variable ◽  
Factor V ◽  
Severe Hemophilia ◽  
Factor V Leiden Mutation ◽  
Bleeding Episodes ◽  
Factor Concentrate

SummaryTo determine whether the factor V Leiden mutation is associated with decreased bleeding in individuals with severe hemophilia A, factor concentrate utilization, maximum annual number of bleeding episodes, and the prevalence of hemophilic arthropathy between carriers and non-carriers of the factor V Leiden mutation were compared. Heterozygosity for the factor V Leiden mutation was found in 6 of 137 subjects (4.4%). Carriers of the factor V Leiden mutation utilized less factor concentrate (geometric mean: 310 vs. 1185 units/kg/year) and had fewer bleeding episodes than non-carriers (proportion with 10 or fewer bleeding episodes in their worst year: 50 vs. 11%). However, the factor V Leiden mutation was not associated with the absence of arthropathy. The intron 22 inversion mutation of the factor VIII gene was tested for in a subgroup of 80 subjects, but it was not found to be a significant variable for any of the bleeding endpoints. The results of this small study are consistent with the hypothesis that the factor V Leiden mutation imparts a protective effect; however, a larger confirmatory study in which the factor VIII molecular defects can be controlled for is needed. Furthermore, most severe hemophiliacs who used fewer than 200 units/kg/year of factor concentrate or who had experienced 10 or fewer bleeding episodes per year did not carry the factor V Leiden mutation, suggesting that the proportion of severe hemophiliacs whose mild clinical course can be attributed to the factor V Leiden mutation is small.

Treatment of von Willebrand disease with a high-purity factor VIII/von Willebrand factor concentrate: a prospective, multicenter study

Blood ◽  
2002 ◽  
Vol 99 (2) ◽  
pp. 450-456 ◽  
Author(s):  
Pier M. Mannucci ◽  
Juan Chediak ◽  
Wahid Hanna ◽  
John Byrnes ◽  
Marlies Ledford ◽  
...  
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
High Purity ◽  
Bleeding Time ◽  
Von Willebrand Disease ◽  
Invasive Procedures ◽  
Bleeding Episodes ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Among patients with von Willebrand disease (VWD) who are unresponsive to desmopressin therapy, replacement with plasma-derived concentrates is the treatment of choice. Because prospective studies are lacking, such treatment has been largely empirical. A multicenter, prospective study has been conducted in 81 patients with VWD (15 patients with type 1, 34 with type 2, and 32 with type 3 disease) to investigate the efficacy of a high-purity factor VIII/von Willebrand factor (FVIII/VWF) concentrate for treatment of bleeding and surgical prophylaxis. Two preparations of the concentrate—one virally inactivated with solvent detergent, the other with an additional heat-treatment step—were evaluated. Pharmacokinetic parameters were similar for both preparations. Using pre-established dosages based on the results of pharmacokinetic studies, 53 patients were administered either preparation for the treatment of 87 bleeding episodes, and 39 patients were treated prophylactically for 71 surgical or invasive procedures. Sixty-five (74.7%) and 10 (11.5%) of the bleeding episodes were controlled with 1 or 2 infusions, respectively. Patients with severe type 3 VWD typically required more infusions and higher doses, at shorter time intervals, than did patients with generally milder types 1 and 2. Among patients undergoing surgical procedures, blood loss was lower than that predicted prospectively, and losses exceeding the predicted value did not correlate with the postinfusion skin bleeding time. In conclusion, the concentrate effectively stopped active bleeding and provided adequate hemostasis for surgical or invasive procedures, even in the absence of bleeding time correction.

scholarly journals Normal cleavage of von Willebrand factor by ADAMTS-13 in the absence of factor VIII in patients with severe hemophilia A

2013 ◽  
Vol 11 (9) ◽  
pp. 1769-1772 ◽  
Author(s):  
J. Chen ◽  
D. W. Chung ◽  
J. Le ◽  
M. Ling ◽  
B. A. Konkle ◽  
...  
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Von Willebrand ◽  
Willebrand Factor

Normal Cleavage of Von Willebrand Factor by ADAMTS13 In the Absence of Factor VIII In Patients with Severe Hemophilia A

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2114-2114
Author(s):  
Junmei Chen ◽  
Dominic W. Chung ◽  
Jennie Le ◽  
Barbara A. Konkle ◽  
José A. López
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Adamts13 Activity ◽  
Severe Hemophilia ◽  
Post Infusion ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Abstract 2114 The size of von Willebrand factor (VWF), a carrier protein for factor VIII (FVIII), is regulated by plasma metalloprotease ADAMTS13 proteolytic activity. Recently studies by Cao et al. (PNAS, 2008; 105: 7416–7421) found that under shear stress, exogenous FVIII enhanced ADAMTS13 cleavage of VWF, especially the high molecular weight multimers, in a system using purified proteins. Based on this result, the authors suggested that in the absence of FVIII, such as in patients with severe hemophilia A, VWF will have ultra-large multimers due to defects in ADAMTS13 proteolytic process, which can be corrected by infusion of FVIII. Here, we assessed VWF multimers, antigen, and ADAMTS13 activity in citrated plasma from seven patients with severe hemophilia A. The FVIII levels in six patients were less than 1% and in one was 4%. Plasma from two patients was available both pre- and post-FVIII replacement therapy (recombinant FVIII). All patients displayed VWF multimer patterns similar to those in pooled normal plasma (PNP), and the two patients receiving FVIII infusions displayed no change in VWF multimer size or pattern between their pre- and post-infusion samples. In all patients, the VWF antigen level (0.32–0.76) was below the PNP value (designated as 1), and all had increased ADAMTS13 activity (measured by the ability of plasma to cleave a small A2 peptide substrate) (1.09–1.79, PNP designated as 1), yielding an increased ratio of ADAMTS13 activity to VWF antigen in these patients (1.4–5.2 compared to PNP). We also examined cleavage of endogenous VWF by ADAMTS13 in the plasmas of the two patients studied pre- and post-infusion, yielding different FVIII levels. In this assay, we first diluted plasma 10-fold with a buffer containing 10 mM HEPES, 6.5 mM BaCl2, and 1.5 M urea, incubated at 37°C, and ADAMTS13 cleavage was stopped at different time points with EDTA. VWF multimer patterns were examined on a 1.5% agarose gel. We found that ADAMTS13 cleaved VWF efficiently in patient plasma deficient in FVIII, similar to that in PNP. The extent of cleavage was correlated with the ratio of ADAMTS13 activity to VWF antigen, rather than with the FVIII levels. In conclusion, patients with severe hemophilia A appear to have normal ADAMTS13 processing of VWF multimers in vivo and ex vivo. Further studies of the effect of FVIII and VWF levels on ADAMTS13 cleavage of VWF and clinical correlation are needed. Disclosures: No relevant conflicts of interest to declare.

Von Willebrand factor-containing factor VIII concentrates and inhibitors in haemophilia A

2010 ◽  
Vol 104 (11) ◽  
pp. 931-940 ◽  
Author(s):  
Giuseppe Lippi ◽  
Massimo Franchini
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Immune Tolerance ◽  
High Titer ◽  
Tolerance Induction ◽  
Haemophilia A ◽  
Immune Tolerance Induction ◽  
Bleeding Episodes ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryThe development of inhibitors that neutralise the function of factor VIII (FVIII) is currently not only the most challenging complication associated with the treatment of haemophilia A but it also increases the disease-related morbidity as bleeding episodes do not respond to standard therapy. The main short-term goal of the treatment of inhibitor patients is to control bleeding episodes while the long-term one is to permanently eradicate the inhibitor by immune tolerance induction, particularly in the case of high-titer antibodies. Due to some in vitro studies and clinical observations, some investigators have suggested that FVIII concentrates containing von Willebrand factor (VWF) may be less immunogenic than high-purity or recombinant FVIII products. It has also been suggested that success rates for immune tolerance induction are higher when plasma-derived FVIII products are used. The currently available data from laboratory and clinical studies on the role of VWF in inhibitor development and eradication in haemophilia A is critically analysed in this review. As a result, we have not found definitive evidence supporting a role for product type on inhibitor incidence and inhibitor eradication in haemophilia A patients.

Safety and Efficacy of Continuous Infusion of a Combined Factor VIII – von Willebrand Factor (vWF) Concentrate (Haemate-P™) in Patients with von Willebrand Disease

1999 ◽  
Vol 81 (02) ◽  
pp. 229-233 ◽  
Author(s):  
Aharon Lubetsky ◽  
Sam Schulman ◽  
David Varon ◽  
Uri Martinowitz ◽  
Gili Kenet ◽  
...  
Keyword(s):  
Factor Viii ◽  
Continuous Infusion ◽  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Safety And Efficacy ◽  
Intermittent Bolus ◽  
Surgical Bleeding ◽  
Bleeding Episodes ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryWe studied the safety and efficacy of treatment with continuous infusion of a von Willebrand factor (vWF) concentrate Haemate-P in patients with von Willebrand disease (vWD). Three patients with mild and 5 patients with severe forms of vWD, were treated with continuous infusion of Haemate-P by minipump. The indications for treatment were: to prevent bleeding during 9 surgical procedures or 1 vaginal delivery in 6 patients and to treat 2 bleeding episodes in 2 patients. The patients were monitored daily for factor VIII (FVIII:C) and ristocetin cofactor (vWF:RCo) levels and the infusion rate was adjusted to maintain the desired therapeutic level of vWF:RCo. The treatment was effective in preventing surgical bleeding and controlling bleeding episodes. All factor VIII:C and most of the vWF:RCo levels measured during the study period were above the target therapeutic levels. A significant decrease in clearance of FVIII:C and vWF:RCo was observed over the treatment period. Haemate-P consumption averaged 24.3 ± 7.9 vWF:RCo U/kg/day which is approximately half the expected dose had intermittent bolus injections been used. We suggest that continuous Haemate-P infusion is superior to intermittent bolus injections for the treatment of vWD patients by virtue of its efficiency, simplicity and considerable savings.

Treatment of Von Willebrand Disease

2001 ◽  
Vol 86 (07) ◽  
pp. 149-153 ◽  
Author(s):  
Pier Mannuccio Mannucci
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Spontaneous Bleeding ◽  
Primary Hemostasis ◽  
Bleeding Prophylaxis ◽  
Bleeding Episodes ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryIn von Willebrand disease, there are two main options for the treatment of spontaneous bleeding episodes and for bleeding prophylaxis: desmopressin and transfusional therapy with plasma products. Desmopressin is the treatment of choice for most patients with type 1, who account for approximately 70 to 80 per cent of all cases with the disease. This non-transfusional hemostatic agent raises endogenous factor VIII and von Willebrand factor three- to fivefold and thereby transiently corrects both the intrinsic coagulation and primary hemostasis defects. In patients with the more severe type 3 and in the majority of those with type 2 desmopressin is not effective or is contraindicated, so that it is usually necessary to resort to plasma concentrates containing factor VIII and von Willebrand factor. Concentrates treated with virus inactivation methods should be preferred to cryoprecipitate because they are equally effective and perceived as safer.

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