scholarly journals Sensitivity analysis of a reduced model of thrombosis under flow: Roles of Factor IX, Factor XI, and γ‘-Fibrin

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0260366
Author(s):  
Jason Chen ◽  
Scott L. Diamond
Keyword(s):  
Sensitivity Analysis ◽  
Binding Sites ◽  
Hemophilia A ◽  
Factor Ix ◽  
Reduced Model ◽  
Percent Reduction ◽  
Extrinsic Pathway ◽  
Normal Ranges ◽  
The Mean ◽  
Rate Limiting

A highly reduced extrinsic pathway coagulation model (8 ODEs) under flow considered a thin 15-micron platelet layer where transport limitations were largely negligible (except for fibrinogen) and where cofactors (FVIIa, FV, FVIII) were not rate-limiting. By including thrombin feedback activation of FXI and the antithrombin-I activities of fibrin, the model accurately simulated measured fibrin formation and thrombin fluxes. Using this reduced model, we conducted 10,000 Monte Carlo (MC) simulations for ±50% variation of 5 plasma zymogens and 2 fibrin binding sites for thrombin. A sensitivity analysis of zymogen concentrations indicated that FIX activity most influenced thrombin generation, a result expected from hemophilia A and B. Averaging all MC simulations confirmed both the mean and standard deviation of measured fibrin generation on 1 tissue factor (TF) molecule per μm2. Across all simulations, free thrombin in the layer ranged from 20 to 300 nM (mean: 50 nM). The top 2% of simulations that produced maximal fibrin were dominated by conditions with low antithrombin-I activity (decreased weak and strong sites) and high FIX concentration. In contrast, the bottom 2% of simulations that produced minimal fibrin were dominated by low FIX and FX. The percent reduction of fibrin by an ideal FXIa inhibitor (FXI = 0) ranged from 71% fibrin reduction in the top 2% of MC simulations to only 34% fibrin reduction in the bottom 2% of MC simulations. Thus, the antithrombotic potency of FXIa inhibitors may vary depending on normal ranges of zymogen concentrations. This reduced model allowed efficient multivariable sensitivity analysis.

Aptamer ARC19499 mediates a procoagulant hemostatic effect by inhibiting tissue factor pathway inhibitor

Blood ◽  
2011 ◽  
Vol 117 (20) ◽  
pp. 5514-5522 ◽  
Author(s):  
Emily K. Waters ◽  
Ryan M. Genga ◽  
Michael C. Schwartz ◽  
Jennifer A. Nelson ◽  
Robert G. Schaub ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Tissue Factor Pathway Inhibitor ◽  
Hemophilia A ◽  
Factor Viia ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Factor Ix ◽  
Intrinsic Pathway ◽  
Extrinsic Pathway ◽  
Tissue Factor Pathway

Abstract Hemophilia A and B are caused by deficiencies in coagulation factor VIII (FVIII) and factor IX, respectively, resulting in deficient blood coagulation via the intrinsic pathway. The extrinsic coagulation pathway, mediated by factor VIIa and tissue factor (TF), remains intact but is negatively regulated by tissue factor pathway inhibitor (TFPI), which inhibits both factor VIIa and its product, factor Xa. This inhibition limits clot initiation via the extrinsic pathway, whereas factor deficiency in hemophilia limits clot propagation via the intrinsic pathway. ARC19499 is an aptamer that inhibits TFPI, thereby enabling clot initiation and propagation via the extrinsic pathway. The core aptamer binds tightly and specifically to TFPI. ARC19499 blocks TFPI inhibition of both factor Xa and the TF/factor VIIa complex. ARC19499 corrects thrombin generation in hemophilia A and B plasma and restores clotting in FVIII-neutralized whole blood. In the present study, using a monkey model of hemophilia, FVIII neutralization resulted in prolonged clotting times as measured by thromboelastography and prolonged saphenous-vein bleeding times, which are consistent with FVIII deficiency. ARC19499 restored thromboelastography clotting times to baseline levels and corrected bleeding times. These results demonstrate that ARC19499 inhibition of TFPI may be an effective alternative to current treatments of bleeding associated with hemophilia.

Is the Detection of Factor IX Inhibitors in Hemophilia B Orphan than Factor VIII Inhibitors in Hemophilia A? A Concise, Systematic Review

2020 ◽  
Vol 20 (3) ◽  
pp. 185-190
Author(s):  
Hassan Mansouritorghabeh ◽  
Seyedeh T. Mohades
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Factor Ix ◽  
Hemophilia B ◽  
World Federation ◽  
Health Provider ◽  
Comprehensive Review ◽  
Significant Challenge ◽  
The World ◽  
The Mean

Objective: Development of inhibitors in hemophilia A and B comprise significant challenge for patients, hematologists, and health provider systems. It has recommended by the World Federation of Hemophilia (WFH) to check inhibitors every 3-4 months. The incidence of inhibitor in hemophilia B is lower than hemophilia A. Here, it tried to unravel whether the detection of inhibitors in hemophilia B neglected compared to hemophilia A or not? Methods: A comprehensive review carried out using six international and local medical search engines on published contributions about inhibitors in hemophilia A and B in Iran. Results: From 699 titles, 12 relevant papers were selected. The mean of factor VIII inhibitors in hemophilia A was 14.8%. The mean of factor IX inhibitors in hemophilia B was 6%. The minimum and maximum reported percentages of factor VIII inhibitors were 4% and 19.6%, while the minimum and maximum of reported percentages of factor IX inhibitors were 0% and 11.8%, respectively. The inhibitors in hemophilia A had reported in 6 papers. One paper had covered the inhibitors in hemophilia B. There were five papers on inhibitors in both hemophilia A and B. The comparison between the reported patients showed that 3020 patients with hemophilia A and 314 patients with hemophilia B had studied. Conclusion: Consistent with the lower frequency of hemophilia B and the lower development of inhibitors in hemophilia B compared to hemophilia A, it was concluded that hemophilia B had not neglected in Iran. It seems to be rational that each country, check rates of detection of inhibitors in hemophilia B to identify whether it has neglected or not.

scholarly journals Immunologic status of hemophilia patients treated with cryoprecipitate or lyophilized concentrate

Blood ◽  
1984 ◽  
Vol 64 (3) ◽  
pp. 715-720
Author(s):  
GF Gjerset ◽  
PJ Martin ◽  
RB Counts ◽  
LD Fast ◽  
JA Hansen
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Absolute Number ◽  
Factor Ix ◽  
Clotting Factor ◽  
Lymphocyte Function ◽  
Laboratory Evidence ◽  
Group I ◽  
The Mean

We evaluated 37 patients with moderate or severe hemophilia A and six patients with severe factor IX deficiency for clinical or laboratory evidence of immune abnormalities. Patients were assigned to one of four groups according to the type of clotting factor replacement. Twenty patients had received only cryoprecipitate during the two years preceding the evaluation (group I); 11 additional patients were treated predominantly with cryoprecipitate but had also received up to nine bottles of factor VIII concentrate (group II); six patients received factor VIII concentrate (group III); six patients received factor IX concentrate (group IV). There was no clinical or laboratory evidence of immunodeficiency among the 43 patients. The mean absolute number of Th cells was normal in all patient groups, but the mean absolute number of Ts cells was increased compared with controls, both in patients treated with cryoprecipitate and in patients treated with factor VIII or factor IX concentrate. There was no correlation between the Th/Ts ratio and patient age, alanine aminotransferase level, hepatitis serology, in vitro lymphocyte function, or amount of clotting factor administered. Our observations demonstrate that the volunteer or commercial origin of clotting factor replacement cannot fully explain the alterations in lymphocyte subset distribution previously described in patients with hemophilia A.

scholarly journals Immunologic status of hemophilia patients treated with cryoprecipitate or lyophilized concentrate

Blood ◽  
1984 ◽  
Vol 64 (3) ◽  
pp. 715-720 ◽  
Author(s):  
GF Gjerset ◽  
PJ Martin ◽  
RB Counts ◽  
LD Fast ◽  
JA Hansen
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Absolute Number ◽  
Factor Ix ◽  
Clotting Factor ◽  
Lymphocyte Function ◽  
Laboratory Evidence ◽  
Group I ◽  
The Mean

Abstract We evaluated 37 patients with moderate or severe hemophilia A and six patients with severe factor IX deficiency for clinical or laboratory evidence of immune abnormalities. Patients were assigned to one of four groups according to the type of clotting factor replacement. Twenty patients had received only cryoprecipitate during the two years preceding the evaluation (group I); 11 additional patients were treated predominantly with cryoprecipitate but had also received up to nine bottles of factor VIII concentrate (group II); six patients received factor VIII concentrate (group III); six patients received factor IX concentrate (group IV). There was no clinical or laboratory evidence of immunodeficiency among the 43 patients. The mean absolute number of Th cells was normal in all patient groups, but the mean absolute number of Ts cells was increased compared with controls, both in patients treated with cryoprecipitate and in patients treated with factor VIII or factor IX concentrate. There was no correlation between the Th/Ts ratio and patient age, alanine aminotransferase level, hepatitis serology, in vitro lymphocyte function, or amount of clotting factor administered. Our observations demonstrate that the volunteer or commercial origin of clotting factor replacement cannot fully explain the alterations in lymphocyte subset distribution previously described in patients with hemophilia A.

scholarly journals Evaluation of Factor Viii and Factor IX Activity among Primary School Children in Owerri, Imo State, Nigeria

2021 ◽  
pp. 235-241
Author(s):  
I. L. Okoroiwu ◽  
Emmanuel Ifeanyi Obeagu ◽  
Lilian Nneka Egbuobi ◽  
Adaobi Maryann Ibekwe ◽  
C. C. N. Vincent ◽  
...  
Keyword(s):  
Primary School ◽  
Factor Viii ◽  
School Children ◽  
Primary Schools ◽  
Factor Ix ◽  
Primary School Children ◽  
Imo State ◽  
Normal Ranges ◽  
Viii And Ix ◽  
The Mean

The values of factor VIII (FVIII) and factor IX (FIX) were evaluated among some primary school children in Owerri zone Imo State. The aim was to assess deficiency state or reduction in activity among these children. A total of two hundred and ten (210) venous blood samples were collected from primary school pupils whose parents consented to, and whose answers to the distributed questionnaires suggested symptoms of haemophilia. The samples were collected from pupils between the ages of five and thirteen years, and from different primary schools to represent different areas of Owerri (Works Layout Area, Nekede Area, Trans Egbu Area, and Akwukuma Area). Samples were preserved using trisodium citrate anticoagulant and transported to the haematology unit of the Federal Medical Centre Owerri within 3 hours for analysis which was done using Rayto semi auto coagulation analyzer RT 2204C with its normal ranges for factor VIII and IX activities as (50% - 200% and 70% - 200%) respectively. Out of the 210 samples collected, 16(7.6%) have <50% of factor VIII activity and 14(6.7%) have <70% of factor IX activity. Akwakuma area produced highest occurrence of factor VIII deficiency (14.8%, 8 pupils) while Works Layout and Trans Egbu Areas produced the least incidence (3.8%, 2 pupils) each. Factor IX deficiency was most prevalent at Trans Egbu Area 6(11.5%) and least at Works Layout 0(0.0%). Six children between the ages of 5 and 7 years had the highest incidence of FVIII deficiency (23.1%), while eight pupils between the ages of 11-13 years showed the highest incidence of FIX deficiency. Eight Females were found to have the highest incidence of both  FVIII and FIX deficiencies (8.2% for both defects ), while the males presented a lower incidence of the same defects (7.1%, 8 pupils and 5.4%, 6 pupils respectively). The mean levels of FVIII and FIX in all the pupils evaluated are 78.61 and 89.98 respectively while the standard deviation of the results from the mean are 2.584 and 1.473 for factor VIII and IX respectively. These data show that haemophilia A and B exist in Owerri and considering the danger it portends to lives of the citizenry, Government should provide facilities in our hospitals to take care of the affected pupils to ensure a healthy society.

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.

A Survey of the Effectiveness of Prothrombin Complex Concentrates in Controlling Hemorrhage in Patients with Hemophilia and Anti-Factor VIII Antibodies

1980 ◽  
Vol 44 (01) ◽  
pp. 039-042 ◽  
Author(s):  
Philip M Blatt ◽  
Doris Ménaché ◽  
Harold R Roberts
Keyword(s):  
Factor Viii ◽  
Ad Hoc ◽  
Hemophilia A ◽  
Working Party ◽  
International Committee ◽  
Factor Ix ◽  
Prothrombin Complex Concentrates ◽  
Factor Viii Concentrates

SummaryThe treatment of patients with hemophilia A and anti-Factor VIII antibodies is difficult. Between July 1977 and June 1978, a survey was carried out by an ad hoc working party of the subcommittee on Factor IX concentrates of the International Committee on Thrombosis and Hemostasis to assess the effectiveness of Prothrombin Complex Concentrates in controlling hemorrhage in these patients. The results are presented in this paper and, although subjective, support the view that these concentrates are not as effective in patients with inhibitors as Factor VIII concentrates are in patients without inhibitors.

scholarly journals Addition of Flucytosine to Fluconazole for the Treatment of Cryptococcal Meningitis in Africa: A Multicountry Cost-effectiveness Analysis

2019 ◽  
Vol 70 (1) ◽  
pp. 26-29 ◽  
Author(s):  
Tinevimbo Shiri ◽  
Angela Loyse ◽  
Lawrence Mwenge ◽  
Tao Chen ◽  
Shabir Lakhi ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Cost Effectiveness ◽  
Cryptococcal Meningitis ◽  
Cost Effective ◽  
Immunodeficiency Virus ◽  
The Mean ◽  
The Cost ◽  
The Impact ◽  
Costing Analysis ◽  
Very High

Abstract Background Mortality from cryptococcal meningitis remains very high in Africa. In the Advancing Cryptococcal Meningitis Treatment for Africa (ACTA) trial, 2 weeks of fluconazole (FLU) plus flucytosine (5FC) was as effective and less costly than 2 weeks of amphotericin-based regimens. However, many African settings treat with FLU monotherapy, and the cost-effectiveness of adding 5FC to FLU is uncertain. Methods The effectiveness and costs of FLU+5FC were taken from ACTA, which included a costing analysis at the Zambian site. The effectiveness of FLU was derived from cohorts of consecutively enrolled patients, managed in respects other than drug therapy, as were participants in ACTA. FLU costs were derived from costs of FLU+5FC in ACTA, by subtracting 5FC drug and monitoring costs. The cost-effectiveness of FLU+5FC vs FLU alone was measured as the incremental cost-effectiveness ratio (ICER). A probabilistic sensitivity analysis assessed uncertainties and a bivariate deterministic sensitivity analysis examined the impact of varying mortality and 5FC drug costs on the ICER. Results The mean costs per patient were US $847 (95% confidence interval [CI] $776–927) for FLU+5FC, and US $628 (95% CI $557–709) for FLU. The 10-week mortality rate was 35.1% (95% CI 28.9–41.7%) with FLU+5FC and 53.8% (95% CI 43.1–64.1%) with FLU. At the current 5FC price of US $1.30 per 500 mg tablet, the ICER of 5FC+FLU versus FLU alone was US $65 (95% CI $28–208) per life-year saved. Reducing the 5FC cost to between US $0.80 and US $0.40 per 500 mg resulted in an ICER between US $44 and US $28 per life-year saved. Conclusions The addition of 5FC to FLU is cost-effective for cryptococcal meningitis treatment in Africa and, if made available widely, could substantially reduce mortality rates among human immunodeficiency virus–infected persons in Africa.

scholarly journals Cost of coils for intracranial aneurysms: clinical decision analysis for implementation of a capitation model

2018 ◽  
Vol 128 (6) ◽  
pp. 1792-1798 ◽  
Author(s):  
Gurpreet S. Gandhoke ◽  
Yash K. Pandya ◽  
Ashutosh P. Jadhav ◽  
Tudor Jovin ◽  
Robert M. Friedlander ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Probabilistic Sensitivity Analysis ◽  
Cost Savings ◽  
Clinical Decision ◽  
Sensitivity Analyses ◽  
List Price ◽  
Maximum Dimension ◽  
Total Length ◽  
The Mean ◽  
Mean Cost

OBJECTIVEThe price of coils used for intracranial aneurysm embolization has continued to rise despite an increase in competition in the marketplace. Coils on the US market range in list price from $500 to $3000. The purpose of this study was to investigate potential cost savings with the use of a price capitation model.METHODSThe authors built a clinical decision analytical tree and compared their institution’s current expenditure on endovascular coils to the costs if a capped-price model were implemented. They retrospectively reviewed coil and cost data for 148 patients who underwent coil embolization from January 2015 through September 2016. Data on the length and number of coils used in all patients were collected and analyzed. The probabilities of a treated aneurysm being ≤/> 10 mm in maximum dimension, the total number of coils used for a case being ≤/> 5, and the total length of coils used for a case being ≤/> 50 cm were calculated, as was the mean cost of the currently used coils for all possible combinations of events with these probabilities. Using the same probabilities, the authors calculated the expected value of the capped-price strategy in comparison with the current one. They also conducted multiple 1-way sensitivity analyses by applying plausible ranges to the probabilities and cost variables. The robustness of the results was confirmed by applying individual distributions to all studied variables and conducting probabilistic sensitivity analysis.RESULTSNinety-five (64%) of 148 patients presented with a rupture, and 53 (36%) were treated on an elective basis. The mean aneurysm size was 6.7 mm. A total of 1061 coils were used from a total of 4 different providers. Companies A (72%) and B (16%) accounted for the major share of coil consumption. The mean number of coils per case was 7.3. The mean cost per case (for all coils) was $10,434. The median total length of coils used, for all coils, was 42 cm. The calculated probability of treating an aneurysm less than 10 mm in maximum dimension was 0.83, for using 5 coils or fewer per case it was 0.42, and for coil length of 50 cm or less it was 0.89. The expected cost per case with the capped policy was calculated to be $4000, a cost savings of $6564 in comparison with using the price of Company A. Multiple 1-way sensitivity analyses revealed that the capped policy was cost saving if its cost was less than $10,500. In probabilistic sensitivity analyses, the lowest cost difference between current and capped policies was $2750.CONCLUSIONSIn comparison with the cost of coils from the authors’ current provider, their decision model and probabilistic sensitivity analysis predicted a minimum $407,000 to a maximum $1,799,976 cost savings in 148 cases by adapting the capped-price policy for coils.

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