Patient-Specific Modelling of Blood Coagulation.

Blood coagulation represents one of the most studied processes in biomedical modelling. However, clinical applications of this modelling remain limited because of the complexity of this process and because of large inter-patient variation of the concentrations of blood factors, kinetic constants and physiological conditions. Determination of some of these patients-specific parameters is experimentally possible, but it would be related to excessive time and material costs impossible in clinical practice. We propose in this work a methodological approach to patient-specific modelling of blood coagulation. It begins with conventional thrombin generation tests allowing the determination of parameters of a reduced kinetic model. Next, this model is used to study spatial distributions of blood factors and blood coagulation in flow, and to evaluate the results of medical treatment of blood coagulation disorders.

Clustering of Thrombin Generation Test Data Using a Reduced Mathematical Model of Blood Coagulation.

Correct interpretation of the data from integral laboratory tests, including Thrombin Generation Test (TGT), requires biochemistry-based mathematical models of blood coagulation. The purpose of this study is to describe the experimental TGT data from healthy donors and hemophilia A (HA) and B (HB) patients. We derive a simplified ODE model and apply it to analyze the TGT data from healthy donors and HA/HB patients with in vitro added tissue factor pathway inhibitor (TFPI) antibody. This model allows the characterization of hemophilia patients in the space of three most important model parameters. The proposed approach may provide a new quantitative tool for the analysis of experimental TGT. Also, it gives a reduced model of coagulation verified against clinical data to be used in future theoretical large-scale modeling of thrombosis in flow.

[Population pharmacokinetics of two recombinant human coagulation factor â § preparations in patients with hemophilia A].

Objective: To compare the differences in population pharmacokinetic (PK) parameters between two recombinant coagulation factor Ⅷ (FⅧ) preparations, Kogenate FS and Advate, in patients with hemophilia A, and to provide the theoretical basis of precise individualized treatment for those patients. Methods: Patients with moderate or severe hemophilia A who had at least one injection of Kogenate FS or Advate at 41 international hemophilia centers were enrolled as subjects from the WAPPS-Hemo project since January 2015 to December 2017. The half-lives of the two drugs and the time of FⅧ activity reaching 2% (TAT 2%) were calculated, and the differences of PK between the two drugs among different age and dose subgroups were further analyzed. Results: ①The mean age of patients in the Kogenate FS (n=117) and Advate groups (n=120) were (27.6±17.7) and (23.4±16.2) years old, respectively. All patients in the two groups were males. ②The administration doses in the Kogenate FS and Advate groups were (31.5±13.1) IU/kg and (38.17±14.83) IU/kg, respectively; the half-lives of the two drugs were (12.3±3.5) h and (10.8±2.9) h, respectively; and the TAT 2% were (65.2±21.7) h and (57.0±17.9) h, respectively. ③In the Kogenate FS group, the drug half-lives in patients aged ≥12 and <12 years old were (12.7±3.7) h and (11.1±2.5) h, respectively; the TAT 2% were (68.6±22.9) h and (55.8±14.6) h, respectively. In the Advate group, the drug half-lives in patients aged ≥12 and <12 years old were (11.4±3.1) h and (9.4±1.8) h, respectively; and the TAT 2% were (61.1±18.0) h and (45.2±11.3) h, respectively. ④In the Kogenate FS group, the drug half-lives in <20 IU/kg, (20-29) IU/kg, (30-39) IU/kg and ≥40 IU/kg groups were (13.3±4.0) h, (12.3±3.6) h, (12.2±3.5) h and (11.6±2.6) h, respectively; and the TAT 2% were (61.5±21.4) h, (63.9±22.4) h, (67.0±24.3) h and (68.0±19.5) h, respectively. In the Advate group, the drug half-lives in <20 IU/kg, (20-29) IU/kg, (30-39) IU/kg and <40 IU/kg groups were (11.5±3.8) h, (11.4±3.7) h, (11.0±2.9) h and (10.4±2.3) h, respectively; and the TAT 2% were (50.8±19.2) h, (56.7±21.0) h, (58.2±18.8) h and (58.1±15.8) h, respectively. Conclusion: The PK parameters of Kogenate FS are superior to those of Advate among different age and dose subgroups.

The effect of unmeasurable endogenous plasma factor activity levels on factor VIII dosing in patients with severe hemophilia A.

BACKGROUND: Patients with hemophilia A are defined as "severe" if they present <0.01 IU mL-1 of clotting factor VIII (FVIII) activity endogenously (i.e. in absence of FVIII concentrate administration). However, an exact measurement of baseline FVIII is often impossible in such patients as the lower limit of quantification for most FVIII assays is around 0.01 IU mL-1, forcing assumptions to be made regarding endogenous circulating level. OBJECTIVE: This work aims to assess the consequences of different assumptions when selecting a prophylaxis regimen for the treatment of hemophilia A using a pharmacokinetics (PK)-driven approach. METHODS: Using a validated population PK model for conventional FVIII, we simulated the dose and frequency required to maintain various target troughs as a function of different postulated baseline levels. RESULTS: Patients with a true baseline of 0 IU mL-1 would require an additional 40 IU kg-1 to achieve any target trough below 0.05 IU mL-1, as compared to those with a true baseline close to 0.01 IU mL-1. When tailoring individual treatment regimens using a PK-based approach, baseline assumptions were highly influential and the assumption producing the most conservative dosing regimen was not consistent; rather, it depended on the particular scenario (e.g. increase vs. decrease of an observed trough). CONCLUSIONS: Targeting a trough close to the assay sensitivity creates a unique problem in forecasting the dose needed for optimal treatment of hemophilia that, while still without solution, deserves consideration when making dosing decisions.

Prediction of individual factor VIII or IX level for the correction of thrombin generation in haemophilic patients.

BACKGROUND: The thrombin generation (TG) assay can assess individual clotting potential. The thrombin generation potential is correlated with the patient's bleeding phenotype and varies from one patient to the other for the same degree of factor VIII or IX deficiency. OBJECTIVE: To define in vitro for individual haemophilic patients the target factor VIII or IX level required to normalize their TG. PATIENTS/METHODS: Plasmas from 20 haemophilic patients were spiked with increasing levels of the deficient coagulation factor and TG parameters were measured. The relationships between factor levels and TG parameters were determined by linear regression. The normal range of thrombin generation was defined in 39 healthy male volunteers. RESULTS: Despite inter-individual heterogeneity in basal TG and responses to spiking, a linear relationship was found between factor VIII or IX levels and TG parameters for individual patients. Based on the individual responses of patient plasmas to spiking, it is possible to define in vitro the target factor VIII or IX levels needed to normalize the TG parameters. For both haemophilic A and haemophilic B patients, significant correlations were found between basal peak values and their correction slopes. The correction slope was steeper in haemophilic B patients, so the factor IX level needed to normalize the TG parameters was lower than for haemophilic A patients. CONCLUSIONS: The TG assay could be used to determine in vitro the patient-specific factor VIII or IX level to be reached to effectively normalize their TG. These in vitro results should be confirmed by ex-vivo studies.

Bridge to dentistry: one dental school's approach to improving its enrollment of underrepresented minorities.

Presently, 25.7% of the U.S. population is comprised of Blacks/African Americans, Hispanics, and Native Americans. The dental school enrollment of underrepresented minorities (URM) does not reflect this demographic distribution. In 1994, URM students comprised 12.68% of enrolled dental students, but in 1999, enrollment decreased to 10.53%. This trend is evident at Baylor College of Dentistry (BCD). Bridge to Dentistry involves formal linkages with local school districts, Texas colleges and universities, community organizations, dental clinics, community dentists, and BCD. The program is unique in that it targets students from kindergarten through dental school. The key components are awareness, attraction, preliminary education, facilitated-entry, admissions, financial aid, and retention. Some important features of the program are visits to area schools, visits to colleges and universities, summer enrichment programs, and academic advising. Preliminary results indicate the effectiveness of the program. BCD has increased its enrollment of URM students 325% over that of 1998. In 1998, 4.7% of the college's first-year student enrollment was URMs. In 2001, 14.6% of Baylor's first-year student enrollment was URMs. Since 1995, BCD has retained 90.6% of its URM students.