Pharmacodynamics Monitoring of Emicizumab in Patients with Hemophilia A.

BACKGROUND: Emicizumab is a bispecific antibody mimicking coagulation factor VIII (FVIII) employed to treat patients with hemophilia A (PwHA) regardless of FVIII inhibitor status. The identification of biological markers reflecting the hemostatic competence of patients under emicizumab therapy would have a great clinical value. Unfortunately, emicizumab over-corrects standard coagulation assays, precluding their use for evaluating the hemostatic correction achieved in vivo. Here, we investigated whether global coagulation assays (GCA) would allow monitoring the biological response to non-factor replacement therapy with emicizumab. MATERIALS AND METHODS: Six adults PwHA received a weekly dose of emicizumab of 3 mg/kg during weeks (W) 1 4 and 1.5 mg/kg from W5 onwards. Response to treatment was monitored weekly by emicizumab plasma concentration, thrombin generation (TG), and fibrin clot formation (FCF) and structure. TG and FCF results were compared to patient baseline, FVIII replacement, and healthy donors. RESULTS: TG and FCF significantly increased in PwHA after the loading period, reaching a plateau that lasted until the end of monitoring. Similarly, fibrin clot network became denser with thinner fibrin fibers. However, TG contrary to FCF remained at the lower limits of reference values. Remarkably, despite having similar plateau concentrations of emicizumab some patients showed markedly different degrees of TG and FCF improvement. CONCLUSION: Our study enriches the knowledge on the use of GCA to monitor non-factor replacement therapy, indicating that TG and FCF could act as direct markers of emicizumab biological activity. GCA allow to capture and visualize the individually variable response to emicizumab, leading a step forward to the personalization of patient treatment.

Preliminary study of the fibrin structure in hypertensive, dyslipidemic and type 2 diabetic patients

Individuals with hypertension, dyslipidemia or diabetes are at a higher risk to suffer cardiovascular disease than other people; while impaired fibrin structure/function may contribute to further raise the cardiovascular risk in the former. The purpose of this work was to study the fibrin network and fibrin degradation properties in hypertensive (HT) patients, pharmacologically treated, 124 ± 11 mmHg, systolic blood pressure, and 70 ± 10 mmHg, diastolic blood pressure, n = 12; metabolic dyslipidemic patients (DL), cholesterol: 5.7 ± 1.5 mmol/L, n = 10; patients with type 2 diabetes mellitus (T2D), fasting plasma glucose: 8.8 ± 2.2 mmol/L, n = 10; and a control group of healthy individuals, n = 9. The fibrinogen concentration was determined by the gravimetric method. Fibrin network formation and porosity were assessed by turbidity and permeation techniques, respectively; fibrin elastic properties were evaluated by compaction and fibrin lysis, by turbidity after addition of external tPA prior to plasma clotting. Fibrinogen concentration was significantly higher only in T2D patients (p = 0.004), compared to the control group. The fibrin polymerization and lysis processes were similar for all patient and control groups. Permeation was significantly slower in DL and T2D patients, p = 0.022 and 0.0002, respectively, whereas the compaction coefficient was significantly smaller in T2D patients, p = 0.0015. Our results suggest that the fibrin structure was altered in DL and T2D patients, probably due to the increased cholesterol and glycation, respectively.

Individuos hipertensos, con dislipidemia o diabetes tipo 2 tienen un mayor riesgo de sufrir enfermedades cardiovasculares, y la alteración en la estructura/función de la malla de fibrina aumenta su riesgo. El propósito del presente trabajo fue estudiar la estructura de la malla de fibrina y su degradación en pacientes hipertensos (HT), tratados farmacológicamente, con una presión arterial sistólica de 124 ± 11 mmHg y una presión arterial diastólica de 70 ± 10 mmHg, n = 12; pacientes con dislipidemia metabólica (DL), colesterol 5,7 ± 1,5 mmoles/L, n = 10; pacientes con diabetes mellitus tipo 2 (DT2), glicemia en ayunas: 8,8 ± 2,2 mmoles/L, n = 10; y un grupo control de individuos sanos, n = 9. Se determinó la concentración de fibrinógeno por el método de la pesada. La formación de la malla de fibrina y su porosidad fue estudiada mediante las técnicas de turbidimetría y permeabilidad, respectivamente; las propiedades elásticas por compactación y la degradación de la fibrina por turbidimetría, añadiendo externamente el activador tisular del plasminógeno (tPA) antes de la coagulación del plasma. Se encontró que la concentración de fibrinógeno fue significativamente mayor solamente en los pacientes DT2 (p = 0,004), en comparación con el grupo control. El proceso de polimerización y degradación de la fibrina de los pacientes fue similar a la del grupo control. La permeabilidad estuvo disminuída significativamente en los pacientes DL y DT2, p = 0,022 and 0,0002, respectivamente, mientras que la compactación fue significativamente mayor solamente en los pacientes DT2, p=0,0015. Nuestros resultados sugieren que la estructura de la malla de fibrina estuvo alterada en los pacientes DL y DT2, probablemente debido al aumento en los valores de colesterol y glicemia, respectivamente.

Preliminary study of the fibrin structure in hypertensive, dyslipidemic and type 2 diabetic patients.

Individuals with hypertension, dyslipidemia or diabetes are at a higher risk to suffer cardiovascular disease than other people; while impaired fibrin structure/function may contribute to further raise the cardiovascular risk in the former. The purpose of this work was to study the fibrin network and fibrin degradation properties in hypertensive (HT) patients, pharmacologically treated, 124 +/- 11 mmHg, systolic blood pressure, and 70 +/- 10 mmHg, diastolic blood pressure, n = 12; metabolic dyslipidemic patients (DL), cholesterol: 5.7 +/- 1.5 mmol/L, n = 10; patients with type 2 diabetes mellitus (T2D), fasting plasma glucose: 8.8 +/- 2.2 mmol/L, n = 10; and a control group of healthy individuals, n = 9. The fibrinogen concentration was determined by the gravimetric method. Fibrin network formation and porosity were assessed by turbidity and permeation techniques, respectively; fibrin elastic properties were evaluated by compaction and fibrin lysis, by turbidity after addition of external tPA prior to plasma clotting. Fibrinogen concentration was significantly higher only in T2D patients (p = 0.004), compared to the control group. The fibrin polymerization and lysis processes were similar for all patient and control groups. Permeation was significantly slower in DL and T2D patients, p = 0.022 and 0.0002, respectively, whereas the compaction coefficient was significantly smaller in T2D patients, p = 0.0015. Our results suggest that the fibrin structure was altered in DL and T2D patients, probably due to the increased cholesterol and glycation, respectively.