Peri-operative desmopressin combined with pharmacokinetic-guided factor VIII concentrate in non-severe haemophilia A patients

Introduction: Non-severe haemophilia A patient can be treated with desmopressin or factor VIII (FVIII) concentrate. Combining both may reduce factor consumption, but its feasibility and safety has never been investigated. Aim: We assessed the feasibility and safety of combination treatment in nonsevere haemophilia A patients. Methods: Non-severe, desmopressin responsive, haemophilia A patients were included in one of two studies investigating peri-operative combination treatment. In the single-arm DAVID study intravenous desmopressin (0.3 μg/kg) once-a-day was, after sampling, immediately followed by PK-guided FVIII concentrate, for maximally three consecutive days. The Little DAVID study was a randomized trial in patients undergoing a minor medical procedure, whom received either PK-guided combination treatment (intervention arm) or PK-guided FVIII concentrate only (standard arm) up to 2 days. Dose predictions were considered accurate if the absolute difference between predicted and measured FVIII:C was ≤0.2 IU/mL. Results: In total 32 patients (33 procedures) were included. In the DAVID study (n = 21), of the FVIII:C trough levels 73.7% (14/19) were predicted accurately on day 1 (D1), 76.5% (13/17) on D2. On D0, 61.9% (13/21) of peak FVIII:C levels predictions were accurate. In the Little DAVID study (n = 12), on D0 83.3% (5/6) FVIII:C peak levels for both study arms were predicted accurately. Combination treatment reduced preoperative FVIII concentrate use by 47% versus FVIII monotherapy. Desmopressin side effects were mild and transient. Two bleeds occurred, both despite FVIII:C &gt; 1.00 IU/mL. Conclusion: Peri-operative combination treatment with desmopressin and PK-guided FVIII concentrate dosing in nonsevere haemophilia A is feasible, safe and reduces FVIII consumption.</p

Fibrinolysis in patients with chemotherapy-induced thrombocytopenia and the effect of platelet transfusion

EssentialsBleeding in chemotherapy induced thrombocytopenia (CIT) might be influenced by hyperfibrinolysis. t-PA-thromboelastography is a fast and reliable assay for hyperfibrinolysis in CIT patients. Clots of CIT patients are more susceptible to t-PA induced lysis compared to healthy individuals. Besides platelets, other factors are likely to influence clot lysis in CIT patients. Background Bleeding events in chemotherapy-induced thrombocytopenic (CIT) patients with similar platelet counts might be influenced by changes in clot lysis potential. Objectives To investigate, in an observational study, thromboelastographic lysis parameters, alterations in clot strength and susceptibility to clot lysis in CIT patients. To identify factors associated with fibrinolytic profiles, and to evaluate the effects of platelet transfusions. Methods Independent determinants of tissue-type plasminogen activator (t-PA)-ROTEM lysis parameters were identified with multivariable linear regression. Clot formation, strength and lysis parameters were compared with the results of healthy individuals. Characteristics of CIT patients with and without hyperfibrinolytic profiles were compared. t-PA-ROTEM results before, 1 hour after and 24 hours after platelet transfusion were compared. Results A total of 72 consecutive CIT patients were included. t-PA-ROTEM lysis parameters correlated with changes in fibrinolytic proteins. Clot formation time was longer, maximum clot firmness was weaker and lysis times were shorter than in healthy individuals. CIT patients had low plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor levels, and 40% showed hyperfibrinolytic profiles. Platelet transfusions resulted in less hyperfibrinolytic profiles in many, but not all CIT patients. Patients without hyperfibrinolytic profiles had higher fibrinogen, factor VIII and alpha(2)-antiplasmin levels. Conclusions t-PA-ROTEM can be used as a fast and reliable assay to detect hyperfibrinolytic profiles in CIT patients. CIT patients have weaker clots, which are more susceptible to clot lysis, than healthy individuals. Besides platelets, other factors are likely to influence clot susceptibility to fibrinolysis in CIT patients. The impact of a hyperfibrinolytic t-PA-ROTEM profile on bleeding remains to be investigated.</p

Donor fecal microbiota transplantation ameliorates intestinal graft-versus-host disease in allogeneic hematopoietic cell transplant recipients.

Disruption of the intestinal microbiota occurs frequently in allogeneic hematopoietic cell transplantation (allo-HCT) recipients and predisposes them to development of graft-versus-host disease (GvHD). In a prospective, single-center, single-arm study, we investigated the effect of donor fecal microbiota transplantation (FMT) on symptoms of steroid-refractory or steroid-dependent, acute or late-onset acute intestinal GvHD in 15 individuals who had undergone allo-HCT. Study participants received a fecal suspension from an unrelated healthy donor via nasoduodenal infusion. Donor FMT was well tolerated, and infection-related adverse events did not seem to be related to the FMT procedure. In 10 of 15 study participants, a complete clinical response was observed within 1 month after FMT, without additional interventions to alleviate GvHD symptoms. This response was accompanied by an increase in gut microbial α-diversity, a partial engraftment of donor bacterial species, and increased abundance of butyrate-producing bacteria, including Clostridiales and Blautia species. In 6 of the 10 responding donor FMT recipients, immunosuppressant drug therapy was successfully tapered. Durable remission of steroid-refractory or steroid-dependent GvHD after donor FMT was associated with improved survival at 24 weeks after donor FMT. This study highlights the potential of donor FMT as a treatment for steroid-refractory or steroid-dependent GvHD, but larger clinical trials are needed to confirm the safety and efficacy of this procedure

Peri-operative desmopressin combined with pharmacokinetic-guided factor VIII concentrate in non-severe haemophilia A patients

Introduction: Non-severe haemophilia A patient can be treated with desmopressin or factor VIII (FVIII) concentrate. Combining both may reduce factor consumption, but its feasibility and safety has never been investigated. Aim: We assessed the feasibility and safety of combination treatment in nonsevere haemophilia A patients. Methods: Non-severe, desmopressin responsive, haemophilia A patients were included in one of two studies investigating peri-operative combination treatment. In the single-arm DAVID study intravenous desmopressin (0.3 μg/kg) once-a-day was, after sampling, immediately followed by PK-guided FVIII concentrate, for maximally three consecutive days. The Little DAVID study was a randomized trial in patients undergoing a minor medical procedure, whom received either PK-guided combination treatment (intervention arm) or PK-guided FVIII concentrate only (standard arm) up to 2 days. Dose predictions were considered accurate if the absolute difference between predicted and measured FVIII:C was ≤0.2 IU/mL. Results: In total 32 patients (33 procedures) were included. In the DAVID study (n = 21), of the FVIII:C trough levels 73.7% (14/19) were predicted accurately on day 1 (D1), 76.5% (13/17) on D2. On D0, 61.9% (13/21) of peak FVIII:C levels predictions were accurate. In the Little DAVID study (n = 12), on D0 83.3% (5/6) FVIII:C peak levels for both study arms were predicted accurately. Combination treatment reduced preoperative FVIII concentrate use by 47% versus FVIII monotherapy. Desmopressin side effects were mild and transient. Two bleeds occurred, both despite FVIII:C &gt; 1.00 IU/mL. Conclusion: Peri-operative combination treatment with desmopressin and PK-guided FVIII concentrate dosing in nonsevere haemophilia A is feasible, safe and reduces FVIII consumption.</p

Design of a Prospective Study on Pharmacokinetic-Guided Dosing of Prophylactic Factor Replacement in Hemophilia A and B (OPTI-CLOT TARGET Study)

In resource-rich countries, almost all severe hemophilia patients receive prophylactic replacement therapy with factor concentrates to prevent spontaneous bleeding in joints and muscles to decrease the development of arthropathy and risk of long-term disability. Pharmacokinetic (PK)-guided dosing can be applied to individualize factor replacement therapy, as interindividual differences in PK parameters influence factor VIII (FVIII) and FIX activity levels. PK-guided dosing may therefore lead to more optimal safeguarding of FVIII/FIX levels during prophylaxis and on demand treatment. The OPTI-CLOT TARGET study is a multicenter, nonrandomized, prospective cohort study that aims to investigate the reliability and feasibility of PK-guided prophylactic dosing of factor concentrates in hemophilia-A and -B patients in daily clinical practice. At least 50 patients of all ages on prophylactic treatment using standard half-life (SHL) and extended half-life (EHL) factor concentrates will be included during 9 months and will receive PK-guided treatment. As primary endpoint, a minimum of four FVIII/FIX levels will be compared with FVIII/FIX levels as predicted by Bayesian forecasting. Secondary endpoints are the association of FVIII and FIX levels with bleeding episodes and physical activity, expectations and experiences, economic analyses, and optimization of population PK models. This study will lead to more insight in the reliability and feasibility of PK-guided dosing in hemophilia patients. Moreover, it will contribute to personalization of treatment by greater knowledge of dosing regimens needed to prevent and treat bleeding in the individual patient and provide evidence to more clearly associate factor activity levels with bleeding risk

Assessment of need for hemostatic evaluation in patients taking valproic acid: A retrospective cross-sectional study

INTRODUCTION: Valproic acid (VPA) is a frequently prescribed anti-epileptic drug. Since its introduction side effects on hemostasis are reported. However, studies show conflicting results, and the clinical relevance is questioned. We aimed to determine the coagulopathies induced by VPA in patients who undergo high-risk surgery. The study results warrant attention to this issue, which might contribute to reducing bleeding complications in future patients. METHODS: Between January 2012 and August 2020, 73 consecutive patients using VPA were retrospectively included. Extensive laboratory hemostatic assessment (including platelet function tests) was performed before elective high-risk surgery. Patient characteristics, details of VPA treatment, and laboratory results were extracted from medical records. RESULTS: 46.6% of the patients using VPA (n = 73) showed coagulopathy. Mainly, platelet function disorder was found (36.4%). Thrombocytopenia was seen in 9.6% of the patients. Data suggested that the incidence of coagulopathies was almost twice as high in children as compared to adults and hypofibrinogenemia was only demonstrated in children. No association was found between the incidence of coagulopathies and VPA dosage (mg/kg/day). CONCLUSION: A considerable number of patients using VPA were diagnosed with coagulopathy, especially platelet function disorder. Further prospective studies are needed to confirm the need for comprehensive laboratory testing before elective high-risk surgery in these patients

Assessment of need for hemostatic evaluation in patients taking valproic acid:A retrospective cross-sectional study

INTRODUCTION: Valproic acid (VPA) is a frequently prescribed anti-epileptic drug. Since its introduction side effects on hemostasis are reported. However, studies show conflicting results, and the clinical relevance is questioned. We aimed to determine the coagulopathies induced by VPA in patients who undergo high-risk surgery. The study results warrant attention to this issue, which might contribute to reducing bleeding complications in future patients. METHODS: Between January 2012 and August 2020, 73 consecutive patients using VPA were retrospectively included. Extensive laboratory hemostatic assessment (including platelet function tests) was performed before elective high-risk surgery. Patient characteristics, details of VPA treatment, and laboratory results were extracted from medical records. RESULTS: 46.6% of the patients using VPA (n = 73) showed coagulopathy. Mainly, platelet function disorder was found (36.4%). Thrombocytopenia was seen in 9.6% of the patients. Data suggested that the incidence of coagulopathies was almost twice as high in children as compared to adults and hypofibrinogenemia was only demonstrated in children. No association was found between the incidence of coagulopathies and VPA dosage (mg/kg/day). CONCLUSION: A considerable number of patients using VPA were diagnosed with coagulopathy, especially platelet function disorder. Further prospective studies are needed to confirm the need for comprehensive laboratory testing before elective high-risk surgery in these patients

Design of a Prospective Study on Pharmacokinetic-Guided Dosing of Prophylactic Factor Replacement in Hemophilia A and B (OPTI-CLOT TARGET Study)

In resource-rich countries, almost all severe hemophilia patients receive prophylactic replacement therapy with factor concentrates to prevent spontaneous bleeding in joints and muscles to decrease the development of arthropathy and risk of long-term disability. Pharmacokinetic (PK)-guided dosing can be applied to individualize factor replacement therapy, as interindividual differences in PK parameters influence factor VIII (FVIII) and FIX activity levels. PK-guided dosing may therefore lead to more optimal safeguarding of FVIII/FIX levels during prophylaxis and on demand treatment. The OPTI-CLOT TARGET study is a multicenter, nonrandomized, prospective cohort study that aims to investigate the reliability and feasibility of PK-guided prophylactic dosing of factor concentrates in hemophilia-A and -B patients in daily clinical practice. At least 50 patients of all ages on prophylactic treatment using standard half-life (SHL) and extended half-life (EHL) factor concentrates will be included during 9 months and will receive PK-guided treatment. As primary endpoint, a minimum of four FVIII/FIX levels will be compared with FVIII/FIX levels as predicted by Bayesian forecasting. Secondary endpoints are the association of FVIII and FIX levels with bleeding episodes and physical activity, expectations and experiences, economic analyses, and optimization of population PK models. This study will lead to more insight in the reliability and feasibility of PK-guided dosing in hemophilia patients. Moreover, it will contribute to personalization of treatment by greater knowledge of dosing regimens needed to prevent and treat bleeding in the individual patient and provide evidence to more clearly associate factor activity levels with bleeding risk

Colorectal cancer screening in patients with inherited bleeding disorders: high cancer detection rate in hemophilia patients

Background: The population-based colorectal cancer (CRC) screening program in individuals aged 55 to 75 years in the Netherlands uses fecal immunochemical testing (FIT), to detect hemoglobin in feces, followed by colonoscopy in individuals with a positive FIT. Objectives: The objectives of this study are to assess the false-positive rate, detection rate, and positive predictive value of FIT for CRC and advanced adenoma (AA) in patients with Von Willebrand disease (VWD) or hemophilia. Methods: We performed a multicenter, nationwide cross-sectional study embedded in 2 nationwide studies on VWD and hemophilia in the Netherlands. Results: In total, 493 patients with hemophilia (n = 329) or VWD (n = 164) were included, of whom 351 patients participated in the CRC screening program (71.2%). FIT positivity and false-positive rate in patients with hemophilia and VWD were significantly higher than those in the general population (14.8% vs. 4.3%, p <.001 and 10.3% vs. 2.3%, p <.001, respectively). In patients with hemophilia, the detection rate of CRC/AA was significantly higher than that in the general male population (4.5% vs. 1.8%, p =.02), and the positive predictive value of FIT for CRC/AA was comparable (32.3% vs. 39.7%, n.s.). In patients with VWD, the detection rate was similar to that of the general population (0.8% vs. 1.4%, n.s.), whereas the positive predictive value was significantly lower than that in the general population (6.3% vs. 36.8%, p =.02). Conclusion: This study indicates that despite a high false-positive rate of FIT in patients with inherited bleeding disorders, the detection rate of CRC and/or AA in hemophilia patients is high. FIT performs different in patients with hemophilia or VWD compared with the general population